G-蛋白偶联CRFR1受体介导模拟高原急性低氧大鼠脑水肿与肺水肿研究
|
摘要
我国西部的青藏高原,最大的自然地理特征就是低氧,低氧不仅影响人们的健康,严重时还可导致高原病。高原低氧脑水肿和肺水肿,是最危险的急性高原病,常发生在严重低氧时,处理不当或不及时会危及生命,然而其发病机制,至今尚不十分清楚。阐明其作用机理,在理论和临床实践方面均有重要意义。
低氧是一种非特异性应激原,它可诱导机体产生应激反应。下丘脑-垂体-肾上腺皮质轴(Hypothalamus-pituitary-adrenal axis, HPA)是机体重要的体液调节系统和应激反应系统,对各种应激做出应答反应,以新的稳态调节,适应变化了的不利环境。下丘脑促肾上腺皮质激素释放激素(Corticotropin releasing factor, CRF)肽是HPA轴的脑中枢调节者,它调节神经和体液两大系统。我们实验室以往研究发现,低氧激活下丘脑PVN区CRF, CRF mRNA和CRFR1受体表达,进而刺激HPA轴级联反应。CRFR1属G-蛋白偶联受体家族,在中枢神经系统和外周组织广泛分布。我们还发现,CRFR1参与低氧应激生理功能调节,对神经-内分泌-免疫网络系统中重要低氧靶基因和蛋白起核心主导调节作用。水通道蛋白(Aquaporins, AQPs)是细胞膜上一类特异性通道蛋白,介导不同类型细胞的水分子跨膜转运。AQP4是脑组织中分布最多的水通道蛋白,广泛存在于星状胶质细胞的终足上。AQP4在正常生理状态下与脑水平衡调节相关,在病理损伤时参与脑水肿形成。因此,我们设想,严重低氧应激时,通过刺激脑CRF分泌,激活CRFR1受体,驱动细胞内信号通路,增加AQP水通道功能,参与脑水肿形成,或低氧时肺内CRFR1参与肺水肿形成。本文阐述CRFR1受体参与低氧诱导脑水肿与肺水肿的形成以及CRFR1受体激活后的细胞内信号调控机制。
本研究以雄性SD大鼠为研究对象,将其置于低气压舱内暴露于7000m(7.8%O2)低氧8小时,模拟急性高原低氧脑水肿和肺水肿,研究CRFR1参与机制。利用核磁共振技术检测脑组织水分子表观弥散系数(ADC)；干湿重法检测脑和肺组织含水量；Western blot法检测前额叶皮层水通道蛋白4(AQP4)蛋白和肺组织中AQP5蛋白表达变化；ELISA法检测前额叶皮层内皮素(ET-1)和血浆皮质酮的变化；RIA法检查肺组织内皮素ET-1的变化；激光共聚焦免疫荧光法等方法检测CRFR1和AQP4在原代培养的大鼠皮层星状胶质细胞和大鼠前额叶皮层中的共表达；免疫共沉淀检测AQP4蛋白磷酸化状态；荧光标记法记录星状胶质细胞内[Ca2+]i变化和细胞膜通透性的改变；比色法检测肺组织NO表达和NOS酶活性的变化。采用相关药盒,检测cAMP/PKA和PKC/Ca2+通路,揭示CRFR1受体激活后第二信使通路参与脑水肿和肺水肿发生的细胞内信号调节机制。
研究结果
第一部分
1 G-蛋白偶联CRFR1受体参与模拟高原急性低氧诱导大鼠脑水肿的形成
模拟7000m高原低氧8小时,可以诱导大鼠脑含水量增加,明显升高脑ADC值,形成脑水肿(P<0.05)。低氧前,预先腹腔注射30mg/kg CRFR1受体拮抗剂CP154,526,可以阻断低氧诱导的脑含水量增加和ADC值的升高(P<0.05 vs.hypoxia).
2 G-蛋白偶联CRFR1受体对模拟高原急性低氧诱导大鼠大脑皮层AQP4和ET-1蛋白的调节作用
免疫荧光激光共聚焦结果显示,CRFR1和AQP4共存于大鼠前额叶皮层中。Western blot实验结果显示：低氧诱导大鼠前额叶皮层AQP4表达升高(P<0.01),低氧前预先腹腔注射CRFR1受体拮抗剂CP154,526,可以阻断这种作用(P<0.05 vs. hypoxia),而预先腹腔注射NF-kB抑制剂PDTC,或CP154,526和PDTC复合注射,对这种作用无明显影响。
与常氧组比较,该低氧诱导大鼠前额叶皮层ET-1表达明显升高(P<0.001),低氧前预先腹腔注射CRFR1拮抗剂CP 154,526、NF-kB抑制剂PDTC,或CP154,526+PDTC复合注射,都可以阻断这种作用(P<0.001 vs. hypoxia)。
与常氧组比较,低氧促使大鼠血浆皮质酮水平明显升高(P<0.01),低氧前预先腹腔注射CRFR1拮抗剂CP154,526,或CP154,526+PDTC复合注射都可以阻断这种作用,而预先注射NF-kB抑制剂PDTC则部分阻断这种作用。拮抗剂CP154,526、抑制剂PDTC,或CP154,526+PDTC复合注射对常氧下血浆皮质酮水平无明显作用。
3 G-蛋白偶联CRFR1受体关联的胞内二信使通路,对星状胶质细胞水通道AQP4磷酸化的调节
免疫荧光实验显示,CRFR1受体与AQP4水通道蛋白在大鼠皮层原代星状胶质细胞中共存。
体外培养原代大鼠星状胶质细胞,与外源CRF共温育,细胞内钙离子[Ca2+]i浓度迅速升高,细胞膜通透性明显增加,此作用可被CRFR1受体拮抗剂所拮抗。
在原代培养的大鼠星状胶质细胞,与CRF共温育10分钟或30分钟可明显升高胞内cAMP水平,该作用在与CRFR1拮抗剂预温育30分钟而阻断；与CRF温育30分钟可导致AQP4蛋白PKA位点磷酸化表达,温育10分钟无明显影响；与CRF共温育30分钟,导致AQP4蛋白PKC位点磷酸化表达,该作用可以被PKC拮抗剂Bisindolylmaleimide预温育30分钟阻断；此外,与CRF共温育10分钟或30分钟对AQP4蛋白PKG位点磷酸化表达无影响,PKG拮抗剂KT-5823预温育30分钟对该作用无明显影响。
原代培养的大鼠星状胶质细胞,暴露于低氧(1% O2)8小时,胞内cAMP水平无明显改变(P>0.05)。与10nM CRF温育时,再暴露于低氧(1% O2)8小时,胞内cAMP水平明显升高(P<0.001),而预先与CRFR1拮抗剂CP154,526共温育,则拮抗了CRF诱导的cAMP水平升高。然而与CRF温育8小时或低氧温育8小时,对AQP4蛋白PKA位点磷酸化表达没有明显影响。Western blot结果显示常氧下或低氧下10nM CRF作用8h都可以促进胶质细胞AQP4蛋白量表达增加。
第二部分
1 G-蛋白偶联CRFR1受体及NF-kB对模拟高原急性低氧诱导肺水肿的作用
NF-kB参与模拟高原低氧诱导的肺水肿。模拟7000m高原急性低氧8小时,可明显升高大鼠肺组织的含水量(P<0.01 vs. control),该作用可被预先腹腔注射NF-kB抑制剂PDTC阻断(P<0.01 vs. hypoxia),但不被预先注射CRFR1受体拮抗剂CP154,526,也不被CP154,526+PDTC复合注射所阻断。
2 G蛋白偶联CRFR1受体及NF-kB对模拟高原急性低氧诱导肺组织ET-1水平的作用
NF-kB参与模拟高原低氧诱导肺组织ET-1水平升高。模拟7000m高原低氧8小时,导致大鼠肺组织中ET-1水平明显升高(p<0.05),此作用不被预先腹腔注射15mg/kg CRFR1拮抗剂CP154,526所拮抗,而预先注射30mg／kg CP154,526则导致低氧增高的肺ET-1水平进一步增高(P<0.05 vs. hypoxia);而预先注射NF-kB抑制剂PDTC,则可抑制这一低氧效应(P<0.05 vs. hypoxia),但预先腹腔注射复合拮抗剂CP154,52+PDTC,也导致低氧诱导的大鼠肺组织ET-1表达进一步升高(P<0.01 vs.hypoxia)。
3 G-蛋白偶联CRFR1受体对模拟高原急性低氧降低肺组织NO含量和NOS酶活力的作用
模拟7000m高原低氧8小时,明显降低大鼠肺组织中NO水平(P<0.01),此作用在预先腹腔注射CRFR1拮抗剂(30mg／kg)后,NO水平进一步降低(P<0.001),15mg/kg CRFR1拮抗剂无明显作用。该低氧还降低总一氧化氮合酶(tNOS)活力水平,CRFR1拮抗剂预注射,不论15mg／kg或30mg／kg均导致低氧降低的总一氧化氮合酶活力进一步降低。该低氧和CRFR1拮抗剂均不影响诱导型一氧化氮合酶(iNOS)酶活力水平。
4 G-偶联蛋白CRFR1受体不参与低氧对肺组织AQP5蛋白表达的调节
模拟7000m高原低氧8小时,诱导大鼠肺组织AQP5蛋白表达升高(P<0.05),预先腹腔注射CRFR拮抗剂,对大鼠肺组织AQP5表达无明显影响。结论：
1模拟7000m高原急性低氧8小时,导致大鼠脑水肿,这与低氧激活脑皮层CRFR1受体相关。CRFR1受体激活,介导皮层ET-1蛋白(NF-kB也介导ET-1的高表达)和AQP4蛋白表达上调。
2离体培养大鼠原代星状胶质细胞,可见AQP4蛋白与CRFR1受体蛋白共存现象；CRF刺激星状胶质细胞上的CRFR1受体,升高胞内钙离子[Ca2+]i浓度、激活cAMP/PKA和PKC通路,使AQP4蛋白PKA、PKC位点磷酸化,改变AQP4通道水通透性,促成脑细胞水肿。
3模拟7000m高原急性低氧,诱导大鼠肺组织含水量增加,形成肺水肿。低氧上调肺组织ET-1表达,下调NO水平和总NOS酶活力,增加水通道AQP5表达,此与肺水肿形成相关。核转录因子NF-kB通过上调ET-1表达参与低氧诱导肺水肿。提示CRFR1受体可能通过NO/NOS途径和ET-1表达影响肺水肿形成。促肾上腺皮质激素释放激素；促肾上腺皮质激素释放激素1型受体；内皮素-1；高原；低氧；核因子KB；一氧化氮；一氧化氮合酶；蛋白激酶A；蛋白激酶C；肺水肿；大鼠
本文创新点：
1发现G蛋白偶联CRFR1受体,通过上调ET-1和水通道AQP4活动,参与了模拟7000m高原急性低氧8小时诱导的大鼠脑水肿形成。NF-kB通过上调ET-1表达参与低氧脑水肿。
2发现在离体培养大鼠原代皮层胶质细胞中,AQP4蛋白与CRFR1受体蛋白共存
The Qinghai-Tibet Plateau in west China, the most significant geographical feature is the low oxygen level. Hypoxia not only affects people health, but also leads to serious altitude sickness. High altitude cerebral edema (HACE) and high altitude pulmonary edema (HAPE), the most serious altitude sickness, often occur in severe hypoxia environment, which would endanger life if improper handling. Its pathogenesis remains obscure, and the mechanism would be important in both theory and clinical practice.
As a non-specific stressor, hypoxia can induce stress response generated. The hypothalamus-pituitary-adrenal axis (HPA axis) is the humoral regulation system and the stress response system, making a variety of stress response to adapt the harmful environment into a new homeostasis. Hypothalamic corticotropin releasing factor (CRF) peptide is the central regulator of HPA axis, which regulates both body fluid system and nervous system. Previous studies in our lab found that hypoxia activated CRF release, CRF mRNA and CRFR1 receptor express in hypothalamic PVN, which led to stimulate HPA axis cascade. Corticotropin releasing factor receptor-1 is a member of G-protein coupled receptor family, widely distribute in the central nervous system and periphery system. We also found that CRFR1 participate hypoxia-induced stress responses, playing a central role in regulation of important hypoxia target genes and proteins in neuro-endocrine-immune network system. Aquaporins (AQPs) are a family of membrane channels that serve as selective pores through which water flow cross the plasma membranes in many cell types. AQP4 is the major water channel in brain tissue, strongly enriched in astrocytes end-feet. AQP4 plays an important role both in the cerebral water balance in normal physiological condition and in the formation of brain edema during pathological injury. Therefore, we assume that:severe hypoxia stress could stimulate CRF secretion from hypothalamus to activate CRFR1, driving intracellular signaling pathways to increase AQP4 water channel permeability, involving in the formation of brain edema at last. Furthermore, CRFR1 and transcriptor NF-kB may play a role in hypoxia-induced pulmonary edema. Therefore, the paper is to explore whether CRFR1 involves in HACE and HAPE as well as what is the intracellular signaling mechanism.
In this study, we developed a hypoxia model for brain edema and pulmonary edema. The rats were exposed to hypoxia (7.8% O2, equal to 7000m altitude) in a hypobaric chamber for 8 hours. Magnetic resonance imaging was applied to measure the ADC value for brain cell water. The water content in brain and lung was assessed by dry/wet ratio. The AQP4 and AQP5 protein expressed in rat brain cortex and in lung tissue respectively were determined by Western blot. ET-1 in cortex and corticosterone in plasma was detected by ELISA kit. ET-1 in lung was detected by RIA. Coexistence of CRFR1 with AQP4 protein was showed by confocal immunofluorescence in brain cortex and in primary cortex astrocytes cell. The AQP4 and AQP5 phosphorylation was detected by protein immunoprecipitation. Intracellular [Ca2+]i was determined by Fluo3/AM calcium indicator. The water permeability was measured using laser scanning confocal microscopy. And the level of nitric oxide and nitric oxide synthase active unit in the pulmonary tissue were measured by colorimetric method.
This study will address whether the CRFR1 contributes to cerebral and pulmonary edema, and what the intracellular signaling pathway driven from CRFR1 is linked to AQPs, making its phosphorylation and altering its permeability to water, then induced cell swelling and the brain and pulmonary edema.
Part One
1 G-protein coupled CRFR1 mediates acutely simulated altitude hypoxia-induced rat brain edema
Acutely simulated hypoxia (7.8% O2,8 h) significantly increased water content in brain and the ADC value for water permeability, leading brain edema, and the effects were blocked by i.p. preinjection with CRFR1 antagonist CP154,526 (30mg/kg).
2 G-protein coupled CRFR1 mediates AQP4 and ET-1 expression induced by acutely simulated altitude hypoxia in rat brain
Confocal immunofluorescence image showed coexistence of CRFR1 protein and AQP4 channel protein in rat prefrontal cortex.
Western blot results showed that AQP4 channel protein was enhanced in the hypoxic rat prefrontal cortex (P<0.01). The effect was significantly blocked by i.p. preinjection of CRFR1 antagonist CP154,526 (P<0.05 vs. hypoxia), but not by i.p. preinjection of NF-kB inhibitor PDTC(pyrrolidinedithio carbamate ammonium), or combination of CP154,526 plus PDTC. These antagonists had no effect on AQP4 expression in control rat.
The hypoxia significantly increased ET-1 expression in rat prefrontal cortex, which was blocked by i.p. preinjection of CP154,526, PDTC, or combination of CP154,526 plus PDTC.
The hypoxia significantly enhanced plasma corticosterone (P<0.01), which was blocked by i.p. preinjection of CRFR1 antagonist CP154,526 and combination of CP154,526 plus PDTC, partly blocked by PDTC. And these antagonists had no effect on plasma corticosterone.
3 Modulations of intracellular pathway driven by G-protein coupled CRFR1 in AQP4 channel protein in primarily cultured rat astrocytes under the hypoxia
Confocal immunofluorescence image showed that coexistence of CRFR1 protein and AQP4 channel protein in the primary cortical astrocytes.
In cultured primary astrocytes, CRF induced intracellular [Ca2+]i fast increase, following water permeability enhancement, which was blocked by i.p. preinjection with CRFR1 antagonist CP154,526 for 30min.
Incubation of rat primary cortical astrocytes with CRF for 10 or 30min increased cAMP accumulation in the cells, which was blocked by preincubation with CRFR1 antagonist for 30min. In CRF treated astrocytes for 30min, but not 10min, induced AQP4 protein phosphorylation at PKA site of AQP4 channel protein. Again CRF induced for 30 min AQP4 protein phosphorylation occured at PKC site of the AQP4 protein, which was blocked by preincubation with PKC antagonist (Bisindolylmaleimide) for 30min. PKG sites appeared to be not involved in CRF challenged astrocytes, and the PKG antagonist KT-5823 had no effect.
In cultured primary astrocytes treated with 10nM CRF for 8h, cAMP levels increased significantly in these cells, which were blocked by preincubation of CRFR1 antagonist. Exposed to CRF for 8h or hypoxia 8h had no effect on AQP4 protein phosphorylation at PKA site. Western blot showed CRF for 8h induced AQP4 protein expression.
Part Two
1 Effects of G-protein coupled CRFR1 and NF-kB on rat pulmonary edema induced by acutely simulated hypoxia
Acutely simulated hypoxia (7.8% O2,8 h) significantly increased water content in rat lung, which was blocked by i.p. preinjection of NF-kB inhibitor PDTC, but not by i.p. preinjection of CP154,526, or combination of PDTC plus CP154,526.
2 Effects of G-protein coupled CRFR1 and NF-kB on rat pulmonary ET-1 upregulation induced by acutely simulated hypoxia
NF-kB mediated rat pulmonary ET-1 upregulation. Acute hypoxia (7.8% O2,8 h) significantly induced ET-1 expression increase in rat lung tissue, the effect was not blocked by i.p. preinjectiont of CRFR1 antagonist CP154,526 (15mg/kg), whereas enhanced by i.p. pretreatment of antagonist CP154,526 (30mg/kg) or combination of PDTC plus CP154,526 (30mg/kg). However the effect was blocked by single pretreatment of PDTC.
3 Effects of G-protein coupled CRFR1 on downregulation of rat pulmonary NO and NOS activity induced by acutely simulated hypoxia
CRFR1 antagonist induced further downregultion of the NO content and NOS activity. Acute hypoxia (7.8% O2,8h) induced NO level decrease in rat lung, which was further reduced by i.p. pretreatment of antagonist CP154,526 (30mg/kg), not by 15mg/kg. Acute hypoxia downregulated NOS activity and the effect was further reduced by i.p. pretreatment of antagonist CP154,526 15 or 30mg/kg. But hypoxia or CRFR1 antagonist had no effect on inducible NOS activity.
4 G-protein coupled CRFR1 is not involved in the regulation of hypoxia-induced upregulation of AQP5 channel protein
Acute hypoxia (7.8% O2,8h) upregulated the expression of AQP5 channel protein in rat lung, the effect was not blocked by i.p. pretreatment of CRFR1 antagonist CP 154,526.
Conclusion:
1 Acute simulated hypoxia (7.8% O2,8 h) induces rat brain edema, which is associated with G-protein coupled CRFR1 triggering, CRFR1 triggering mediates hypoxia-induced ET-1 and AQP4 upregulation in the brain. ET-1 upregulation contributes to brain edema via NF-kB transcription
2 In the primary cultured rat cortical astrocytes, CRFR1 and AQP4 co-exist. CRF stimulates CRFR1 on the astrocytes, elevating [Ca2+]i concentration, activating the cAMP/PKA and PKC pathways, inducing AQP4 phosphorylation at the PKA and PKC site of AQP4 channel protein which lead to increase AQP4 channel permeability and make the astrocyte swelling.
3 The acute hypoxia (7.8% O2,8 h) increased water content in rat lung and pulmonary ET-1 expression, as well as decreased NO level, total NOS activity, and upregulated AQP5 channel expression, which all associate with hypoxia-induced pulmonary edema. Nuclear transcription factor NF-kB may contribute to pulmonary edema by upreguating ET-1 expression. And CRFR1 may potentially be involved in altitude hypoxic pulmonary edema through the NO/NOS pathways and the ET-1 expression.
低氧是一种非特异性应激原,它可诱导机体产生应激反应。下丘脑-垂体-肾上腺皮质轴(Hypothalamus-pituitary-adrenal axis, HPA)是机体重要的体液调节系统和应激反应系统,对各种应激做出应答反应,以新的稳态调节,适应变化了的不利环境。下丘脑促肾上腺皮质激素释放激素(Corticotropin releasing factor, CRF)肽是HPA轴的脑中枢调节者,它调节神经和体液两大系统。我们实验室以往研究发现,低氧激活下丘脑PVN区CRF, CRF mRNA和CRFR1受体表达,进而刺激HPA轴级联反应。CRFR1属G-蛋白偶联受体家族,在中枢神经系统和外周组织广泛分布。我们还发现,CRFR1参与低氧应激生理功能调节,对神经-内分泌-免疫网络系统中重要低氧靶基因和蛋白起核心主导调节作用。水通道蛋白(Aquaporins, AQPs)是细胞膜上一类特异性通道蛋白,介导不同类型细胞的水分子跨膜转运。AQP4是脑组织中分布最多的水通道蛋白,广泛存在于星状胶质细胞的终足上。AQP4在正常生理状态下与脑水平衡调节相关,在病理损伤时参与脑水肿形成。因此,我们设想,严重低氧应激时,通过刺激脑CRF分泌,激活CRFR1受体,驱动细胞内信号通路,增加AQP水通道功能,参与脑水肿形成,或低氧时肺内CRFR1参与肺水肿形成。本文阐述CRFR1受体参与低氧诱导脑水肿与肺水肿的形成以及CRFR1受体激活后的细胞内信号调控机制。
本研究以雄性SD大鼠为研究对象,将其置于低气压舱内暴露于7000m(7.8%O2)低氧8小时,模拟急性高原低氧脑水肿和肺水肿,研究CRFR1参与机制。利用核磁共振技术检测脑组织水分子表观弥散系数(ADC)；干湿重法检测脑和肺组织含水量；Western blot法检测前额叶皮层水通道蛋白4(AQP4)蛋白和肺组织中AQP5蛋白表达变化；ELISA法检测前额叶皮层内皮素(ET-1)和血浆皮质酮的变化；RIA法检查肺组织内皮素ET-1的变化；激光共聚焦免疫荧光法等方法检测CRFR1和AQP4在原代培养的大鼠皮层星状胶质细胞和大鼠前额叶皮层中的共表达；免疫共沉淀检测AQP4蛋白磷酸化状态；荧光标记法记录星状胶质细胞内[Ca2+]i变化和细胞膜通透性的改变；比色法检测肺组织NO表达和NOS酶活性的变化。采用相关药盒,检测cAMP/PKA和PKC/Ca2+通路,揭示CRFR1受体激活后第二信使通路参与脑水肿和肺水肿发生的细胞内信号调节机制。
研究结果
第一部分
1 G-蛋白偶联CRFR1受体参与模拟高原急性低氧诱导大鼠脑水肿的形成
模拟7000m高原低氧8小时,可以诱导大鼠脑含水量增加,明显升高脑ADC值,形成脑水肿(P<0.05)。低氧前,预先腹腔注射30mg/kg CRFR1受体拮抗剂CP154,526,可以阻断低氧诱导的脑含水量增加和ADC值的升高(P<0.05 vs.hypoxia).
2 G-蛋白偶联CRFR1受体对模拟高原急性低氧诱导大鼠大脑皮层AQP4和ET-1蛋白的调节作用
免疫荧光激光共聚焦结果显示,CRFR1和AQP4共存于大鼠前额叶皮层中。Western blot实验结果显示：低氧诱导大鼠前额叶皮层AQP4表达升高(P<0.01),低氧前预先腹腔注射CRFR1受体拮抗剂CP154,526,可以阻断这种作用(P<0.05 vs. hypoxia),而预先腹腔注射NF-kB抑制剂PDTC,或CP154,526和PDTC复合注射,对这种作用无明显影响。
与常氧组比较,该低氧诱导大鼠前额叶皮层ET-1表达明显升高(P<0.001),低氧前预先腹腔注射CRFR1拮抗剂CP 154,526、NF-kB抑制剂PDTC,或CP154,526+PDTC复合注射,都可以阻断这种作用(P<0.001 vs. hypoxia)。
与常氧组比较,低氧促使大鼠血浆皮质酮水平明显升高(P<0.01),低氧前预先腹腔注射CRFR1拮抗剂CP154,526,或CP154,526+PDTC复合注射都可以阻断这种作用,而预先注射NF-kB抑制剂PDTC则部分阻断这种作用。拮抗剂CP154,526、抑制剂PDTC,或CP154,526+PDTC复合注射对常氧下血浆皮质酮水平无明显作用。
3 G-蛋白偶联CRFR1受体关联的胞内二信使通路,对星状胶质细胞水通道AQP4磷酸化的调节
免疫荧光实验显示,CRFR1受体与AQP4水通道蛋白在大鼠皮层原代星状胶质细胞中共存。
体外培养原代大鼠星状胶质细胞,与外源CRF共温育,细胞内钙离子[Ca2+]i浓度迅速升高,细胞膜通透性明显增加,此作用可被CRFR1受体拮抗剂所拮抗。
在原代培养的大鼠星状胶质细胞,与CRF共温育10分钟或30分钟可明显升高胞内cAMP水平,该作用在与CRFR1拮抗剂预温育30分钟而阻断；与CRF温育30分钟可导致AQP4蛋白PKA位点磷酸化表达,温育10分钟无明显影响；与CRF共温育30分钟,导致AQP4蛋白PKC位点磷酸化表达,该作用可以被PKC拮抗剂Bisindolylmaleimide预温育30分钟阻断；此外,与CRF共温育10分钟或30分钟对AQP4蛋白PKG位点磷酸化表达无影响,PKG拮抗剂KT-5823预温育30分钟对该作用无明显影响。
原代培养的大鼠星状胶质细胞,暴露于低氧(1% O2)8小时,胞内cAMP水平无明显改变(P>0.05)。与10nM CRF温育时,再暴露于低氧(1% O2)8小时,胞内cAMP水平明显升高(P<0.001),而预先与CRFR1拮抗剂CP154,526共温育,则拮抗了CRF诱导的cAMP水平升高。然而与CRF温育8小时或低氧温育8小时,对AQP4蛋白PKA位点磷酸化表达没有明显影响。Western blot结果显示常氧下或低氧下10nM CRF作用8h都可以促进胶质细胞AQP4蛋白量表达增加。
第二部分
1 G-蛋白偶联CRFR1受体及NF-kB对模拟高原急性低氧诱导肺水肿的作用
NF-kB参与模拟高原低氧诱导的肺水肿。模拟7000m高原急性低氧8小时,可明显升高大鼠肺组织的含水量(P<0.01 vs. control),该作用可被预先腹腔注射NF-kB抑制剂PDTC阻断(P<0.01 vs. hypoxia),但不被预先注射CRFR1受体拮抗剂CP154,526,也不被CP154,526+PDTC复合注射所阻断。
2 G蛋白偶联CRFR1受体及NF-kB对模拟高原急性低氧诱导肺组织ET-1水平的作用
NF-kB参与模拟高原低氧诱导肺组织ET-1水平升高。模拟7000m高原低氧8小时,导致大鼠肺组织中ET-1水平明显升高(p<0.05),此作用不被预先腹腔注射15mg/kg CRFR1拮抗剂CP154,526所拮抗,而预先注射30mg／kg CP154,526则导致低氧增高的肺ET-1水平进一步增高(P<0.05 vs. hypoxia);而预先注射NF-kB抑制剂PDTC,则可抑制这一低氧效应(P<0.05 vs. hypoxia),但预先腹腔注射复合拮抗剂CP154,52+PDTC,也导致低氧诱导的大鼠肺组织ET-1表达进一步升高(P<0.01 vs.hypoxia)。
3 G-蛋白偶联CRFR1受体对模拟高原急性低氧降低肺组织NO含量和NOS酶活力的作用
模拟7000m高原低氧8小时,明显降低大鼠肺组织中NO水平(P<0.01),此作用在预先腹腔注射CRFR1拮抗剂(30mg／kg)后,NO水平进一步降低(P<0.001),15mg/kg CRFR1拮抗剂无明显作用。该低氧还降低总一氧化氮合酶(tNOS)活力水平,CRFR1拮抗剂预注射,不论15mg／kg或30mg／kg均导致低氧降低的总一氧化氮合酶活力进一步降低。该低氧和CRFR1拮抗剂均不影响诱导型一氧化氮合酶(iNOS)酶活力水平。
4 G-偶联蛋白CRFR1受体不参与低氧对肺组织AQP5蛋白表达的调节
模拟7000m高原低氧8小时,诱导大鼠肺组织AQP5蛋白表达升高(P<0.05),预先腹腔注射CRFR拮抗剂,对大鼠肺组织AQP5表达无明显影响。结论：
1模拟7000m高原急性低氧8小时,导致大鼠脑水肿,这与低氧激活脑皮层CRFR1受体相关。CRFR1受体激活,介导皮层ET-1蛋白(NF-kB也介导ET-1的高表达)和AQP4蛋白表达上调。
2离体培养大鼠原代星状胶质细胞,可见AQP4蛋白与CRFR1受体蛋白共存现象；CRF刺激星状胶质细胞上的CRFR1受体,升高胞内钙离子[Ca2+]i浓度、激活cAMP/PKA和PKC通路,使AQP4蛋白PKA、PKC位点磷酸化,改变AQP4通道水通透性,促成脑细胞水肿。
3模拟7000m高原急性低氧,诱导大鼠肺组织含水量增加,形成肺水肿。低氧上调肺组织ET-1表达,下调NO水平和总NOS酶活力,增加水通道AQP5表达,此与肺水肿形成相关。核转录因子NF-kB通过上调ET-1表达参与低氧诱导肺水肿。提示CRFR1受体可能通过NO/NOS途径和ET-1表达影响肺水肿形成。促肾上腺皮质激素释放激素；促肾上腺皮质激素释放激素1型受体；内皮素-1；高原；低氧；核因子KB；一氧化氮；一氧化氮合酶；蛋白激酶A；蛋白激酶C；肺水肿；大鼠
本文创新点：
1发现G蛋白偶联CRFR1受体,通过上调ET-1和水通道AQP4活动,参与了模拟7000m高原急性低氧8小时诱导的大鼠脑水肿形成。NF-kB通过上调ET-1表达参与低氧脑水肿。
2发现在离体培养大鼠原代皮层胶质细胞中,AQP4蛋白与CRFR1受体蛋白共存
The Qinghai-Tibet Plateau in west China, the most significant geographical feature is the low oxygen level. Hypoxia not only affects people health, but also leads to serious altitude sickness. High altitude cerebral edema (HACE) and high altitude pulmonary edema (HAPE), the most serious altitude sickness, often occur in severe hypoxia environment, which would endanger life if improper handling. Its pathogenesis remains obscure, and the mechanism would be important in both theory and clinical practice.
As a non-specific stressor, hypoxia can induce stress response generated. The hypothalamus-pituitary-adrenal axis (HPA axis) is the humoral regulation system and the stress response system, making a variety of stress response to adapt the harmful environment into a new homeostasis. Hypothalamic corticotropin releasing factor (CRF) peptide is the central regulator of HPA axis, which regulates both body fluid system and nervous system. Previous studies in our lab found that hypoxia activated CRF release, CRF mRNA and CRFR1 receptor express in hypothalamic PVN, which led to stimulate HPA axis cascade. Corticotropin releasing factor receptor-1 is a member of G-protein coupled receptor family, widely distribute in the central nervous system and periphery system. We also found that CRFR1 participate hypoxia-induced stress responses, playing a central role in regulation of important hypoxia target genes and proteins in neuro-endocrine-immune network system. Aquaporins (AQPs) are a family of membrane channels that serve as selective pores through which water flow cross the plasma membranes in many cell types. AQP4 is the major water channel in brain tissue, strongly enriched in astrocytes end-feet. AQP4 plays an important role both in the cerebral water balance in normal physiological condition and in the formation of brain edema during pathological injury. Therefore, we assume that:severe hypoxia stress could stimulate CRF secretion from hypothalamus to activate CRFR1, driving intracellular signaling pathways to increase AQP4 water channel permeability, involving in the formation of brain edema at last. Furthermore, CRFR1 and transcriptor NF-kB may play a role in hypoxia-induced pulmonary edema. Therefore, the paper is to explore whether CRFR1 involves in HACE and HAPE as well as what is the intracellular signaling mechanism.
In this study, we developed a hypoxia model for brain edema and pulmonary edema. The rats were exposed to hypoxia (7.8% O2, equal to 7000m altitude) in a hypobaric chamber for 8 hours. Magnetic resonance imaging was applied to measure the ADC value for brain cell water. The water content in brain and lung was assessed by dry/wet ratio. The AQP4 and AQP5 protein expressed in rat brain cortex and in lung tissue respectively were determined by Western blot. ET-1 in cortex and corticosterone in plasma was detected by ELISA kit. ET-1 in lung was detected by RIA. Coexistence of CRFR1 with AQP4 protein was showed by confocal immunofluorescence in brain cortex and in primary cortex astrocytes cell. The AQP4 and AQP5 phosphorylation was detected by protein immunoprecipitation. Intracellular [Ca2+]i was determined by Fluo3/AM calcium indicator. The water permeability was measured using laser scanning confocal microscopy. And the level of nitric oxide and nitric oxide synthase active unit in the pulmonary tissue were measured by colorimetric method.
This study will address whether the CRFR1 contributes to cerebral and pulmonary edema, and what the intracellular signaling pathway driven from CRFR1 is linked to AQPs, making its phosphorylation and altering its permeability to water, then induced cell swelling and the brain and pulmonary edema.
Part One
1 G-protein coupled CRFR1 mediates acutely simulated altitude hypoxia-induced rat brain edema
Acutely simulated hypoxia (7.8% O2,8 h) significantly increased water content in brain and the ADC value for water permeability, leading brain edema, and the effects were blocked by i.p. preinjection with CRFR1 antagonist CP154,526 (30mg/kg).
2 G-protein coupled CRFR1 mediates AQP4 and ET-1 expression induced by acutely simulated altitude hypoxia in rat brain
Confocal immunofluorescence image showed coexistence of CRFR1 protein and AQP4 channel protein in rat prefrontal cortex.
Western blot results showed that AQP4 channel protein was enhanced in the hypoxic rat prefrontal cortex (P<0.01). The effect was significantly blocked by i.p. preinjection of CRFR1 antagonist CP154,526 (P<0.05 vs. hypoxia), but not by i.p. preinjection of NF-kB inhibitor PDTC(pyrrolidinedithio carbamate ammonium), or combination of CP154,526 plus PDTC. These antagonists had no effect on AQP4 expression in control rat.
The hypoxia significantly increased ET-1 expression in rat prefrontal cortex, which was blocked by i.p. preinjection of CP154,526, PDTC, or combination of CP154,526 plus PDTC.
The hypoxia significantly enhanced plasma corticosterone (P<0.01), which was blocked by i.p. preinjection of CRFR1 antagonist CP154,526 and combination of CP154,526 plus PDTC, partly blocked by PDTC. And these antagonists had no effect on plasma corticosterone.
3 Modulations of intracellular pathway driven by G-protein coupled CRFR1 in AQP4 channel protein in primarily cultured rat astrocytes under the hypoxia
Confocal immunofluorescence image showed that coexistence of CRFR1 protein and AQP4 channel protein in the primary cortical astrocytes.
In cultured primary astrocytes, CRF induced intracellular [Ca2+]i fast increase, following water permeability enhancement, which was blocked by i.p. preinjection with CRFR1 antagonist CP154,526 for 30min.
Incubation of rat primary cortical astrocytes with CRF for 10 or 30min increased cAMP accumulation in the cells, which was blocked by preincubation with CRFR1 antagonist for 30min. In CRF treated astrocytes for 30min, but not 10min, induced AQP4 protein phosphorylation at PKA site of AQP4 channel protein. Again CRF induced for 30 min AQP4 protein phosphorylation occured at PKC site of the AQP4 protein, which was blocked by preincubation with PKC antagonist (Bisindolylmaleimide) for 30min. PKG sites appeared to be not involved in CRF challenged astrocytes, and the PKG antagonist KT-5823 had no effect.
In cultured primary astrocytes treated with 10nM CRF for 8h, cAMP levels increased significantly in these cells, which were blocked by preincubation of CRFR1 antagonist. Exposed to CRF for 8h or hypoxia 8h had no effect on AQP4 protein phosphorylation at PKA site. Western blot showed CRF for 8h induced AQP4 protein expression.
Part Two
1 Effects of G-protein coupled CRFR1 and NF-kB on rat pulmonary edema induced by acutely simulated hypoxia
Acutely simulated hypoxia (7.8% O2,8 h) significantly increased water content in rat lung, which was blocked by i.p. preinjection of NF-kB inhibitor PDTC, but not by i.p. preinjection of CP154,526, or combination of PDTC plus CP154,526.
2 Effects of G-protein coupled CRFR1 and NF-kB on rat pulmonary ET-1 upregulation induced by acutely simulated hypoxia
NF-kB mediated rat pulmonary ET-1 upregulation. Acute hypoxia (7.8% O2,8 h) significantly induced ET-1 expression increase in rat lung tissue, the effect was not blocked by i.p. preinjectiont of CRFR1 antagonist CP154,526 (15mg/kg), whereas enhanced by i.p. pretreatment of antagonist CP154,526 (30mg/kg) or combination of PDTC plus CP154,526 (30mg/kg). However the effect was blocked by single pretreatment of PDTC.
3 Effects of G-protein coupled CRFR1 on downregulation of rat pulmonary NO and NOS activity induced by acutely simulated hypoxia
CRFR1 antagonist induced further downregultion of the NO content and NOS activity. Acute hypoxia (7.8% O2,8h) induced NO level decrease in rat lung, which was further reduced by i.p. pretreatment of antagonist CP154,526 (30mg/kg), not by 15mg/kg. Acute hypoxia downregulated NOS activity and the effect was further reduced by i.p. pretreatment of antagonist CP154,526 15 or 30mg/kg. But hypoxia or CRFR1 antagonist had no effect on inducible NOS activity.
4 G-protein coupled CRFR1 is not involved in the regulation of hypoxia-induced upregulation of AQP5 channel protein
Acute hypoxia (7.8% O2,8h) upregulated the expression of AQP5 channel protein in rat lung, the effect was not blocked by i.p. pretreatment of CRFR1 antagonist CP 154,526.
Conclusion:
1 Acute simulated hypoxia (7.8% O2,8 h) induces rat brain edema, which is associated with G-protein coupled CRFR1 triggering, CRFR1 triggering mediates hypoxia-induced ET-1 and AQP4 upregulation in the brain. ET-1 upregulation contributes to brain edema via NF-kB transcription
2 In the primary cultured rat cortical astrocytes, CRFR1 and AQP4 co-exist. CRF stimulates CRFR1 on the astrocytes, elevating [Ca2+]i concentration, activating the cAMP/PKA and PKC pathways, inducing AQP4 phosphorylation at the PKA and PKC site of AQP4 channel protein which lead to increase AQP4 channel permeability and make the astrocyte swelling.
3 The acute hypoxia (7.8% O2,8 h) increased water content in rat lung and pulmonary ET-1 expression, as well as decreased NO level, total NOS activity, and upregulated AQP5 channel expression, which all associate with hypoxia-induced pulmonary edema. Nuclear transcription factor NF-kB may contribute to pulmonary edema by upreguating ET-1 expression. And CRFR1 may potentially be involved in altitude hypoxic pulmonary edema through the NO/NOS pathways and the ET-1 expression.
引文
Basnyat B. High altitude cerebral and pulmonary edema. Travel Med Infect Dis. 3:199-211.2005.
Dehnert C, Berger M M, Mairbaurl H, Bartsch P. High altitude pulmonary edema:a pressure-induced leak. Respir Physiolo Neurobiol.158:266-273.2007.
Gravanis A, Margioris AN. The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation:potential therapeutic applications. Curr Med Chem.12:1503-1512.2005.
He JJ, Chen XQ, Wang L. Xu JF, Du JZ. Corticotropin-releasing hormone receptor 1 coexists with endothelin-1 and modulates its mRNA expression and release in rat paraventricular nucleus during hypoxia. Neuroscience 152(4): 1006-1014.2008.
Hillhouse EW, Grammatopoulos DK. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev.27:260-286.2006.
Kalantaridou S, Makrigiannakis A, Zoumakis E, Chrousos GP. Peripheral corticotropin-releasing hormone is produced in the immune and reproductive systems:actions, potential roles and clinical implications. Front Biosci 12:572-580.2007.
Leshem E, Pandey P, Shlim DR, Hiramatsu K, Sidi Y, Schwartz E. Clinical features of patients with severe altitude illness in Nepal. J Travel Med.15:315-322.2008.
Moudgil R, Michelakis ED, Archer SL. Hypoxic pulmonary vasoconstriction. J Appl Physiol.98:390-403.2005.
Nazarloo HP, Buttrick PM, Saadat H, Dunn AJ. The roles of corticotropin-releasing factor-related peptides and their receptors in the cardiovascular system. Curr Protein Pept Sci.7:229-239.2006.
Roach RC, Hackett PH. Frontiers of hypoxia research:acute mountain sickness. J Exp Biol.204:3161-3170.2001.
Tsagarakis S, Grossman A. Corticotropin-releasing hormone:interactions with the immune system. Neuroimmunomodulation.1:329-334.1994.
Wang TY, Chen XQ, Du JZ, Xu NY, Wei CB, Vale WW. Corticotropin-releasing factor receptor type 1 and 2 mRNA expression in the rat anterior pituitary is modulated by intermittent hypoxia, cold and restraint. Neuroscience.128:111-119.2004.
West JB. The physiologic basis of high-altitude diseases. Ann Intern Med. 141:789-800.2004.
WHO. World Health Statistics Annual 1995. World Health Organization,Geneva.1996.
Wu TY, Ding SQ, Liu JL, Yu MT, Jia JH, Chai ZC, Dai RC, Zhang SL, Li BY, Pan L, Liang BZ, Zhao JZ, Qi de T, Sun YF, Kayser B. Who should not go high: chronic disease and work at altitude during construction of the Qinghai-Tibet railroad. High Alt Med Biol.8:88-107.2007.
Xu JF, Chen XQ, Du JZ, Wang TY. CRF receptor type 1 mediates continual hypoxia-induced CRF peptide and CRF mRNA expression increase in hypothalamic PVN of rats. Peptides.26:639-646.2005.
徐建芬.低氧对中枢神经免疫的调节.博士论文.浙江杭州.浙江大学：54-63.2005.
吕永达,霍仲厚.特殊环境生理学.军事医学科学院出版社.第1版：3-23.2005.
吴天一.高原肺水肿与急性呼吸窘迫综合症.高原医学杂志11：62-66.2001.
吴天一.高原低氧环境对人类的挑战.医学研究杂志10：1-3.2006.
Alexander AL, Lee JE, Lazar M, Field AS. Diffusion tensor imaging of the brain. Neurotherapeutics.4:316-329.2007.
Chen XQ, Du JZ, Wang YS. Regulation of hypoxia-induced release of corticotropin-releasing factor in the rat hypothalamus by norepinephrine. Regul Pept.119:221-228.2004.
Ebisu T, Naruse S, Horikawa Y, Ueda S, Tanaka C, Uto M, Umeda M, Higuchi T. Discrimination between different types of white matter edema with diffusion-weighted MR imaging. J Magn Reson Imaging.3:863-868.1993.
Esposito P, Basu S, Letourneau R, Jacobson S, Theoharides TC. Corticotropin-releasing factor (CRF) can directly affect brain microvessel endothelial cells. Brain Res. 968:192-198.2003.
Esposito P, Chandler N, Kandere K, Basu S, Jacobson S, Connolly R, Tutor D, Theoharides TC. Corticotropin-releasing hormone and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J Pharmacol Exp Ther. 303:1061-1066.2002.
Hackett PH, Roach RC. High altitude cerebral edema. High Alt Med Biol. 5:136-146.2004.
He JJ, Chen XQ, Wang L, Xu JF, Du JZ. Corticotropin-releasing hormone receptor 1 coexists with endothelin-1 and modulates its mRNA expression and release in rat paraventricular nucleus during hypoxia. Neuroscience.152:1006-1014.2008.
Hendryk S, Jedrzejowska-Szypulka H, Josko J, Jarzab B, Dohler KD. Influence of the corticotropin releasing hormone (CRH) on the brain-blood barrier permeability in cerebral ischemia in rats. J Physiol Pharmacol.53:85-94.2002.
Hillhouse EW, Grammatopoulos DK. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev.27:260-286.2006.
Hsuchou H, Kastin AJ, Wu X, Pan W. Corticotropin releasing hormone Receptor-1 in cerebral microvessels changes during development and influence Urocrotin transport across the blood brain barrier. Endocrinology.2010. doi:10.1210/en. 2009-1039.
Jin G, Arai K, Murata Y, Wang S, Stins MF, Lo EH, van Leyen K Protecting against cerebrovascular injury:contributions of 12/15-lipoxygenase to edema formation after transient focal ischemia. Stroke 39:2538-2543.2008.
Kallenberg K, Bailey DM, Christ S, Mohr A, Roukens R, Menold E, Steiner T, Bartsch P, Knauth M. Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness. J Cereb Blood Flow Metab.27:1064-1071.2007.
Kimelberg HK. Current concepts of brain edema. Review of laboratory investigations. J Neurosurg.83:1051-1059.1995.
Maiti P, Singh SB, Muthuraju S, Veleri S, Ilavazhagan G. Hypobaric hypoxia damages the hippocampal pyramidal neurons in the rat brain. Brain Res.1175:1-9.2007.
Mascalchi M, Filippi M, Floris R, Fonda C, Gasparotti R, Villari N. Diffusion-weighted MR of the brain:methodology and clinical application. Radiol Med (Torino). 109:155-197.2005.
Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol. 164:1875-1882.2004.
Morocz IA, Zientara GP, Gudbjartsson H, Muza S, Lyons T, Rock PB, Kikinis R, Jolesz FA. Volumetric quantification of brain swelling after hypobaric hypoxia exposure. Exp Neurol.168:96-104.2001.
Nag S, Manias JL, Stewart DJ. Pathology and new players in the pathogenesis of brain
edema. Acta Neuropathol.118:197-217.2009.
Obenaus A, Ashwal S. Magnetic resonance imaging in cerebral ischemia:focus on neonates. Neuropharmacology.55:271-280.2008.
Schoonman GG, Sandor PS, Nirkko AC, Lange T, Jaermann T, Dydak U, Kremer C, Ferrari MD, Boesiger P, Baumgartner RW. Hypoxia-induced acute mountain sickness is associated with intracellular cerebral edema:a 3 T magnetic resonance imaging study. J Cereb Blood Flow Metab.28:198-206.2008.
Stevens SL, Shaw TE, Dykhuizen E, Lessov NS, Hill JK, Wurst W, Stenzel-Poore MP. Reduced cerebral injury in CRH-R1 deficient mice after focal ischemia:a potential link to microglia and atrocytes that express CRH-R1. J Cereb Blood Flow Metab.23:1151-1159.2003.
Strbian D, Tatlisumak T, Ramadan UA, Lindsberg PJ. Mast cell blocking reduces brain edema and hematoma volume and improves outcome after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab 27:795-802.2007.
Titus AD, Shankaranarayana Rao BS, Harsha HN, Ramkumar K, Srikumar BN, Singh SB, Chattarji S, Raju TR. Hypobaric hypoxia-induced dendritic atrophy of hippocampal neurons is associated with cognitive impairment in adult rats. Neuroscience.145:265-278.2007.
Tjuvajev J, Uehara H, Desai R, Beattie B, Matei C, Zhou Y, Kreek MJ, Koutcher J, Blasberg R. Corticotropin-releasing factor decreases vasogenic brain edema. Cancer Res.56:1352-1360.1996.
Tourdias T, Dragonu I, Fushimi Y, Deloire MS, Boiziau C, Brochet B, Moonen C, Petry KG, Dousset V. Aquaporin 4 correlates with apparent diffusion coefficient and hydrocephalus severity in the rat brain:a combined MRI-histological study. NeuroImage.47:659-666.2009.
Viapiano MS, Mitridate de Novara AM, Fiszer de Plazas S, Bozzini CE. Prolonged exposure to hypobaric hypoxia transiently reduces GABA(A) receptor number in mice cerebral cortex. Brain Res.894:31-36.2001.
Wallace MG, Hartle KD, Snow WM, Ward NL, Ivanco TL. Effect of hypoxia on the morphology of mouse striatal neurons. Neuroscience.147:90-96.2007.
Wang TY, Chen XQ, Du JZ, Xu NY, Wei CB, Vale WW. Corticotropin-releasing factor receptor type 1 and 2 mRNA expression in the rat anterior pituitary is modulated by intermittent hypoxia, cold and restraint. Neuroscience 128:111-119.2004.
Witt KA, Mark KS, Hom S, Davis TP. Effects of hypoxia-reoxygenation on rat blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol 285:H2820-2831.2003.
Wu T, Ding S, Liu J, Jia J, Dai R, Liang B, Zhao J, Qi D. Ataxia:an early indicator in high altitude cerebral edema. High Alt Med Biol.7:275-280.2006a.
Yang Y, Hahm E, Kim Y, Kang J, Lee W, Han I, Myung P, Kang H, Park H, Cho D. Regulation of IL-18 expression by CRH in mouse microglial cells. Immunol Lett.98:291-296.2005.
白海波,杜继曾.促肾上腺皮质激素释放因子介导低氧应激抑制淋巴细胞转化的实验研究.中国应用生理学杂志.11.1995.
白海波,杜继曾,贾红卫.低氧对大鼠体液免疫的抑制作用.生理学报167-172.1997.
杜宁,聂鸿靖,晋凌云,马燕,谢印芝.低氧致脑水肿的磁共振扩散加权成像和病理观察.航天医学与医学工程.18：415-418.2005.
徐建芬.持续低氧对中枢神经免疫的调节.博士论文.浙江杭州.浙江大学.56-58.2005.
Badaut J, Ashwal S, Tone B, Regli L, Tian HR, Obenaus A. Temporal and regional evolution of aquaporin-4 expression and magnetic resonance imaging in a rat pup model of neonatal stroke. Pediatr Res.62:248-254.2007.
Behan DP, Maciejewski D, Chalmers D, De Souza EB. Corticotropin releasing factor binding protein (CRF-BP) is expressed in neuronal and astrocytic cells. Brain Res.698:259-264.1995.
Bishop GA, Seelandt CM, King JS. Cellular localization of corticotropin releasing factor receptors in the adult mouse cerebellum. Neuroscience. 101:1083-1092.2000.
Blomstrand F, Giaume C, Hansson E, Ronnback L. Distinct pharmacological properties of ET-1 and ET-3 on astroglial gap junctions and Ca(2+) signaling. Am J Physiol. 277:C616-627.1999.
Castle NA Aquaporins as targets for drug discovery. Drug Discov Today. 10:485-493.2005.
Denker BM, Smith BL, Kuhajda FP, Agre P. Identification, purification, and partial characterization of a novel Mr 28,000 integral membrane protein from erythrocytes and renal tubules. J Biol Chem.263:15634-15642.1988.
Fabricio AS, Rae GA, Zampronio AR, D'Orleans-Juste P, Souza GE. Central endothelin ET(B) receptors mediate IL-1-dependent fever induced by preformed pyrogenic factor and corticotropin-releasing factor in the rat. Am J Physiol Regul Integr Comp Physiol.290:R164-171.2006.
Figueroa YG, Chan AK, Ibrahim R, Tang Y, Burow ME, Alam J, Scandurro AB, Beckman BS. NF-kappaB plays a key role in hypoxia-inducible factor-1-regulated erythropoietin gene expression. Exp Hematol. 30:1419-1427.2002.
Fu X, Li Q, Feng Z, Mu D The roles of aquaporin-4 in brain edema following neonatal hypoxia ischemia and reoxygenation in a cultured rat astrocyte model. Glia. 55:935-941.2007.
Gunnarson E, Zelenina M, Aperia A. Regulation of brain aquaporins. Neuroscience. 129:947-955.2004.
Ha BK, Bishop GA, King JS, Burry RW. Corticotropin releasing factor induces proliferation of cerebellar astrocytes. J Neurosci Res.62:789-798.2000.
He JJ, Chen XQ, Wang L, Xu JF, Du JZ. Corticotropin-releasing hormone receptor 1 coexists with endothelin-1 and modulates its mRNA expression and release in rat paraventricular nucleus during hypoxia. Neuroscience.152:1006-1014.2008.
Hillhouse EW, Grammatopoulos DK. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev.27:260-286.2006.
Ho MC, Lo AC, Kurihara H, Yu AC, Chung SS, Chung SK. Endothelin-1 protects astrocytes from hypoxic/ischemic injury. Faseb J.15:618-626.2001.
Ito H, Yamamoto N, Arima H, Hirate H, Morishima T, Umenishi F, Tada T, Asai K, Katsuya H, Sobue K. Interleukin-lbeta induces the expression of aquaporin-4 through a nuclear factor-kappaB pathway in rat astrocytes. J Neurochem. 99:107-118.2006.
Kanazawa F, Nakanishi K, Osada H, Kanamaru Y, Ohrui N, Uenoyama M, Masaki Y, Kanatani Y, Hiroi S, Tominaga S, Yakata-Suzuki A, Matsuyama S, Kawai T. Expression of endothelin-1 in the brain and lung of rats exposed to permanent hypobaric hypoxia. Brain Res.1036:145-154.2005.
Kapcala LP, Dicke JA. Brain corticotropin-releasing hormone receptors on neurons and astrocytes. Brain Res.589:143-148.1992.
King LS, Kozono D, Agre P. From structure to disease:the evolving tale of aquaporin biology. Nat Rev Mol Cell Biol.5:687-698.2004.
Lo AC, Chen AY, Hung VK, Yaw LP, Fung MK, Ho MC, Tsang MC, Chung SS, Chung SK. Endothelin-1 overexpression leads to further water accumulation and brain edema after middle cerebral artery occlusion via aquaporin 4 expression in astrocytic end-feet. J Cereb Blood Flow Metab.25:998-1011.2005.
MacCumber MW, Ross CA, Snyder SH. Endothelin in brain:receptors, mitogenesis, and biosynthesis in glial cells. Proc Natl Acad Sci U S A.87:2359-2363.1990.
Manley GT, Binder DK, Papadopoulos MC, Verkman AS. New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice. Neuroscience.129:983-991.2004.
Matsui H, Ihara Y, Fujio Y, Kunisada K, Akira S, Kishimoto T, Yamauchi-Takihara K. Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-kappa B and NF-IL6 in cardiac myocytes. Cardiovasc Res. 42:104-112.1999.
Morin C, Asselin C, Boudreau F, Provencher PH. Transcriptional regulation of pre-pro-endothelin-1 gene by glucocorticoids in vascular smooth muscle cells. Biochem Biophys Res Commun.244:583-587.1998.
Naidoo V, Naidoo S, Raidoo DM. Immunolocalisation of endothelin-1 in human brain. J Chem Neuroanat.27:193-200.2004.
Natarajan R, Fisher BJ, Jones DG. Reoxygenating microvascular endothelium exhibits temporal dissociation of NF-kappaB and AP-1 activation. Free Radic Biol Med. 32:1033-1045.2002.
Nicchia GP, Nico B, Camassa LM, Mola MG, Loh N, Dermietzel R, Spray DC, Svelto M, Frigeri A. The role of aquaporin-4 in the blood-brain barrier development and integrity:studies in animal and cell culture models. Neuroscience. 129:935-945.2004.
Petrov T, Steiner J, Braun B, Rafols JA. Sources of endothelin-1 in hippocampus and cortex following traumatic brain injury. Neuroscience.115:275-283.2002.
Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1 alpha. Nature. 453:807-811.2008.
Stevens SL, Shaw TE, Dykhuizen E, Lessov NS, Hill JK, Wurst W, Stenzel-Poore MP. Reduced cerebral injury in CRH-R1 deficient mice after focal ischemia:a potential link to microglia and atrocytes that express CRH-R1. J Cereb Blood Flow Metab.23:1151-1159.2003.
Tait MJ, Saadoun S, Bell BA, Papadopoulos MC. Water movements in the brain:role of aquaporins. Trends Neurosci.31:37-43.2008.
Takuma K, Matsuda T, Yoshikawa T, Kitanaka J, Gotoh M, Hayata K, Baba A. Corticotropin-releasing factor stimulates Ca2+ influx in cultured rat astrocytes. Biochem Biophys Res Commun.199:1103-1107.1994.
Taniguchi M, Yamashita T, Kumura E, Tamatani M, Kobayashi A, Yokawa T, Maruno M, Kato A, Ohnishi T, Kohmura E, Tohyama M, Yoshimine T. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Brain Res. 78:131-137.2000.
Ting AY, Endy D. Signal transduction. Decoding NF-kappaB signaling. Science. 298:1189-1190.2002.
Verkman AS. More than just water channels:unexpected cellular roles of aquaporins. J Cell Sci.118:3225-3232.2005.
Verkman AS, Binder DK, Bloch O, Auguste K, Papadopoulos MC. Three distinct roles of aquaporin-4 in brain function revealed by knockout mice. Biochim Biophys Acta 1758:1085-1093.2006.
Wells T. Vesicular osmometers, vasopression secretion and aquaporin-4:a new mechanism for osmoreception? Mol Cell Endocrinol.136:103-107.1998.
Wilbert-Lampen U, Trapp A, Modrzik M, Fiedler B, Straube F, Plasse A. Effects of corticotropin-releasing hormone (CRH) on endothelin-1 and NO release, mediated by CRH receptor subtype R2:a potential link between stress and endothelial dysfunction? J Psychosom Res.61:453-460.2006.
Yang Y, Hahm E, Kim Y, Kang J, Lee W, Han I, Myung P, Kang H, Park H, Cho D. Regulation of IL-18 expression by CRH in mouse microglial cells. Immunol Lett.98:291-296.2005.
徐建芬.低氧对中枢神经免疫的调节.博士论文.浙江杭州.浙江大学：54-63.2005.
Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci.4:991-1001.2003.
Azenabor AA, Hoffman-Goetz L. Effect of exhaustive exercise on membrane estradiol concentration, intracellular calcium, and oxidative damage in mouse thymic lymphocytes. Free Radic Biol Med.28:84-90.2000.
Behan DP, Maciejewski D, Chalmers D, De Souza EB. Corticotropin releasing factor binding protein (CRF-BP) is expressed in neuronal and astrocytic cells. Brain Res.698:259-264.1995.
Bishop GA, Seelandt CM, King JS. Cellular localization of corticotropin releasing factor receptors in the adult mouse cerebellum. Neuroscience. 101:1083-1092.2000.
Carmosino M, Procino G, Tamma G, Mannucci R, Svelto M, Valenti G. Trafficking and phosphorylation dynamics of AQP4 in histamine-treated human gastric cells. Biol Cell.99:25-36.2007.
Dautzenberg FM, Hauger RL. The CRF peptide family and their receptors:yet more partners discovered. Trends Pharmacol Sci.23:71-77.2002.
Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol.28:138-145.2007.
Fu X, Li Q, Feng Z, Mu D. The roles of aquaporin-4 in brain edema following neonatal hypoxia ischemia and reoxygenation in a cultured rat astrocyte model. Glia. 55:935-941.2007.
Fujita Y, Yamamoto N, Sobue K, Inagaki M, Ito H, Arima H, Morishima T, Takeuchi A, Tsuda T, Katsuya H, Asai K. Effect of mild hypothermia on the expression of aquaporin family in cultured rat astrocytes under hypoxic condition. Neurosci Res.47:437-444.2003.
Gunnarson E, Song YT, Kowalewski JM, Brismar H, Brines M, Cerami A, Andersson U, Zelenina M, Aperia A. Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection. Proc Natl Acad Sci U S A. 106:1602-1607.2009.
Gunnarson E, Zelenina M, Aperia A. Regulation of brain aquaporins. Neuroscience. 129:947-955.2004.
Gunnarson E, Zelenina M, Axehult G, Song YT, Bondar A, Krieger P, Brismar H, Zelenin S, Aperia A. Identification of a molecular target for glutamate regulation of astrocyte water permeability. Glia.56:587-596.2008.
Hackett PH, Roach RC. High altitude cerebral edema. High Alt Med Biol. 5:136-146.2004.
Han Z, Wax MB, Patil RV. Regulation of aquaporin-4 water channels by phorbol ester-dependent protein phosphorylation. J Biol Chem.273:6001-6004.1998.
Hillhouse EW, Grammatopoulos DK. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev.27:260-286.2006.
Justice NJ, Yuan ZF, Sawchenko PE, Vale W. Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice:implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J Comp Neurol.511:479-496.2008.
Kaur C, Sivakumar V, Zhang Y, Ling EA. Hypoxia-induced astrocytic reaction and increased vascular permeability in the rat cerebellum. Glia.54:826-839.2006.
Nicchia GP, Rossi A, Mola MG, Procino G, Frigeri A, Svelto M. Actin cytoskeleton remodeling governs aquaporin-4 localization in astrocytes. Glia. 56:1755-1766.2008.
Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP. Specialized membrane domains for water transport in glial cells:high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci. 17:171-180.1997.
Petrovic MM, Vales K, Stojan G, Basta-Jovanovic G, Mitrovic DM. Regulation of selectivity and translocation of aquaporins:an update. Folia Biol. 52:173-180.2006.
Seifert G, Schilling K, Steinhauser C. Astrocyte dysfunction in neurological disorders:a molecular perspective. Nat Rev Neurosci.7:194-206.2006.
Stevens SL, Shaw TE, Dykhuizen E, Lessov NS, Hill JK, Wurst W, Stenzel-Poore MP. Reduced cerebral injury in CRH-R1 deficient mice after focal ischemia:a potential link to microglia and atrocytes that express CRH-R1. J Cereb Blood Flow Metab.23:1151-1159.2003.
Tait MJ, Saadoun S, Bell BA, Papadopoulos MC. Water movements in the brain:role of aquaporins. Trends Neurosci.31:37-43.2008.
Verkman AS. More than just water channels:unexpected cellular roles of aquaporins. J Cell Sci.118:3225-3232.2005.
Verkman AS. Aquaporins:translating bench research to human disease. J Exp Biol. 212:1707-1715.2009.
Yamamoto N, Sobue K, Fujita M, Katsuya H, Asai K. Differential regulation of aquaporin-5 and-9 expression in astrocytes by protein kinase A. Brain Res Mol Brain Res.104:96-102.2002.
Yamamoto N, Sobue K, Miyachi T, Inagaki M, Miura Y, Katsuya H, Asai K. Differential regulation of aquaporin expression in astrocytes by protein kinase C. Brain Res Mol Brain Res.95:110-116.2001.
Yukutake Y, Yasui M. Regulation of water permeability through aquaporin-4. Neuroscience.2009. Oct 20.
Zelenina M, Brismar H. Osmotic water permeability measurements using confocal laser scanning microscopy. Eur Biophys J.29:165-171.2000.
Zelenina M, Zelenin S, Bondar AA, Brismar H, Aperia A. Water permeability of aquaporin-4 is decreased by protein kinase C and dopamine. Am J Physiol Renal Physiol.283:F309-318.2002.
Aaronson PI, Robertson TP, Ward JP. Endothelium-derived mediators and hypoxic pulmonary vasoconstriction. Respir Physiol Neurobiol.132:107-120.2002.
Agorreta J, Garayoa M, Montuenga LM, Zulueta JJ. Effects of acute hypoxia and lipopolysaccharide on nitric oxide synthase-2 expression in acute lung injury. Am J Respir Crit Care Med.168:287-296.2003.
Anand IS, Prasad BA, Chugh SS, Rao KR, Cornfield DN, Milla CE, Singh N, Singh S, Selvamurthy W. Effects of inhaled nitric oxide and oxygen in high-altitude pulmonary edema. Circulation.98:2441-2445.1998.
Bartsch P, Mairbaurl H, Maggiorini M, Swenson ER. Physiological aspects of high-altitude pulmonary edema. J Appl Physiol.98:1101-1110.2005.
Basnyat B. High altitude cerebral and pulmonary edema. Travel medicine and infectious disease 3:199-211.2005a.
Basnyat B. The physiologic basis of high-altitude diseases. Ann Intern Med.16: 789-800.2005b.
Berger MM, Hesse C, Dehnert C, Siedler H, Kleinbongard P, Bardenheuer HJ, Kelm M, Bartsch P, Haefeli WE. Hypoxia impairs systemic endothelial function in individuals prone to high-altitude pulmonary edema. Am J Respir Crit Care Med. 172:763-767.2005.
Berger MM, Rozendal CS, Schieber C, Dehler M, Zugel S, Bardenheuer HJ, Bartsch P, Mairbaurl H. The effect of endothelin-1 on alveolar fluid clearance and pulmonary edema formation in the rat. Anesth Analg.108:225-231.2009.
Busch T, Bartsch P, Pappert D, Grunig E, Hildebrandt W, Elser H, Falke KJ, Swenson ER. Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high-altitude pulmonary edema. Am J Respir Crit Care Med.163:368-373.2001.
Calza L, Giardino L, Pozza M, Micera A, Aloe L. Time-course changes of nerve growth factor, corticotropin-releasing hormone, and nitric oxide synthase isoforms and their possible role in the development of inflammatory response in experimental allergic encephalomyelitis. Proc Natl Acad Sci U S A.94:3368-3373.1997.
Chan YC, Yao XQ, Lau CW, Chan FL, He GW, Bourreau JP, Huang Y. The relaxant effect of urocortin in rat pulmonary arteries. Regul Pept.121:11-18.2004.
Chen SJ, Chen YF, Opgenorth TJ, Wessale JL, Meng QC, Durand J, DiCarlo VS, Oparil S. The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Sprague-Dawley rats. J Cardiovasc Pharmacol. 29:713-725.1997.
Daniliuc S, Bitterman H, Rahat MA, Kinarty A, Rosenzweig D, Lahat N. Hypoxia inactivates inducible nitric oxide synthase in mouse macrophages by disrupting its interaction with alpha-actinin 4. J Immunol.171:3225-3232.2003.
Dieterich KD, Grigoriadis DE, De Souza EB. Corticotropin-releasing factor receptors in human small cell lung carcinoma cells:radioligand binding, second messenger, and northern blot analysis data. Endocrinology.135:1551-1558.1994.
Duplain H, Sartori C, Lepori M, Egli M, Allemann Y, Nicod P, Scherrer U. Exhaled nitric oxide in high-altitude pulmonary edema:role in the regulation of pulmonary vascular tone and evidence for a role against inflammation. Am J Respir Crit Care Med.162:221-224.2000.
Figueroa YG, Chan AK, Ibrahim R, Tang Y, Burow ME, Alam J, Scandurro AB, Beckman BS. NF-kappaB plays a key role in hypoxia-inducible factor-1-regulated erythropoietin gene expression. Exp Hematol. 30:1419-1427.2002.
Goldie RG Endothelin receptor subtypes:distribution and function in the lung. Pulm Pharmacol Ther.11:89-95.1998.
Hackett PH, Roach RC. High-altitude illness. N Engl J Med.345:107-114.2001.
He JJ, Chen XQ, Wang L, Xu JF, Du JZ. Corticotropin-releasing hormone receptor 1 coexists with endothelin-1 and modulates its mRNA expression and release in rat paraventricular nucleus during hypoxia. Neuroscience.152:1006-1014.2008.
Hehl A, Richon J, Ravussin P. Altitude diseases:acute mountain disease, pulmonary edema, and high altitude cerebral edema. Rev Med Suisse Romande. 123:703-707.2003.
Hultgren HN. High-altitude pulmonary edema:current concepts. Annu Rev Med. 47:267-284.1996.
Hultgren HN, Lopez CE, Lundberg E, Miller H. Physiologic Studies of Pulmonary Edema at High Altitude. Circulation 29:393-408.1964.
Jain V, Vedernikov YP, Saade GR, Chwalisz K, Garfield RE. Endothelium-dependent and-independent mechanisms of vasorelaxation by corticotropin-releasing factor in pregnant rat uterine artery. J Pharmacol Exp Ther.288:407-413.1999.
Kolluru GK, Tamilarasan KP, Rajkumar AS, Geetha Priya S, Rajaram M, Saleem NK, Majumder S, Jaffar Ali BM, Illavazagan G, Chatterjee S. Nitric oxide/cGMP protects endothelial cells from hypoxia-mediated leakiness. Eur J Cell Biol. 87:147-161.2008.
Li H, Elton TS, Chen YF, Oparil S. Increased endothelin receptor gene expression in hypoxic rat lung. Am J Physiol.266:L553-560.1994.
Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, Sofi F, Savia G, Mancia G, Gensini GF, Parati G. Role of endothelin-1 in exposure to high altitude:Acute Mountain Sickness and Endothelin-1 (ACME-1) study. Circulation.114:1410-1416.2006.
Moffatt JD, Lever R, Page CP. Activation of corticotropin-releasing factor receptor-2 causes bronchorelaxation and inhibits pulmonary inflammation in mice. Faseb J. 20:1877-1879.2006.
Moudgil R, Michelakis ED, Archer SL. Hypoxic pulmonary vasoconstriction. J Appl Physiol.98:390-403.2005.
Ohinata A, Nagai K, Nomura J, Hashimoto K, Hisatsune A, Miyata T, Isohama Y. Lipopolysaccharide changes the subcellular distribution of aquaporin 5 and increases plasma membrane water permeability in mouse lung epithelial cells. Biochem Biophys Res Commun.326:521-526.2005.
Omura A, Roy R, Jennings T. Inhaled nitric oxide improves survival in the rat model of high-altitude pulmonary edema. Wilderness Environ Med.11:251-256.2000.
Phelan MW, Faller DV. Hypoxia decreases constitutive nitric oxide synthase transcript and protein in cultured endothelial cells. J Cell Physiol.167:469-476.1996.
Rademarker MT, Charles CJ, Espiner EA, Frampton CM, Lainchbury JG, Richards AM. Endogenous urocortins reduce vascular tone and renin-aldosterone/endothelin activity in experimental heart failure. Eur Heart J.26:2046-2054.2006.
Ralph JA, Zocco D, Bresnihan B, FitzGerald O, McEVoy AN, Murphy EP. A role for type la corticotropin releasing hormone receptors in mediating local changes in chronically inflamed tissue. Am J Pathol.170:1121-1133.2007.
Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1 alpha. Nature. 453:807-811.2008.
Rodman DM, Stelzner TJ, Zamora MR, Bonvallet ST, Oka M, Sato K, O'Brien RF, McMurtry IF. Endothelin-1 increases the pulmonary micro vascular pressure and causes pulmonary edema in salt solution but not blood-perfused rat lungs. J Cardiovasc Pharmacol.20:658-663.1992.
Sarada S, Himadri P, Mishra C, Geetali P, Ram MS, Ilavazhagan G. Role of oxidative stress and NFkB in hypoxia-induced pulmonary edema. Exp Biol Med (Maywood).233:1088-1098.2008.
Scherrer U, Vollenweider L, Delabays A, Savcic M, Eichenberger U, Kleger GR, Fikrle A, Ballmer PE, Nicod P, Bartsch P. Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med.334:624-629.1996.
Serda SM, Wei ET. Epinephrine-induced pulmonary oedema in rats is inhibited by corticotropin-releasing factor. Pharmacol Res.26:85-91.1992.
Shimoda LA, Sham JS, Liu Q, Sylvester JT. Acute and chronic hypoxic pulmonary vasoconstriction:a central role for endothelin-1? Respir Physiol Neurobiol. 132:93-106.2002.
Sidhaye VK, Schweitzer KS, Caterina MJ, Shimoda L, King LS. Shear stress regulates aquaporin-5 and airway epithelial barrier function. Proc Natl Acad Sci U S A. 105:3345-3350.2008.
Smith EM, Gregg M, Hashemi F, Schott L, Hughes TK. Corticotropin releasing factor (CRF) activation of NF-κB-directed transcription in leukocytes. Cell Mol Neurobiol.26:1021-1036.2006.
Smith GW, Aubry JM, Delhi F, Contarino A, Bilezikjian LM, Gold LH, Chen R, Marchuk Y, Hauser C, Bentley CA, Sawchenko PE, Koob GF, Vale W, Lee KF. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20:1093-1102.1998.
Soon Lee, Rivier C. Role played by hypothalamic nuclear factor-KB in alcohol-mediated activation of the rat hypothalamic-pituitary-adrenal axis. Endocrinology.146:2006-2014.2005.
Stelzner TJ, O'Brien RF, Sato K, Weil JV. Hypoxia-induced increases in pulmonary transvascular protein escape in rats. Modulation by glucocorticoids. J Clin Invest. 82:1840-1847.1988.
Swenson ER, Maggiorini M, Mongovin S, Gibbs JS, Greve I, Mairbaurl H, Bartsch P. Pathogenesis of high-altitude pulmonary edema:inflammation is not an etiologic factor. JAMA.287:2228-2235.2002.
Ting AY, Endy D. Signal transduction. Decoding NF-kappaB signaling. Science. 298:1189-1190.2002.
Ward ME, Toporsian M, Scott JA, Teoh H, Govindaraju V, Quan A, Wener AD, Wang G, Bevan SC, Newton DC, Marsden PA. Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant. J Clin Invest. 115:3128-3139.2005.
West JB, Colice GL, Lee YJ, Namba Y, Kurdak SS, Fu Z, Ou LC, Mathieu-Costello O. Pathogenesis of high-altitude pulmonary oedema:direct evidence of stress failure of pulmonary capillaries. Eur Respir J.8:523-529.1995.
Wu TY, Ding SQ, Liu JL, Yu MT, Jia JH, Chai ZC, Dai RC, Zhang SL, Li BY, Pan L, Liang BZ, Zhao JZ, Qi de T, Sun YF, Kayser B. Who should not go high: chronic disease and work at altitude during construction of the Qinghai-Tibet railroad. High Alt Med Biol.8:88-107.2007.
Wu Y, Xu Y, Zhou H, Tao J, Li S. Expression of urocortin in rat lung and its effect on pulmonary vascular permeability. J Endocrinol.189:167-178.2006.
Xu JF, Chen XQ, Du JZ, Wang TY. CRF receptor type 1 mediates continual hypoxia-induced CRF peptide and CRF mRNA expression increase in hypothalamic PVN of rats. Peptides.26:639-646.2005.
Aaronson PI, Robertson TP, Ward JP. Endothelium-derived mediators and hypoxic pulmonary vasoconstriction. Respir Physiol Neurobiol.132:107-120.2002.
Abbott N. Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat 200:527.2002.
Ahsan A, Mohd G, Norboo T, Baig MA, Pasha MA. Heterozygotes of NOS3 polymorphisms contribute to reduced nitrogen oxides in high-altitude pulmonary edema. Chest.130:1511-1519.2006.
Ainslie PN, Barach A, Murrell C, Hamlin M, Hellemans J, Ogoh S. Alterations in cerebral autoregulation and cerebral blood flow velocity during acute hypoxia: rest and exercise. Am J Physiol Heart Circ Physiol.292:H976-983.2007.
Ainslie PN, Ogoh S, Burgess K, Celi L, McGrattan K, Peebles K, Murrell C, Subedi P, Burgess KR. Differential effects of acute hypoxia and high altitude on cerebral blood flow velocity and dynamic cerebral autoregulation:alterations with hyperoxia. J Appl Physiol.104:490-498.2008.
Alexander AL, Lee JE, Lazar M, Field AS. Diffusion tensor imaging of the brain. Neurotherapeutics.4:316-329.2007.
Amiry-Moghaddam M, Frydenlund DS, Ottersen OP. Anchoring of aquaporin-4 in brain: molecular mechanisms and implications for the physiology and pathophysiology of water transport. Neuroscience.129:999-1010.2004.
Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci.4:991-1001.2003.
Anand IS, Prasad BA, Chugh SS, Rao KR, Cornfield DN, Milla CE, Singh N, Singh S, Selvamurthy W. Effects of inhaled nitric oxide and oxygen in high-altitude pulmonary edema. Circulation.98:2441-2445.1998.
Badaut J, Petit JM, Brunet JF, Magistretti PJ, Charriaut-Marlangue C, Regli L. Distribution of Aquaporin 9 in the adult rat brain:preferential expression in catecholaminergic neurons and in glial cells. Neuroscience.128:27-38.2004.
Bailey DM, Evans KA, James PE, McEneny J, Young IS, Fall L, Gutowski M, Kewley E, McCord JM, Moller K, Ainslie PN. Altered free radical metabolism in acute mountain sickness:implications for dynamic cerebral autoregulation and blood-brain barrier function. J Physiol.587:73-85.2009a.
Bailey DM, Kleger GR, Holzgraefe M, Ballmer PE, Bartsch P. Pathophysiological significance of peroxidative stress, neuronal damage, and membrane permeability in acute mountain sickness. J Appl Physiol.96:1459-1463.2004.
Bailey DM, Taudorf S, Berg RM, Lundby C, McEneny J, Young IS, Evans KA, James PE, Shore A, Hullin DA, McCord JM, Pedersen BK, Moller K. Increased cerebral output of free radicals during hypoxia:implications for acute mountain sickness? Am J Physiol Regul Integr Comp Physiol.297:R1283-1292.2009b.
Ballabh P, Braun A, Nedergaard M. The blood-brain barrier:an overview:structure, regulation, and clinical implications. Neurobiol Dis.16:1-13.2004.
Basnyat B. High altitude cerebral and pulmonary edema. Travel Med Infect Dis. 3:199-211.2005.
Basnyat B, Murdoch DR. High-altitude illness. Lancet.361:1967-1974.2003.
Baumgartner RW, Spyridopoulos I, Bartsch P, Maggiorini M, Oelz O. Acute mountain sickness is not related to cerebral blood flow:a decompression chamber study. J Appl Physiol.86:1578-1582.1999.
Benfenati V, Nicchia GP, Svelto M, Rapisarda C, Frigeri A, Ferroni S. Functional down-regulation of volume-regulated anion channels in AQP4 knockdown cultured rat cortical astrocytes. J Neurochem.100:87-104.2007.
Berger MM, Hesse C, Dehnert C, Siedler H, Kleinbongard P, Bardenheuer HJ, Kelm M, Bartsch P, Haefeli WE. Hypoxia impairs systemic endothelial function in individuals prone to high-altitude pulmonary edema. Am J Respir Crit Care Med. 172:763-767.2005.
Boulard G, Marguinaud E, Sesay M. Osmotic cerebral oedema:the role of plasma osmolarity and blood brain barrier. Ann Fr Anesth Reanim.22:215-219.2003.
Busch T, Bartsch P, Pappert D, Grunig E, Hildebrandt W, Elser H, Falke KJ, Swenson ER. Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high-altitude pulmonary edema. Am J Respir Crit Care Med.163:368-373.2001.
Castle NA. Aquaporins as targets for drug discovery. Drug Discov Today. 10:485-493.2005.
Chan H, Butterworth RF, Hazell AS. Primary cultures of rat astrocytes respond to thiamine deficiency-induced swelling by downregulating aquaporin-4 levels. Neurosci Lett.366:231-234.2004.
Dada LA, Chandel NS, Ridge KM, Pedemonte C, Bertorello AM, Sznajder JI. Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-zeta. J Clin Invest. 111:1057-1064.2003.
Dada LA, Sznajder JI. Hypoxic inhibition of alveolar fluid reabsorption. Adv Exp Med Biol.618:159-168.2007.
Dehnert C, Berger MM, Mairbaurl H, Bartsch P. High altitude pulmonary edema:a pressure-induced leak. Respir Physiol Neurobiol.158:266-273.2007.
Dellasanta P, Gaillard S, Loutan L, Kayser B. Comparing questionnaires for the assessment of acute mountain sickness. High Alt Med Biol.8:184-191.2007.
Denker BM, Smith BL, Kuhajda FP, Agre P. Identification, purification, and partial characterization of a novel Mr 28,000 integral membrane protein from erythrocytes and renal tubules. J Biol Chem.263:15634-15642.1988.
Dubowitz DJ, Dyer EA, Theilmann RJ, Buxton RB, Hopkins SR. Early brain swelling in acute hypoxia. J Appl Physiol 107:244-252.2009.
Duplain H, Sartori C, Lepori M, Egli M, Allemann Y, Nicod P, Scherrer U. Exhaled nitric oxide in high-altitude pulmonary edema:role in the regulation of pulmonary vascular tone and evidence for a role against inflammation. Am J Respir Crit Care Med.162:221-224.2000.
Dyer EA, Hopkins SR, Perthen JE, Buxton RB, Dubowitz DJ. Regional cerebral blood flow during acute hypoxia in individuals susceptible to acute mountain sickness. Respir Physiol Neurobiol.160:267-276.2008.
Echevarria M, Munoz-Cabello AM, Sanchez-Silva R, Toledo-Aral JJ, Lopez-Barneo J. Development of cytosolic hypoxia and hypoxia-inducible factor stabilization are facilitated by aquaporin-1 expression. J Biol Chem.282:30207-30215.2007.
Fagenholz PJ, Gutman JA, Murray AF, Noble VE, Camargo CA, Jr., Harris NS. Evidence for increased intracranial pressure in high altitude pulmonary edema. High Alt Med Biol.8:331-336.2007.
Firth PG, Zheng H, Windsor JS, Sutherland AI, Imray CH, Moore GW, Semple JL, Roach RC, Salisbury RA. Mortality on Mount Everest,1921-2006:descriptive study. BMJ.337:a2654.2008.
Fischer R, Vollmar C, Thiere M, Born C, Leitl M, Pfluger T, Huber RM. No evidence of cerebral oedema in severe acute mountain sickness. Cephalalgia.24:66-71.2004.
Fischer S, Renz D, Schaper W, Karliczek GF. Barbiturates decrease the expression of vascular endothelial growth factor in hypoxic cultures of porcine brain derived microvascular endothelial cells. Brain Res Mol Brain Res.60:89-97.1998.
Fu X, Li Q, Feng Z, Mu D. The roles of aquaporin-4 in brain edema following neonatal hypoxia ischemia and reoxygenation in a cultured rat astrocyte model. Glia. 55:935-941.2007.
Gass A, Niendorf T, Hirsch JG. Acute and chronic changes of the apparent diffusion coefficient in neurological disorders—biophysical mechanisms and possible underlying histopathology. J Neurol Sci.186 Suppll:S15-23.2001.
Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest. 115:500-508.2005.
Gunnarson E, Song YT, Kowalewski JM, Brismar H, Brines M, Cerami A, Andersson U, Zelenina M, Aperia A. Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection. Proc Natl Acad Sci U S A. 106:1602-1607.2009.
Gunnarson E, Zelenina M, Aperia A. Regulation of brain aquaporins. Neuroscience. 129:947-955.2004.
Gunnarson E, Zelenina M, Axehult G, Song YT, Bondar A, Krieger P, Brismar H, Zelenin S, Aperia A. Identification of a molecular target for glutamate regulation of astrocyte water permeability. Glia.56:587-596.2008.
Guo Q, Sayeed I, Baronne LM, Hoffman SW, Guennoun R, Stein DG. Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats. Exp Neurol.198:469-478.2006.
Hackett PH, Roach RC. High-altitude illness. N Engl J Med.345:107-114.2001.
Hackett PH, Roach RC. High altitude cerebral edema. High Alt Med Biol. 5:136-146.2004.
Hackett PH, Yarnell PR, Hill R, Reynard K, Heit J, McCormick J. High-altitude cerebral edema evaluated with magnetic resonance imaging:clinical correlation and pathophysiology. JAMA 280:1920-1925.1998.
Han Z, Wax MB, Patil RV. Regulation of aquaporin-4 water channels by phorbol ester-dependent protein phosphorylation. J Biol Chem.273:6001-6004.1998.
Hanaoka M, Droma Y, Ota M, Ito M, Katsuyama Y, Kubo K. Polymorphisms of human vascular endothelial growth factor gene in high-altitude pulmonary oedema susceptible subjects. Respirology.14:46-52.2009.
Haussinger D, Schliess F. Pathogenetic mechanisms of hepatic encephalopathy. Gut. 57:1156-1165.2008.
Ho JD, Yeh R, Sandstrom A, Chorny I, Harries WE, Robbins RA, Miercke LJ, Stroud RM. Crystal structure of human aquaporin 4 at 1.8 A and its mechanism of conductance. Proc Natl Acad Sci U S A 106:7437-7442.2009.
Hultgren HN. High-altitude pulmonary edema:current concepts. Annu Rev Med. 47:267-284.1996.
Jansen GF, Krins A, Basnyat B, Bosch A, Odoom JA. Cerebral autoregulation in subjects adapted and not adapted to high altitude. Stroke.31:2314-2318.2000.
Johnson W, Nohria A, Garrett L, Fang JC, Igo J, Katai M, Ganz P, Creager MA. Contribution of endothelin to pulmonary vascular tone under normoxic and hypoxic conditions. Am J Physiol Heart Circ Physiol.283:H568-575.2002.
Kallenberg K, Bailey DM, Christ S, Mohr A, Roukens R, Menold E, Steiner T, Bartsch P, Knauth M. Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness. J Cereb Blood Flow Metab.27:1064-1071.2007.
Kallenberg K, Dehnert C, Dorfler A, Schellinger PD, Bailey DM, Knauth M, Bartsch PD. Microhemorrhages in nonfatal high-altitude cerebral edema. J Cereb Blood Flow Metab.28:1635-1642.2008.
Kaminsky DA, Jones K, Schoene RB, Voelkel NF. Urinary leukotriene E4 levels in high-altitude pulmonary edema. A possible role for inflammation. Chest. 110:939-945.1996.
Kaur C, Sivakumar V, Yong Z, Lu J, Foulds W, Ling E. Blood-retinal barrier disruption and ultrastructural changes in the hypoxic retina in adult rats:the beneficial effect of melatonin administration. J Pathol.212:429-439.2007.
Kaur C, Sivakumar V, Zhang Y, Ling EA. Hypoxia-induced astrocytic reaction and increased vascular permeability in the rat cerebellum. Glia.54:826-839.2006.
Kawedia JD, Nieman ML, Boivin GP, Melvin JE, Kikuchi K, Hand AR, Lorenz JN, Menon AG. Interaction between transcellular and paracellular water transport pathways through Aquaporin 5 and the tight junction complex. Proc Natl Acad Sci U S A.104:3621-3626.2007.
Ke C, Poon WS, Ng HK, Lai FM, Tang NL, Pang JC. Impact of experimental acute hyponatremia on severe traumatic brain injury in rats:influences on injuries, permeability of blood-brain barrier, ultrastructural features, and aquaporin-4 expression. Exp Neurol.178:194-206.2002.
Ke C, Poon WS, Ng HK, Pang JC, Chan Y. Heterogeneous responses of aquaporin-4 in oedema formation in a replicated severe traumatic brain injury model in rats. Neurosci Lett.301:21-24.2001.
Kiening KL, van Landeghem FK, Schreiber S, Thomale UW, von Deimling A, Unterberg AW, Stover JF. Decreased hemispheric Aquaporin-4 is linked to evolving brain edema following controlled cortical impact injury in rats. Neurosci Lett.324:105-108.2002.
Kimelberg HK. Current concepts of brain edema. Review of laboratory investigations. J Neurosurg.83:1051-1059.1995.
King LS, Kozono D, Agre P. From structure to disease:the evolving tale of aquaporin biology. Nat Rev Mol Cell Biol.5:687-698.2004.
Klatzo I. Pathophysiological aspects of brain edema. Acta Neuropathol (Berl). 72:236-239.1987.
Kolluru GK, Tamilarasan KP, Rajkumar AS, Geetha Priya S, Rajaram M, Saleem NK, Majumder S, Jaffar Ali BM, Illavazagan G, Chatterjee S. Nitric oxide/cGMP protects endothelial cells from hypoxia-mediated leakiness. Eur J Cell Biol. 87:147-161.2008.
Krane CM, Fortner CN, Hand AR, McGraw DW, Lorenz JN, Wert SE, Towne JE, Paul RJ, Whitsett JA, Menon AG. Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation. Proc Natl Acad Sci U S A. 98:14114-14119.2001.
Lal H, Yu Q, Ivor Williams K, Woodward B. Hypoxia augments conversion of big-endothelin-1 and endothelin ET(B) receptor-mediated actions in rat lungs. Eur J Pharmacol.402:101-110.2000.
Leshem E, Pandey P, Shlim DR, Hiramatsu K, Sidi Y, Schwartz E. Clinical features of patients with severe altitude illness in Nepal. J Travel Med.15:315-322.2008.
Li H, Elton TS, Chen YF, Oparil S. Increased endothelin receptor gene expression in hypoxic rat lung. Am J Physiol.266:L553-560.1994.
Lorenzo VF, Yang Y, Simonson TS, Nussenzveig R, Jorde LB, Prchal JT, Ge RL. Genetic adaptation to extreme hypoxia:study of high-altitude pulmonary edema in a three-generation Han Chinese family. Blood Cells Mol Dis. 43:221-225.2009.
Ma T, Fukuda N, Song Y, Matthay MA, Verkman AS. Lung fluid transport in aquaporin-5 knockout mice. J Clin Invest.105:93-100.2000.
Maignan M, Rivera-Ch M, Privat C, Leon-Velarde F, Richalet JP, Pham I. Pulmonary pressure and cardiac function in chronic mountain sickness patients. Chest. 135:499-504.2009.
Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med.6:159-163.2000.
Mao X, Enno TL, Del Bigio MR. Aquaporin 4 changes in rat brain with severe hydrocephalus. Eur J Neurosci.23:2929-2936.2006.
Mark KS, Davis TP. Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation. Am J Physiol.282:H1485-1494.2002.
Mascalchi M, Filippi M, Floris R, Fonda C, Gasparotti R, Villari N. Diffusion-weighted MR of the brain:methodology and clinical application. Radiol Med. 109:155-197.2005.
Mazzuero G, Mazzuero A, Pascariello A. Severe acute mountain sickness and suspect high altitude cerebral edema related to nitroglycerin use. High Alt Med Biol. 9:241-243.2008.
Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol. 164:1875-1882.2004.
Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, Sofi F, Savia G, Mancia G, Gensini GF, Parati G. Role of endothelin-1 in exposure to high altitude:Acute Mountain Sickness and Endothelin-1 (ACME-1) study. Circulation.114:1410-1416.2006.
Nagai K, Watanabe M, Seto M, Hisatsune A, Miyata T, Isohama Y. Nitric oxide decreases cell surface expression of aquaporin-5 and membrane water permeability in lung epithelial cells. Biochem Biophys Res Commun. 354:579-584.2007.
Neely JD, Moghaddam MA, Ottersen OP. Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein. Proc Natl Acad Sci U S A 98:14108-14113.2001.
Nicchia GP, Nico B, Camassa LM, Mola MG, Loh N, Dermietzel R, Spray DC, Svelto M, Frigeri A. The role of aquaporin-4 in the blood-brain barrier development and integrity:studies in animal and cell culture models. Neuroscience 129:935-945.2004.
Nielsen S, Nagelhus EA, Moghaddam MA. Specialized Membrane Domains for Water Transport in Glial Cells:High-Resolution Immunogold Cytochemistry of Aquaporin-4 in Rat Brain. J Neurosci.17:171-180.1997.
Ohinata A, Nagai K, Nomura J, Hashimoto K, Hisatsune A, Miyata T, Isohama Y. Lipopolysaccharide changes the subcellular distribution of aquaporin 5 and increases plasma membrane water permeability in mouse lung epithelial cells. Biochem Biophys Res Commun.326:521-526.2005.
Omura A, Roy R, Jennings T. Inhaled nitric oxide improves survival in the rat model of high-altitude pulmonary edema. Wilderness Environ Med.11:251-256.2000.
Panesar NS. High altitude sickness. Is acute cortisol deficiency involved in its pathophysiology? Med Hypotheses.63:507-510.2004.
Papadopoulos MC, Verkman AS. Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis. J Biol Chem. 280:13906-13912.2005.
Papandreou I, Powell A, Lim AL, Denko N. Cellular reaction to hypoxia:sensing and responding to an adverse environment. Mutat Res.569:87-100.2005.
Rodman DM, Stelzner TJ, Zamora MR, Bonvallet ST, Oka M, Sato K, Obrien RF, Mcmurtry IF. Endothelin-1 Increases the Pulmonary Microvascular Pressure and Causes Pulmonary-Edema in Salt Solution but Not Blood-Perfused Rat Lungs. J Cardiovasc Pharmacol.20:658-663.1992.
Rosenblum WI. Cytotoxic edema:monitoring its magnitude and contribution to brain swelling. J Neuropathol Exp Neurol.66:771-778.2007.
Saadoun S, Bell BA, Verkman AS, Papadopoulos MC. Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice. Brain. 131:1087-1098.2008.
Saadoun S, Papadopoulos MC, Davies DC, Krishna S, Bell BA. Aquaporin-4 expression is increased in oedematous human brain tumours. J Neurol Neurosurg Psychiatry.72:262-265.2002.
Sarada S, Himadri P, Mishra C, Geetali P, Ram MS, Ilavazhagan G. Role of oxidative stress and NFkB in hypoxia-induced pulmonary edema. Exp Biol Med. 233:1088-1098.2008.
Scherrer U, Vollenweider L, Delabays A, Savcic M, Eichenberger U, Kleger GR, Fikrle A, Ballmer PE, Nicod P, Bartsch P. Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med.334:624-629.1996.
Schoch HJ, Fischer S, Marti HH. Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain.125:2549-2557.2002.
Schoonman GG, Sandor PS, Nirkko AC, Lange T, Jaermann T, Dydak U, Kremer C, Ferrari MD, Boesiger P, Baumgartner RW. Hypoxia-induced acute mountain sickness is associated with intracellular cerebral edema:a 3 T magnetic resonance imaging study. J Cereb Blood Flow Metab.28:198-206.2008.
Senger DR, Connolly DT, Van de Water L, Feder J, Dvorak HF. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res.50:1774-1778.1990.
Shimoda LA, Sham JS, Liu Q, Sylvester JT. Acute and chronic hypoxic pulmonary vasoconstriction:a central role for endothelin-1? Respir Physiol Neurobiol. 132:93-106.2002.
Sidhaye V, Hoffert JD, King LS. cAMP has distinct acute and chronic effects on aquaporin-5 in lung epithelial cells. J Biol Chem.280:3590-3596.2005.
Sidhaye VK, Schweitzer KS, Caterina MJ, Shimoda L, King LS. Shear stress regulates aquaporin-5 and airway epithelial barrier function. Proc Natl Acad Sci U S A. 105:3345-3350.2008.
Smith EM, Baillie JK, Thompson AA, Irving JB, Porteous D, Webb DJ. Endothelial nitric oxide synthase polymorphisms do not influence pulmonary artery systolic pressure at altitude. High Alt Med Biol.7:221-227.2006.
Song Y, Fukuda N, Bai C, Ma T, Matthay MA, Verkman AS. Role of aquaporins in alveolar fluid clearance in neonatal and adult lung, and in oedema formation following acute lung injury:studies in transgenic aquaporin null mice. J Physiol. 3:771-779.2000.
Sotak CH. Nuclear magnetic resonance (NMR) measurement of the apparent diffusion coefficient (ADC) of tissue water and its relationship to cell volume changes in pathological states. Neurochem Int.45:569-582.2004.
Stelzner TJ, O'Brien RF, Sato K, Weil JV. Hypoxia-induced increases in pulmonary transvascular protein escape in rats. Modulation by glucocorticoids. J Clin Invest. 82:1840-1847.1988.
Swenson ER, Maggiorini M, Mongovin S, Gibbs JS, Greve I, Mairbaurl H, Bartsch P. Pathogenesis of high-altitude pulmonary edema:inflammation is not an etiologic factor. JAMA.287:2228-2235.2002.
Taniguchi M, Yamashita T, Kumura E, Tamatani M, Kobayashi A, Yokawa T, Maruno M, Kato A, Ohnishi T, Kohmura E, Tohyama M, Yoshimine T. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Brain Res. 78:131-137.2000.
Tissot van Patot MC, Leadbetter G, Keyes LE, Bendrick-Peart J, Beckey VE, Christians U, Hackett P. Greater free plasma VEGF and lower soluble VEGF receptor-1 in acute mountain sickness. J Appl Physiol.98:1626-1629.2005.
Trang AJ, Teoh H, Ward ME. Inhibition of prostanoid-mediated contraction to endothelin-1 after hypoxia in rat aorta. Eur J Pharmacol.423:57-61.2001.
Vajda Z, Promeneur D, Doczi T, Sulyok E, Frokiaer J, Ottersen OP, Nielsen S. Increased aquaporin-4 immunoreactivity in rat brain in response to systemic hyponatremia. Biochem Biophys Res Commun.270:495-503.2000.
Van Osta A, Moraine JJ, Melot C, Mairbaurl H, Maggiorini M, Naeije R. Effects of high altitude exposure on cerebral hemodynamics in normal subjects. Stroke. 36:557-560.2005.
Verkman AS, Mitra AK. Structrue and function of aquaporin water channels. Am J Physiol Renal Physiol 278:13-28.2000.
Verkman AS. More than just water channels:unexpected cellular roles of aquaporins. J Cell Sci.118:3225-3232.2005.
Verkman AS, Binder DK, Bloch O, Auguste K, Papadopoulos MC. Three distinct roles of aquaporin-4 in brain function revealed by knockout mice. Biochim Biophys Acta.1758:1085-1093.2006.
Vizuete ML, Venero JL, Vargas C, Ilundain AA, Echevarria M, Machado A, Cano J. Differential upregulation of aquaporin-4 mRNA expression in reactive astrocytes after brain injury:potential role in brain edema. Neurobiol Dis.6:245-258.1999.
Vock P, Fretz C, Franciolli M, Bartsch P. High-Altitude Pulmonary-Edema-Findings at High-Altitude Chest Radiography and Physical-Examination. Radiology. 170:661-666.1989.
Wagner PD. The biology of oxygen. Eur Respir J.31:887-890.2008.
Wang ML, Huang XJ, Fang SH, Yuan YM, Zhang WP, Lu YB, Ding Q, Wei EQ. Leukotriene D4 induces brain edema and enhances CysLT2 receptor-mediated aquaporin 4 expression. Biochem Biophys Res Commun.350:399-404.2006.
West JB. The physiologic basis of high-altitude diseases. Ann Intern Med. 141:789-800.2004.
West JB, Colice GL, Lee YJ, Namba Y, Kurdak SS, Fu Z, Ou LC, Mathieu-Costello O. Pathogenesis of high-altitude pulmonary oedema:direct evidence of stress failure of pulmonary capillaries. Eur Respir J.8:523-529.1995.
Wu T, Ding S, Liu J, Jia J, Dai R, Liang B, Zhao J, Qi D. Ataxia:an early indicator in high altitude cerebral edema. High Alt Med Biol.7:275-280.2006.
Wu TY, Ding SQ, Liu JL, Yu MT, Jia JH, Chai ZC, Dai RC, Zhang SL, Li BY, Pan L, Liang BZ, Zhao JZ, Qi de T, Sun YF, Kayser B. Who should not go high: chronic disease and work at altitude during construction of the Qinghai-Tibet railroad. High Alt Med Biol.8:88-107.2007.
Xu F, Severinghaus JW. Rat brain VEGF expression in alveolar hypoxia:possible role in high-altitude cerebral edema. J Appl Physiol.85:53-57.1998.
Yamamoto N, Sobue K, Miyachi T, Inagaki M, Miura Y, Katsuya H, Asai K. Differential regulation of aquaporin expression in astrocytes by protein kinase C. Brain Res Mol Brain Res.95:110-116.2001.
Yang B, Zador Z, Verkman AS. Glial cell aquaporin-4 overexpression in transgenic mice accelerates cytotoxic brain swelling. J Biol Chem.283:15280-15286.2008.
Yao X, Hrabetova S, Nicholson C, Manley GT. Aquaporin-4-deficient mice have increased extracellular space without tortuosity change. J Neurosci. 28:5460-5464.2008.
Zelenina M, Zelenin S, Bondar AA, Brismar H, Aperia A. Water permeability of aquaporin-4 is decreased by protein kinase C and dopamine. Am J Physiol Renal Physiol.283:F309-318.2002.
Zelenina M. Regulation of brain aquaporins. Neurochem Int. doi:10.1016/j.neuint. 2010.03.022
Zeynalov E, Chen CH, Froehner SC, Adams ME, Ottersen OP, Amiry-Moghaddam M, Bhardwaj A. The perivascular pool of aquaporin-4 mediates the effect of osmotherapy in postischemic cerebral edema. Crit Care Med. 36:2634-2640.2008.
Zhao J, Moore AN, Clifton GL, Dash PK. Sulforaphane enhances aquaporin-4 expression and decreases cerebral edema following traumatic brain injury. J Neurosci Res.82:499-506.2005.
Zhou G, Dada LA, Chandel NS, Iwai K, Lecuona E, Ciechanover A, Sznajder JI. Hypoxia-mediated Na-K-ATPase degradation requires von Hippel Lindau protein. FASEB J.22:1335-1342.2008a.
Zhou J, Kong H, Hua X, Xiao M, Ding J, Hu G. Altered blood-brain barrier integrity in adult aquaporin-4 knockout mice. Neuroreport 19:1-5.2008b.
江晓波.中国山地范围界定的初步意见.山地学报.26：129.2008.
邓伟,程根伟,文安邦.中国山地科学发展构想.中国科学院院刊23：156-161.2008.
Dehnert C, Berger M M, Mairbaurl H, Bartsch P. High altitude pulmonary edema:a pressure-induced leak. Respir Physiolo Neurobiol.158:266-273.2007.
Gravanis A, Margioris AN. The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation:potential therapeutic applications. Curr Med Chem.12:1503-1512.2005.
He JJ, Chen XQ, Wang L. Xu JF, Du JZ. Corticotropin-releasing hormone receptor 1 coexists with endothelin-1 and modulates its mRNA expression and release in rat paraventricular nucleus during hypoxia. Neuroscience 152(4): 1006-1014.2008.
Hillhouse EW, Grammatopoulos DK. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev.27:260-286.2006.
Kalantaridou S, Makrigiannakis A, Zoumakis E, Chrousos GP. Peripheral corticotropin-releasing hormone is produced in the immune and reproductive systems:actions, potential roles and clinical implications. Front Biosci 12:572-580.2007.
Leshem E, Pandey P, Shlim DR, Hiramatsu K, Sidi Y, Schwartz E. Clinical features of patients with severe altitude illness in Nepal. J Travel Med.15:315-322.2008.
Moudgil R, Michelakis ED, Archer SL. Hypoxic pulmonary vasoconstriction. J Appl Physiol.98:390-403.2005.
Nazarloo HP, Buttrick PM, Saadat H, Dunn AJ. The roles of corticotropin-releasing factor-related peptides and their receptors in the cardiovascular system. Curr Protein Pept Sci.7:229-239.2006.
Roach RC, Hackett PH. Frontiers of hypoxia research:acute mountain sickness. J Exp Biol.204:3161-3170.2001.
Tsagarakis S, Grossman A. Corticotropin-releasing hormone:interactions with the immune system. Neuroimmunomodulation.1:329-334.1994.
Wang TY, Chen XQ, Du JZ, Xu NY, Wei CB, Vale WW. Corticotropin-releasing factor receptor type 1 and 2 mRNA expression in the rat anterior pituitary is modulated by intermittent hypoxia, cold and restraint. Neuroscience.128:111-119.2004.
West JB. The physiologic basis of high-altitude diseases. Ann Intern Med. 141:789-800.2004.
WHO. World Health Statistics Annual 1995. World Health Organization,Geneva.1996.
Wu TY, Ding SQ, Liu JL, Yu MT, Jia JH, Chai ZC, Dai RC, Zhang SL, Li BY, Pan L, Liang BZ, Zhao JZ, Qi de T, Sun YF, Kayser B. Who should not go high: chronic disease and work at altitude during construction of the Qinghai-Tibet railroad. High Alt Med Biol.8:88-107.2007.
Xu JF, Chen XQ, Du JZ, Wang TY. CRF receptor type 1 mediates continual hypoxia-induced CRF peptide and CRF mRNA expression increase in hypothalamic PVN of rats. Peptides.26:639-646.2005.
徐建芬.低氧对中枢神经免疫的调节.博士论文.浙江杭州.浙江大学：54-63.2005.
吕永达,霍仲厚.特殊环境生理学.军事医学科学院出版社.第1版：3-23.2005.
吴天一.高原肺水肿与急性呼吸窘迫综合症.高原医学杂志11：62-66.2001.
吴天一.高原低氧环境对人类的挑战.医学研究杂志10：1-3.2006.
Alexander AL, Lee JE, Lazar M, Field AS. Diffusion tensor imaging of the brain. Neurotherapeutics.4:316-329.2007.
Chen XQ, Du JZ, Wang YS. Regulation of hypoxia-induced release of corticotropin-releasing factor in the rat hypothalamus by norepinephrine. Regul Pept.119:221-228.2004.
Ebisu T, Naruse S, Horikawa Y, Ueda S, Tanaka C, Uto M, Umeda M, Higuchi T. Discrimination between different types of white matter edema with diffusion-weighted MR imaging. J Magn Reson Imaging.3:863-868.1993.
Esposito P, Basu S, Letourneau R, Jacobson S, Theoharides TC. Corticotropin-releasing factor (CRF) can directly affect brain microvessel endothelial cells. Brain Res. 968:192-198.2003.
Esposito P, Chandler N, Kandere K, Basu S, Jacobson S, Connolly R, Tutor D, Theoharides TC. Corticotropin-releasing hormone and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J Pharmacol Exp Ther. 303:1061-1066.2002.
Hackett PH, Roach RC. High altitude cerebral edema. High Alt Med Biol. 5:136-146.2004.
He JJ, Chen XQ, Wang L, Xu JF, Du JZ. Corticotropin-releasing hormone receptor 1 coexists with endothelin-1 and modulates its mRNA expression and release in rat paraventricular nucleus during hypoxia. Neuroscience.152:1006-1014.2008.
Hendryk S, Jedrzejowska-Szypulka H, Josko J, Jarzab B, Dohler KD. Influence of the corticotropin releasing hormone (CRH) on the brain-blood barrier permeability in cerebral ischemia in rats. J Physiol Pharmacol.53:85-94.2002.
Hillhouse EW, Grammatopoulos DK. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev.27:260-286.2006.
Hsuchou H, Kastin AJ, Wu X, Pan W. Corticotropin releasing hormone Receptor-1 in cerebral microvessels changes during development and influence Urocrotin transport across the blood brain barrier. Endocrinology.2010. doi:10.1210/en. 2009-1039.
Jin G, Arai K, Murata Y, Wang S, Stins MF, Lo EH, van Leyen K Protecting against cerebrovascular injury:contributions of 12/15-lipoxygenase to edema formation after transient focal ischemia. Stroke 39:2538-2543.2008.
Kallenberg K, Bailey DM, Christ S, Mohr A, Roukens R, Menold E, Steiner T, Bartsch P, Knauth M. Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness. J Cereb Blood Flow Metab.27:1064-1071.2007.
Kimelberg HK. Current concepts of brain edema. Review of laboratory investigations. J Neurosurg.83:1051-1059.1995.
Maiti P, Singh SB, Muthuraju S, Veleri S, Ilavazhagan G. Hypobaric hypoxia damages the hippocampal pyramidal neurons in the rat brain. Brain Res.1175:1-9.2007.
Mascalchi M, Filippi M, Floris R, Fonda C, Gasparotti R, Villari N. Diffusion-weighted MR of the brain:methodology and clinical application. Radiol Med (Torino). 109:155-197.2005.
Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol. 164:1875-1882.2004.
Morocz IA, Zientara GP, Gudbjartsson H, Muza S, Lyons T, Rock PB, Kikinis R, Jolesz FA. Volumetric quantification of brain swelling after hypobaric hypoxia exposure. Exp Neurol.168:96-104.2001.
Nag S, Manias JL, Stewart DJ. Pathology and new players in the pathogenesis of brain
edema. Acta Neuropathol.118:197-217.2009.
Obenaus A, Ashwal S. Magnetic resonance imaging in cerebral ischemia:focus on neonates. Neuropharmacology.55:271-280.2008.
Schoonman GG, Sandor PS, Nirkko AC, Lange T, Jaermann T, Dydak U, Kremer C, Ferrari MD, Boesiger P, Baumgartner RW. Hypoxia-induced acute mountain sickness is associated with intracellular cerebral edema:a 3 T magnetic resonance imaging study. J Cereb Blood Flow Metab.28:198-206.2008.
Stevens SL, Shaw TE, Dykhuizen E, Lessov NS, Hill JK, Wurst W, Stenzel-Poore MP. Reduced cerebral injury in CRH-R1 deficient mice after focal ischemia:a potential link to microglia and atrocytes that express CRH-R1. J Cereb Blood Flow Metab.23:1151-1159.2003.
Strbian D, Tatlisumak T, Ramadan UA, Lindsberg PJ. Mast cell blocking reduces brain edema and hematoma volume and improves outcome after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab 27:795-802.2007.
Titus AD, Shankaranarayana Rao BS, Harsha HN, Ramkumar K, Srikumar BN, Singh SB, Chattarji S, Raju TR. Hypobaric hypoxia-induced dendritic atrophy of hippocampal neurons is associated with cognitive impairment in adult rats. Neuroscience.145:265-278.2007.
Tjuvajev J, Uehara H, Desai R, Beattie B, Matei C, Zhou Y, Kreek MJ, Koutcher J, Blasberg R. Corticotropin-releasing factor decreases vasogenic brain edema. Cancer Res.56:1352-1360.1996.
Tourdias T, Dragonu I, Fushimi Y, Deloire MS, Boiziau C, Brochet B, Moonen C, Petry KG, Dousset V. Aquaporin 4 correlates with apparent diffusion coefficient and hydrocephalus severity in the rat brain:a combined MRI-histological study. NeuroImage.47:659-666.2009.
Viapiano MS, Mitridate de Novara AM, Fiszer de Plazas S, Bozzini CE. Prolonged exposure to hypobaric hypoxia transiently reduces GABA(A) receptor number in mice cerebral cortex. Brain Res.894:31-36.2001.
Wallace MG, Hartle KD, Snow WM, Ward NL, Ivanco TL. Effect of hypoxia on the morphology of mouse striatal neurons. Neuroscience.147:90-96.2007.
Wang TY, Chen XQ, Du JZ, Xu NY, Wei CB, Vale WW. Corticotropin-releasing factor receptor type 1 and 2 mRNA expression in the rat anterior pituitary is modulated by intermittent hypoxia, cold and restraint. Neuroscience 128:111-119.2004.
Witt KA, Mark KS, Hom S, Davis TP. Effects of hypoxia-reoxygenation on rat blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol 285:H2820-2831.2003.
Wu T, Ding S, Liu J, Jia J, Dai R, Liang B, Zhao J, Qi D. Ataxia:an early indicator in high altitude cerebral edema. High Alt Med Biol.7:275-280.2006a.
Yang Y, Hahm E, Kim Y, Kang J, Lee W, Han I, Myung P, Kang H, Park H, Cho D. Regulation of IL-18 expression by CRH in mouse microglial cells. Immunol Lett.98:291-296.2005.
白海波,杜继曾.促肾上腺皮质激素释放因子介导低氧应激抑制淋巴细胞转化的实验研究.中国应用生理学杂志.11.1995.
白海波,杜继曾,贾红卫.低氧对大鼠体液免疫的抑制作用.生理学报167-172.1997.
杜宁,聂鸿靖,晋凌云,马燕,谢印芝.低氧致脑水肿的磁共振扩散加权成像和病理观察.航天医学与医学工程.18：415-418.2005.
徐建芬.持续低氧对中枢神经免疫的调节.博士论文.浙江杭州.浙江大学.56-58.2005.
Badaut J, Ashwal S, Tone B, Regli L, Tian HR, Obenaus A. Temporal and regional evolution of aquaporin-4 expression and magnetic resonance imaging in a rat pup model of neonatal stroke. Pediatr Res.62:248-254.2007.
Behan DP, Maciejewski D, Chalmers D, De Souza EB. Corticotropin releasing factor binding protein (CRF-BP) is expressed in neuronal and astrocytic cells. Brain Res.698:259-264.1995.
Bishop GA, Seelandt CM, King JS. Cellular localization of corticotropin releasing factor receptors in the adult mouse cerebellum. Neuroscience. 101:1083-1092.2000.
Blomstrand F, Giaume C, Hansson E, Ronnback L. Distinct pharmacological properties of ET-1 and ET-3 on astroglial gap junctions and Ca(2+) signaling. Am J Physiol. 277:C616-627.1999.
Castle NA Aquaporins as targets for drug discovery. Drug Discov Today. 10:485-493.2005.
Denker BM, Smith BL, Kuhajda FP, Agre P. Identification, purification, and partial characterization of a novel Mr 28,000 integral membrane protein from erythrocytes and renal tubules. J Biol Chem.263:15634-15642.1988.
Fabricio AS, Rae GA, Zampronio AR, D'Orleans-Juste P, Souza GE. Central endothelin ET(B) receptors mediate IL-1-dependent fever induced by preformed pyrogenic factor and corticotropin-releasing factor in the rat. Am J Physiol Regul Integr Comp Physiol.290:R164-171.2006.
Figueroa YG, Chan AK, Ibrahim R, Tang Y, Burow ME, Alam J, Scandurro AB, Beckman BS. NF-kappaB plays a key role in hypoxia-inducible factor-1-regulated erythropoietin gene expression. Exp Hematol. 30:1419-1427.2002.
Fu X, Li Q, Feng Z, Mu D The roles of aquaporin-4 in brain edema following neonatal hypoxia ischemia and reoxygenation in a cultured rat astrocyte model. Glia. 55:935-941.2007.
Gunnarson E, Zelenina M, Aperia A. Regulation of brain aquaporins. Neuroscience. 129:947-955.2004.
Ha BK, Bishop GA, King JS, Burry RW. Corticotropin releasing factor induces proliferation of cerebellar astrocytes. J Neurosci Res.62:789-798.2000.
He JJ, Chen XQ, Wang L, Xu JF, Du JZ. Corticotropin-releasing hormone receptor 1 coexists with endothelin-1 and modulates its mRNA expression and release in rat paraventricular nucleus during hypoxia. Neuroscience.152:1006-1014.2008.
Hillhouse EW, Grammatopoulos DK. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev.27:260-286.2006.
Ho MC, Lo AC, Kurihara H, Yu AC, Chung SS, Chung SK. Endothelin-1 protects astrocytes from hypoxic/ischemic injury. Faseb J.15:618-626.2001.
Ito H, Yamamoto N, Arima H, Hirate H, Morishima T, Umenishi F, Tada T, Asai K, Katsuya H, Sobue K. Interleukin-lbeta induces the expression of aquaporin-4 through a nuclear factor-kappaB pathway in rat astrocytes. J Neurochem. 99:107-118.2006.
Kanazawa F, Nakanishi K, Osada H, Kanamaru Y, Ohrui N, Uenoyama M, Masaki Y, Kanatani Y, Hiroi S, Tominaga S, Yakata-Suzuki A, Matsuyama S, Kawai T. Expression of endothelin-1 in the brain and lung of rats exposed to permanent hypobaric hypoxia. Brain Res.1036:145-154.2005.
Kapcala LP, Dicke JA. Brain corticotropin-releasing hormone receptors on neurons and astrocytes. Brain Res.589:143-148.1992.
King LS, Kozono D, Agre P. From structure to disease:the evolving tale of aquaporin biology. Nat Rev Mol Cell Biol.5:687-698.2004.
Lo AC, Chen AY, Hung VK, Yaw LP, Fung MK, Ho MC, Tsang MC, Chung SS, Chung SK. Endothelin-1 overexpression leads to further water accumulation and brain edema after middle cerebral artery occlusion via aquaporin 4 expression in astrocytic end-feet. J Cereb Blood Flow Metab.25:998-1011.2005.
MacCumber MW, Ross CA, Snyder SH. Endothelin in brain:receptors, mitogenesis, and biosynthesis in glial cells. Proc Natl Acad Sci U S A.87:2359-2363.1990.
Manley GT, Binder DK, Papadopoulos MC, Verkman AS. New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice. Neuroscience.129:983-991.2004.
Matsui H, Ihara Y, Fujio Y, Kunisada K, Akira S, Kishimoto T, Yamauchi-Takihara K. Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-kappa B and NF-IL6 in cardiac myocytes. Cardiovasc Res. 42:104-112.1999.
Morin C, Asselin C, Boudreau F, Provencher PH. Transcriptional regulation of pre-pro-endothelin-1 gene by glucocorticoids in vascular smooth muscle cells. Biochem Biophys Res Commun.244:583-587.1998.
Naidoo V, Naidoo S, Raidoo DM. Immunolocalisation of endothelin-1 in human brain. J Chem Neuroanat.27:193-200.2004.
Natarajan R, Fisher BJ, Jones DG. Reoxygenating microvascular endothelium exhibits temporal dissociation of NF-kappaB and AP-1 activation. Free Radic Biol Med. 32:1033-1045.2002.
Nicchia GP, Nico B, Camassa LM, Mola MG, Loh N, Dermietzel R, Spray DC, Svelto M, Frigeri A. The role of aquaporin-4 in the blood-brain barrier development and integrity:studies in animal and cell culture models. Neuroscience. 129:935-945.2004.
Petrov T, Steiner J, Braun B, Rafols JA. Sources of endothelin-1 in hippocampus and cortex following traumatic brain injury. Neuroscience.115:275-283.2002.
Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1 alpha. Nature. 453:807-811.2008.
Stevens SL, Shaw TE, Dykhuizen E, Lessov NS, Hill JK, Wurst W, Stenzel-Poore MP. Reduced cerebral injury in CRH-R1 deficient mice after focal ischemia:a potential link to microglia and atrocytes that express CRH-R1. J Cereb Blood Flow Metab.23:1151-1159.2003.
Tait MJ, Saadoun S, Bell BA, Papadopoulos MC. Water movements in the brain:role of aquaporins. Trends Neurosci.31:37-43.2008.
Takuma K, Matsuda T, Yoshikawa T, Kitanaka J, Gotoh M, Hayata K, Baba A. Corticotropin-releasing factor stimulates Ca2+ influx in cultured rat astrocytes. Biochem Biophys Res Commun.199:1103-1107.1994.
Taniguchi M, Yamashita T, Kumura E, Tamatani M, Kobayashi A, Yokawa T, Maruno M, Kato A, Ohnishi T, Kohmura E, Tohyama M, Yoshimine T. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Brain Res. 78:131-137.2000.
Ting AY, Endy D. Signal transduction. Decoding NF-kappaB signaling. Science. 298:1189-1190.2002.
Verkman AS. More than just water channels:unexpected cellular roles of aquaporins. J Cell Sci.118:3225-3232.2005.
Verkman AS, Binder DK, Bloch O, Auguste K, Papadopoulos MC. Three distinct roles of aquaporin-4 in brain function revealed by knockout mice. Biochim Biophys Acta 1758:1085-1093.2006.
Wells T. Vesicular osmometers, vasopression secretion and aquaporin-4:a new mechanism for osmoreception? Mol Cell Endocrinol.136:103-107.1998.
Wilbert-Lampen U, Trapp A, Modrzik M, Fiedler B, Straube F, Plasse A. Effects of corticotropin-releasing hormone (CRH) on endothelin-1 and NO release, mediated by CRH receptor subtype R2:a potential link between stress and endothelial dysfunction? J Psychosom Res.61:453-460.2006.
Yang Y, Hahm E, Kim Y, Kang J, Lee W, Han I, Myung P, Kang H, Park H, Cho D. Regulation of IL-18 expression by CRH in mouse microglial cells. Immunol Lett.98:291-296.2005.
徐建芬.低氧对中枢神经免疫的调节.博士论文.浙江杭州.浙江大学：54-63.2005.
Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci.4:991-1001.2003.
Azenabor AA, Hoffman-Goetz L. Effect of exhaustive exercise on membrane estradiol concentration, intracellular calcium, and oxidative damage in mouse thymic lymphocytes. Free Radic Biol Med.28:84-90.2000.
Behan DP, Maciejewski D, Chalmers D, De Souza EB. Corticotropin releasing factor binding protein (CRF-BP) is expressed in neuronal and astrocytic cells. Brain Res.698:259-264.1995.
Bishop GA, Seelandt CM, King JS. Cellular localization of corticotropin releasing factor receptors in the adult mouse cerebellum. Neuroscience. 101:1083-1092.2000.
Carmosino M, Procino G, Tamma G, Mannucci R, Svelto M, Valenti G. Trafficking and phosphorylation dynamics of AQP4 in histamine-treated human gastric cells. Biol Cell.99:25-36.2007.
Dautzenberg FM, Hauger RL. The CRF peptide family and their receptors:yet more partners discovered. Trends Pharmacol Sci.23:71-77.2002.
Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol.28:138-145.2007.
Fu X, Li Q, Feng Z, Mu D. The roles of aquaporin-4 in brain edema following neonatal hypoxia ischemia and reoxygenation in a cultured rat astrocyte model. Glia. 55:935-941.2007.
Fujita Y, Yamamoto N, Sobue K, Inagaki M, Ito H, Arima H, Morishima T, Takeuchi A, Tsuda T, Katsuya H, Asai K. Effect of mild hypothermia on the expression of aquaporin family in cultured rat astrocytes under hypoxic condition. Neurosci Res.47:437-444.2003.
Gunnarson E, Song YT, Kowalewski JM, Brismar H, Brines M, Cerami A, Andersson U, Zelenina M, Aperia A. Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection. Proc Natl Acad Sci U S A. 106:1602-1607.2009.
Gunnarson E, Zelenina M, Aperia A. Regulation of brain aquaporins. Neuroscience. 129:947-955.2004.
Gunnarson E, Zelenina M, Axehult G, Song YT, Bondar A, Krieger P, Brismar H, Zelenin S, Aperia A. Identification of a molecular target for glutamate regulation of astrocyte water permeability. Glia.56:587-596.2008.
Hackett PH, Roach RC. High altitude cerebral edema. High Alt Med Biol. 5:136-146.2004.
Han Z, Wax MB, Patil RV. Regulation of aquaporin-4 water channels by phorbol ester-dependent protein phosphorylation. J Biol Chem.273:6001-6004.1998.
Hillhouse EW, Grammatopoulos DK. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev.27:260-286.2006.
Justice NJ, Yuan ZF, Sawchenko PE, Vale W. Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice:implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J Comp Neurol.511:479-496.2008.
Kaur C, Sivakumar V, Zhang Y, Ling EA. Hypoxia-induced astrocytic reaction and increased vascular permeability in the rat cerebellum. Glia.54:826-839.2006.
Nicchia GP, Rossi A, Mola MG, Procino G, Frigeri A, Svelto M. Actin cytoskeleton remodeling governs aquaporin-4 localization in astrocytes. Glia. 56:1755-1766.2008.
Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP. Specialized membrane domains for water transport in glial cells:high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci. 17:171-180.1997.
Petrovic MM, Vales K, Stojan G, Basta-Jovanovic G, Mitrovic DM. Regulation of selectivity and translocation of aquaporins:an update. Folia Biol. 52:173-180.2006.
Seifert G, Schilling K, Steinhauser C. Astrocyte dysfunction in neurological disorders:a molecular perspective. Nat Rev Neurosci.7:194-206.2006.
Stevens SL, Shaw TE, Dykhuizen E, Lessov NS, Hill JK, Wurst W, Stenzel-Poore MP. Reduced cerebral injury in CRH-R1 deficient mice after focal ischemia:a potential link to microglia and atrocytes that express CRH-R1. J Cereb Blood Flow Metab.23:1151-1159.2003.
Tait MJ, Saadoun S, Bell BA, Papadopoulos MC. Water movements in the brain:role of aquaporins. Trends Neurosci.31:37-43.2008.
Verkman AS. More than just water channels:unexpected cellular roles of aquaporins. J Cell Sci.118:3225-3232.2005.
Verkman AS. Aquaporins:translating bench research to human disease. J Exp Biol. 212:1707-1715.2009.
Yamamoto N, Sobue K, Fujita M, Katsuya H, Asai K. Differential regulation of aquaporin-5 and-9 expression in astrocytes by protein kinase A. Brain Res Mol Brain Res.104:96-102.2002.
Yamamoto N, Sobue K, Miyachi T, Inagaki M, Miura Y, Katsuya H, Asai K. Differential regulation of aquaporin expression in astrocytes by protein kinase C. Brain Res Mol Brain Res.95:110-116.2001.
Yukutake Y, Yasui M. Regulation of water permeability through aquaporin-4. Neuroscience.2009. Oct 20.
Zelenina M, Brismar H. Osmotic water permeability measurements using confocal laser scanning microscopy. Eur Biophys J.29:165-171.2000.
Zelenina M, Zelenin S, Bondar AA, Brismar H, Aperia A. Water permeability of aquaporin-4 is decreased by protein kinase C and dopamine. Am J Physiol Renal Physiol.283:F309-318.2002.
Aaronson PI, Robertson TP, Ward JP. Endothelium-derived mediators and hypoxic pulmonary vasoconstriction. Respir Physiol Neurobiol.132:107-120.2002.
Agorreta J, Garayoa M, Montuenga LM, Zulueta JJ. Effects of acute hypoxia and lipopolysaccharide on nitric oxide synthase-2 expression in acute lung injury. Am J Respir Crit Care Med.168:287-296.2003.
Anand IS, Prasad BA, Chugh SS, Rao KR, Cornfield DN, Milla CE, Singh N, Singh S, Selvamurthy W. Effects of inhaled nitric oxide and oxygen in high-altitude pulmonary edema. Circulation.98:2441-2445.1998.
Bartsch P, Mairbaurl H, Maggiorini M, Swenson ER. Physiological aspects of high-altitude pulmonary edema. J Appl Physiol.98:1101-1110.2005.
Basnyat B. High altitude cerebral and pulmonary edema. Travel medicine and infectious disease 3:199-211.2005a.
Basnyat B. The physiologic basis of high-altitude diseases. Ann Intern Med.16: 789-800.2005b.
Berger MM, Hesse C, Dehnert C, Siedler H, Kleinbongard P, Bardenheuer HJ, Kelm M, Bartsch P, Haefeli WE. Hypoxia impairs systemic endothelial function in individuals prone to high-altitude pulmonary edema. Am J Respir Crit Care Med. 172:763-767.2005.
Berger MM, Rozendal CS, Schieber C, Dehler M, Zugel S, Bardenheuer HJ, Bartsch P, Mairbaurl H. The effect of endothelin-1 on alveolar fluid clearance and pulmonary edema formation in the rat. Anesth Analg.108:225-231.2009.
Busch T, Bartsch P, Pappert D, Grunig E, Hildebrandt W, Elser H, Falke KJ, Swenson ER. Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high-altitude pulmonary edema. Am J Respir Crit Care Med.163:368-373.2001.
Calza L, Giardino L, Pozza M, Micera A, Aloe L. Time-course changes of nerve growth factor, corticotropin-releasing hormone, and nitric oxide synthase isoforms and their possible role in the development of inflammatory response in experimental allergic encephalomyelitis. Proc Natl Acad Sci U S A.94:3368-3373.1997.
Chan YC, Yao XQ, Lau CW, Chan FL, He GW, Bourreau JP, Huang Y. The relaxant effect of urocortin in rat pulmonary arteries. Regul Pept.121:11-18.2004.
Chen SJ, Chen YF, Opgenorth TJ, Wessale JL, Meng QC, Durand J, DiCarlo VS, Oparil S. The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Sprague-Dawley rats. J Cardiovasc Pharmacol. 29:713-725.1997.
Daniliuc S, Bitterman H, Rahat MA, Kinarty A, Rosenzweig D, Lahat N. Hypoxia inactivates inducible nitric oxide synthase in mouse macrophages by disrupting its interaction with alpha-actinin 4. J Immunol.171:3225-3232.2003.
Dieterich KD, Grigoriadis DE, De Souza EB. Corticotropin-releasing factor receptors in human small cell lung carcinoma cells:radioligand binding, second messenger, and northern blot analysis data. Endocrinology.135:1551-1558.1994.
Duplain H, Sartori C, Lepori M, Egli M, Allemann Y, Nicod P, Scherrer U. Exhaled nitric oxide in high-altitude pulmonary edema:role in the regulation of pulmonary vascular tone and evidence for a role against inflammation. Am J Respir Crit Care Med.162:221-224.2000.
Figueroa YG, Chan AK, Ibrahim R, Tang Y, Burow ME, Alam J, Scandurro AB, Beckman BS. NF-kappaB plays a key role in hypoxia-inducible factor-1-regulated erythropoietin gene expression. Exp Hematol. 30:1419-1427.2002.
Goldie RG Endothelin receptor subtypes:distribution and function in the lung. Pulm Pharmacol Ther.11:89-95.1998.
Hackett PH, Roach RC. High-altitude illness. N Engl J Med.345:107-114.2001.
He JJ, Chen XQ, Wang L, Xu JF, Du JZ. Corticotropin-releasing hormone receptor 1 coexists with endothelin-1 and modulates its mRNA expression and release in rat paraventricular nucleus during hypoxia. Neuroscience.152:1006-1014.2008.
Hehl A, Richon J, Ravussin P. Altitude diseases:acute mountain disease, pulmonary edema, and high altitude cerebral edema. Rev Med Suisse Romande. 123:703-707.2003.
Hultgren HN. High-altitude pulmonary edema:current concepts. Annu Rev Med. 47:267-284.1996.
Hultgren HN, Lopez CE, Lundberg E, Miller H. Physiologic Studies of Pulmonary Edema at High Altitude. Circulation 29:393-408.1964.
Jain V, Vedernikov YP, Saade GR, Chwalisz K, Garfield RE. Endothelium-dependent and-independent mechanisms of vasorelaxation by corticotropin-releasing factor in pregnant rat uterine artery. J Pharmacol Exp Ther.288:407-413.1999.
Kolluru GK, Tamilarasan KP, Rajkumar AS, Geetha Priya S, Rajaram M, Saleem NK, Majumder S, Jaffar Ali BM, Illavazagan G, Chatterjee S. Nitric oxide/cGMP protects endothelial cells from hypoxia-mediated leakiness. Eur J Cell Biol. 87:147-161.2008.
Li H, Elton TS, Chen YF, Oparil S. Increased endothelin receptor gene expression in hypoxic rat lung. Am J Physiol.266:L553-560.1994.
Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, Sofi F, Savia G, Mancia G, Gensini GF, Parati G. Role of endothelin-1 in exposure to high altitude:Acute Mountain Sickness and Endothelin-1 (ACME-1) study. Circulation.114:1410-1416.2006.
Moffatt JD, Lever R, Page CP. Activation of corticotropin-releasing factor receptor-2 causes bronchorelaxation and inhibits pulmonary inflammation in mice. Faseb J. 20:1877-1879.2006.
Moudgil R, Michelakis ED, Archer SL. Hypoxic pulmonary vasoconstriction. J Appl Physiol.98:390-403.2005.
Ohinata A, Nagai K, Nomura J, Hashimoto K, Hisatsune A, Miyata T, Isohama Y. Lipopolysaccharide changes the subcellular distribution of aquaporin 5 and increases plasma membrane water permeability in mouse lung epithelial cells. Biochem Biophys Res Commun.326:521-526.2005.
Omura A, Roy R, Jennings T. Inhaled nitric oxide improves survival in the rat model of high-altitude pulmonary edema. Wilderness Environ Med.11:251-256.2000.
Phelan MW, Faller DV. Hypoxia decreases constitutive nitric oxide synthase transcript and protein in cultured endothelial cells. J Cell Physiol.167:469-476.1996.
Rademarker MT, Charles CJ, Espiner EA, Frampton CM, Lainchbury JG, Richards AM. Endogenous urocortins reduce vascular tone and renin-aldosterone/endothelin activity in experimental heart failure. Eur Heart J.26:2046-2054.2006.
Ralph JA, Zocco D, Bresnihan B, FitzGerald O, McEVoy AN, Murphy EP. A role for type la corticotropin releasing hormone receptors in mediating local changes in chronically inflamed tissue. Am J Pathol.170:1121-1133.2007.
Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1 alpha. Nature. 453:807-811.2008.
Rodman DM, Stelzner TJ, Zamora MR, Bonvallet ST, Oka M, Sato K, O'Brien RF, McMurtry IF. Endothelin-1 increases the pulmonary micro vascular pressure and causes pulmonary edema in salt solution but not blood-perfused rat lungs. J Cardiovasc Pharmacol.20:658-663.1992.
Sarada S, Himadri P, Mishra C, Geetali P, Ram MS, Ilavazhagan G. Role of oxidative stress and NFkB in hypoxia-induced pulmonary edema. Exp Biol Med (Maywood).233:1088-1098.2008.
Scherrer U, Vollenweider L, Delabays A, Savcic M, Eichenberger U, Kleger GR, Fikrle A, Ballmer PE, Nicod P, Bartsch P. Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med.334:624-629.1996.
Serda SM, Wei ET. Epinephrine-induced pulmonary oedema in rats is inhibited by corticotropin-releasing factor. Pharmacol Res.26:85-91.1992.
Shimoda LA, Sham JS, Liu Q, Sylvester JT. Acute and chronic hypoxic pulmonary vasoconstriction:a central role for endothelin-1? Respir Physiol Neurobiol. 132:93-106.2002.
Sidhaye VK, Schweitzer KS, Caterina MJ, Shimoda L, King LS. Shear stress regulates aquaporin-5 and airway epithelial barrier function. Proc Natl Acad Sci U S A. 105:3345-3350.2008.
Smith EM, Gregg M, Hashemi F, Schott L, Hughes TK. Corticotropin releasing factor (CRF) activation of NF-κB-directed transcription in leukocytes. Cell Mol Neurobiol.26:1021-1036.2006.
Smith GW, Aubry JM, Delhi F, Contarino A, Bilezikjian LM, Gold LH, Chen R, Marchuk Y, Hauser C, Bentley CA, Sawchenko PE, Koob GF, Vale W, Lee KF. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20:1093-1102.1998.
Soon Lee, Rivier C. Role played by hypothalamic nuclear factor-KB in alcohol-mediated activation of the rat hypothalamic-pituitary-adrenal axis. Endocrinology.146:2006-2014.2005.
Stelzner TJ, O'Brien RF, Sato K, Weil JV. Hypoxia-induced increases in pulmonary transvascular protein escape in rats. Modulation by glucocorticoids. J Clin Invest. 82:1840-1847.1988.
Swenson ER, Maggiorini M, Mongovin S, Gibbs JS, Greve I, Mairbaurl H, Bartsch P. Pathogenesis of high-altitude pulmonary edema:inflammation is not an etiologic factor. JAMA.287:2228-2235.2002.
Ting AY, Endy D. Signal transduction. Decoding NF-kappaB signaling. Science. 298:1189-1190.2002.
Ward ME, Toporsian M, Scott JA, Teoh H, Govindaraju V, Quan A, Wener AD, Wang G, Bevan SC, Newton DC, Marsden PA. Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant. J Clin Invest. 115:3128-3139.2005.
West JB, Colice GL, Lee YJ, Namba Y, Kurdak SS, Fu Z, Ou LC, Mathieu-Costello O. Pathogenesis of high-altitude pulmonary oedema:direct evidence of stress failure of pulmonary capillaries. Eur Respir J.8:523-529.1995.
Wu TY, Ding SQ, Liu JL, Yu MT, Jia JH, Chai ZC, Dai RC, Zhang SL, Li BY, Pan L, Liang BZ, Zhao JZ, Qi de T, Sun YF, Kayser B. Who should not go high: chronic disease and work at altitude during construction of the Qinghai-Tibet railroad. High Alt Med Biol.8:88-107.2007.
Wu Y, Xu Y, Zhou H, Tao J, Li S. Expression of urocortin in rat lung and its effect on pulmonary vascular permeability. J Endocrinol.189:167-178.2006.
Xu JF, Chen XQ, Du JZ, Wang TY. CRF receptor type 1 mediates continual hypoxia-induced CRF peptide and CRF mRNA expression increase in hypothalamic PVN of rats. Peptides.26:639-646.2005.
Aaronson PI, Robertson TP, Ward JP. Endothelium-derived mediators and hypoxic pulmonary vasoconstriction. Respir Physiol Neurobiol.132:107-120.2002.
Abbott N. Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat 200:527.2002.
Ahsan A, Mohd G, Norboo T, Baig MA, Pasha MA. Heterozygotes of NOS3 polymorphisms contribute to reduced nitrogen oxides in high-altitude pulmonary edema. Chest.130:1511-1519.2006.
Ainslie PN, Barach A, Murrell C, Hamlin M, Hellemans J, Ogoh S. Alterations in cerebral autoregulation and cerebral blood flow velocity during acute hypoxia: rest and exercise. Am J Physiol Heart Circ Physiol.292:H976-983.2007.
Ainslie PN, Ogoh S, Burgess K, Celi L, McGrattan K, Peebles K, Murrell C, Subedi P, Burgess KR. Differential effects of acute hypoxia and high altitude on cerebral blood flow velocity and dynamic cerebral autoregulation:alterations with hyperoxia. J Appl Physiol.104:490-498.2008.
Alexander AL, Lee JE, Lazar M, Field AS. Diffusion tensor imaging of the brain. Neurotherapeutics.4:316-329.2007.
Amiry-Moghaddam M, Frydenlund DS, Ottersen OP. Anchoring of aquaporin-4 in brain: molecular mechanisms and implications for the physiology and pathophysiology of water transport. Neuroscience.129:999-1010.2004.
Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci.4:991-1001.2003.
Anand IS, Prasad BA, Chugh SS, Rao KR, Cornfield DN, Milla CE, Singh N, Singh S, Selvamurthy W. Effects of inhaled nitric oxide and oxygen in high-altitude pulmonary edema. Circulation.98:2441-2445.1998.
Badaut J, Petit JM, Brunet JF, Magistretti PJ, Charriaut-Marlangue C, Regli L. Distribution of Aquaporin 9 in the adult rat brain:preferential expression in catecholaminergic neurons and in glial cells. Neuroscience.128:27-38.2004.
Bailey DM, Evans KA, James PE, McEneny J, Young IS, Fall L, Gutowski M, Kewley E, McCord JM, Moller K, Ainslie PN. Altered free radical metabolism in acute mountain sickness:implications for dynamic cerebral autoregulation and blood-brain barrier function. J Physiol.587:73-85.2009a.
Bailey DM, Kleger GR, Holzgraefe M, Ballmer PE, Bartsch P. Pathophysiological significance of peroxidative stress, neuronal damage, and membrane permeability in acute mountain sickness. J Appl Physiol.96:1459-1463.2004.
Bailey DM, Taudorf S, Berg RM, Lundby C, McEneny J, Young IS, Evans KA, James PE, Shore A, Hullin DA, McCord JM, Pedersen BK, Moller K. Increased cerebral output of free radicals during hypoxia:implications for acute mountain sickness? Am J Physiol Regul Integr Comp Physiol.297:R1283-1292.2009b.
Ballabh P, Braun A, Nedergaard M. The blood-brain barrier:an overview:structure, regulation, and clinical implications. Neurobiol Dis.16:1-13.2004.
Basnyat B. High altitude cerebral and pulmonary edema. Travel Med Infect Dis. 3:199-211.2005.
Basnyat B, Murdoch DR. High-altitude illness. Lancet.361:1967-1974.2003.
Baumgartner RW, Spyridopoulos I, Bartsch P, Maggiorini M, Oelz O. Acute mountain sickness is not related to cerebral blood flow:a decompression chamber study. J Appl Physiol.86:1578-1582.1999.
Benfenati V, Nicchia GP, Svelto M, Rapisarda C, Frigeri A, Ferroni S. Functional down-regulation of volume-regulated anion channels in AQP4 knockdown cultured rat cortical astrocytes. J Neurochem.100:87-104.2007.
Berger MM, Hesse C, Dehnert C, Siedler H, Kleinbongard P, Bardenheuer HJ, Kelm M, Bartsch P, Haefeli WE. Hypoxia impairs systemic endothelial function in individuals prone to high-altitude pulmonary edema. Am J Respir Crit Care Med. 172:763-767.2005.
Boulard G, Marguinaud E, Sesay M. Osmotic cerebral oedema:the role of plasma osmolarity and blood brain barrier. Ann Fr Anesth Reanim.22:215-219.2003.
Busch T, Bartsch P, Pappert D, Grunig E, Hildebrandt W, Elser H, Falke KJ, Swenson ER. Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high-altitude pulmonary edema. Am J Respir Crit Care Med.163:368-373.2001.
Castle NA. Aquaporins as targets for drug discovery. Drug Discov Today. 10:485-493.2005.
Chan H, Butterworth RF, Hazell AS. Primary cultures of rat astrocytes respond to thiamine deficiency-induced swelling by downregulating aquaporin-4 levels. Neurosci Lett.366:231-234.2004.
Dada LA, Chandel NS, Ridge KM, Pedemonte C, Bertorello AM, Sznajder JI. Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-zeta. J Clin Invest. 111:1057-1064.2003.
Dada LA, Sznajder JI. Hypoxic inhibition of alveolar fluid reabsorption. Adv Exp Med Biol.618:159-168.2007.
Dehnert C, Berger MM, Mairbaurl H, Bartsch P. High altitude pulmonary edema:a pressure-induced leak. Respir Physiol Neurobiol.158:266-273.2007.
Dellasanta P, Gaillard S, Loutan L, Kayser B. Comparing questionnaires for the assessment of acute mountain sickness. High Alt Med Biol.8:184-191.2007.
Denker BM, Smith BL, Kuhajda FP, Agre P. Identification, purification, and partial characterization of a novel Mr 28,000 integral membrane protein from erythrocytes and renal tubules. J Biol Chem.263:15634-15642.1988.
Dubowitz DJ, Dyer EA, Theilmann RJ, Buxton RB, Hopkins SR. Early brain swelling in acute hypoxia. J Appl Physiol 107:244-252.2009.
Duplain H, Sartori C, Lepori M, Egli M, Allemann Y, Nicod P, Scherrer U. Exhaled nitric oxide in high-altitude pulmonary edema:role in the regulation of pulmonary vascular tone and evidence for a role against inflammation. Am J Respir Crit Care Med.162:221-224.2000.
Dyer EA, Hopkins SR, Perthen JE, Buxton RB, Dubowitz DJ. Regional cerebral blood flow during acute hypoxia in individuals susceptible to acute mountain sickness. Respir Physiol Neurobiol.160:267-276.2008.
Echevarria M, Munoz-Cabello AM, Sanchez-Silva R, Toledo-Aral JJ, Lopez-Barneo J. Development of cytosolic hypoxia and hypoxia-inducible factor stabilization are facilitated by aquaporin-1 expression. J Biol Chem.282:30207-30215.2007.
Fagenholz PJ, Gutman JA, Murray AF, Noble VE, Camargo CA, Jr., Harris NS. Evidence for increased intracranial pressure in high altitude pulmonary edema. High Alt Med Biol.8:331-336.2007.
Firth PG, Zheng H, Windsor JS, Sutherland AI, Imray CH, Moore GW, Semple JL, Roach RC, Salisbury RA. Mortality on Mount Everest,1921-2006:descriptive study. BMJ.337:a2654.2008.
Fischer R, Vollmar C, Thiere M, Born C, Leitl M, Pfluger T, Huber RM. No evidence of cerebral oedema in severe acute mountain sickness. Cephalalgia.24:66-71.2004.
Fischer S, Renz D, Schaper W, Karliczek GF. Barbiturates decrease the expression of vascular endothelial growth factor in hypoxic cultures of porcine brain derived microvascular endothelial cells. Brain Res Mol Brain Res.60:89-97.1998.
Fu X, Li Q, Feng Z, Mu D. The roles of aquaporin-4 in brain edema following neonatal hypoxia ischemia and reoxygenation in a cultured rat astrocyte model. Glia. 55:935-941.2007.
Gass A, Niendorf T, Hirsch JG. Acute and chronic changes of the apparent diffusion coefficient in neurological disorders—biophysical mechanisms and possible underlying histopathology. J Neurol Sci.186 Suppll:S15-23.2001.
Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest. 115:500-508.2005.
Gunnarson E, Song YT, Kowalewski JM, Brismar H, Brines M, Cerami A, Andersson U, Zelenina M, Aperia A. Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection. Proc Natl Acad Sci U S A. 106:1602-1607.2009.
Gunnarson E, Zelenina M, Aperia A. Regulation of brain aquaporins. Neuroscience. 129:947-955.2004.
Gunnarson E, Zelenina M, Axehult G, Song YT, Bondar A, Krieger P, Brismar H, Zelenin S, Aperia A. Identification of a molecular target for glutamate regulation of astrocyte water permeability. Glia.56:587-596.2008.
Guo Q, Sayeed I, Baronne LM, Hoffman SW, Guennoun R, Stein DG. Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats. Exp Neurol.198:469-478.2006.
Hackett PH, Roach RC. High-altitude illness. N Engl J Med.345:107-114.2001.
Hackett PH, Roach RC. High altitude cerebral edema. High Alt Med Biol. 5:136-146.2004.
Hackett PH, Yarnell PR, Hill R, Reynard K, Heit J, McCormick J. High-altitude cerebral edema evaluated with magnetic resonance imaging:clinical correlation and pathophysiology. JAMA 280:1920-1925.1998.
Han Z, Wax MB, Patil RV. Regulation of aquaporin-4 water channels by phorbol ester-dependent protein phosphorylation. J Biol Chem.273:6001-6004.1998.
Hanaoka M, Droma Y, Ota M, Ito M, Katsuyama Y, Kubo K. Polymorphisms of human vascular endothelial growth factor gene in high-altitude pulmonary oedema susceptible subjects. Respirology.14:46-52.2009.
Haussinger D, Schliess F. Pathogenetic mechanisms of hepatic encephalopathy. Gut. 57:1156-1165.2008.
Ho JD, Yeh R, Sandstrom A, Chorny I, Harries WE, Robbins RA, Miercke LJ, Stroud RM. Crystal structure of human aquaporin 4 at 1.8 A and its mechanism of conductance. Proc Natl Acad Sci U S A 106:7437-7442.2009.
Hultgren HN. High-altitude pulmonary edema:current concepts. Annu Rev Med. 47:267-284.1996.
Jansen GF, Krins A, Basnyat B, Bosch A, Odoom JA. Cerebral autoregulation in subjects adapted and not adapted to high altitude. Stroke.31:2314-2318.2000.
Johnson W, Nohria A, Garrett L, Fang JC, Igo J, Katai M, Ganz P, Creager MA. Contribution of endothelin to pulmonary vascular tone under normoxic and hypoxic conditions. Am J Physiol Heart Circ Physiol.283:H568-575.2002.
Kallenberg K, Bailey DM, Christ S, Mohr A, Roukens R, Menold E, Steiner T, Bartsch P, Knauth M. Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness. J Cereb Blood Flow Metab.27:1064-1071.2007.
Kallenberg K, Dehnert C, Dorfler A, Schellinger PD, Bailey DM, Knauth M, Bartsch PD. Microhemorrhages in nonfatal high-altitude cerebral edema. J Cereb Blood Flow Metab.28:1635-1642.2008.
Kaminsky DA, Jones K, Schoene RB, Voelkel NF. Urinary leukotriene E4 levels in high-altitude pulmonary edema. A possible role for inflammation. Chest. 110:939-945.1996.
Kaur C, Sivakumar V, Yong Z, Lu J, Foulds W, Ling E. Blood-retinal barrier disruption and ultrastructural changes in the hypoxic retina in adult rats:the beneficial effect of melatonin administration. J Pathol.212:429-439.2007.
Kaur C, Sivakumar V, Zhang Y, Ling EA. Hypoxia-induced astrocytic reaction and increased vascular permeability in the rat cerebellum. Glia.54:826-839.2006.
Kawedia JD, Nieman ML, Boivin GP, Melvin JE, Kikuchi K, Hand AR, Lorenz JN, Menon AG. Interaction between transcellular and paracellular water transport pathways through Aquaporin 5 and the tight junction complex. Proc Natl Acad Sci U S A.104:3621-3626.2007.
Ke C, Poon WS, Ng HK, Lai FM, Tang NL, Pang JC. Impact of experimental acute hyponatremia on severe traumatic brain injury in rats:influences on injuries, permeability of blood-brain barrier, ultrastructural features, and aquaporin-4 expression. Exp Neurol.178:194-206.2002.
Ke C, Poon WS, Ng HK, Pang JC, Chan Y. Heterogeneous responses of aquaporin-4 in oedema formation in a replicated severe traumatic brain injury model in rats. Neurosci Lett.301:21-24.2001.
Kiening KL, van Landeghem FK, Schreiber S, Thomale UW, von Deimling A, Unterberg AW, Stover JF. Decreased hemispheric Aquaporin-4 is linked to evolving brain edema following controlled cortical impact injury in rats. Neurosci Lett.324:105-108.2002.
Kimelberg HK. Current concepts of brain edema. Review of laboratory investigations. J Neurosurg.83:1051-1059.1995.
King LS, Kozono D, Agre P. From structure to disease:the evolving tale of aquaporin biology. Nat Rev Mol Cell Biol.5:687-698.2004.
Klatzo I. Pathophysiological aspects of brain edema. Acta Neuropathol (Berl). 72:236-239.1987.
Kolluru GK, Tamilarasan KP, Rajkumar AS, Geetha Priya S, Rajaram M, Saleem NK, Majumder S, Jaffar Ali BM, Illavazagan G, Chatterjee S. Nitric oxide/cGMP protects endothelial cells from hypoxia-mediated leakiness. Eur J Cell Biol. 87:147-161.2008.
Krane CM, Fortner CN, Hand AR, McGraw DW, Lorenz JN, Wert SE, Towne JE, Paul RJ, Whitsett JA, Menon AG. Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation. Proc Natl Acad Sci U S A. 98:14114-14119.2001.
Lal H, Yu Q, Ivor Williams K, Woodward B. Hypoxia augments conversion of big-endothelin-1 and endothelin ET(B) receptor-mediated actions in rat lungs. Eur J Pharmacol.402:101-110.2000.
Leshem E, Pandey P, Shlim DR, Hiramatsu K, Sidi Y, Schwartz E. Clinical features of patients with severe altitude illness in Nepal. J Travel Med.15:315-322.2008.
Li H, Elton TS, Chen YF, Oparil S. Increased endothelin receptor gene expression in hypoxic rat lung. Am J Physiol.266:L553-560.1994.
Lorenzo VF, Yang Y, Simonson TS, Nussenzveig R, Jorde LB, Prchal JT, Ge RL. Genetic adaptation to extreme hypoxia:study of high-altitude pulmonary edema in a three-generation Han Chinese family. Blood Cells Mol Dis. 43:221-225.2009.
Ma T, Fukuda N, Song Y, Matthay MA, Verkman AS. Lung fluid transport in aquaporin-5 knockout mice. J Clin Invest.105:93-100.2000.
Maignan M, Rivera-Ch M, Privat C, Leon-Velarde F, Richalet JP, Pham I. Pulmonary pressure and cardiac function in chronic mountain sickness patients. Chest. 135:499-504.2009.
Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med.6:159-163.2000.
Mao X, Enno TL, Del Bigio MR. Aquaporin 4 changes in rat brain with severe hydrocephalus. Eur J Neurosci.23:2929-2936.2006.
Mark KS, Davis TP. Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation. Am J Physiol.282:H1485-1494.2002.
Mascalchi M, Filippi M, Floris R, Fonda C, Gasparotti R, Villari N. Diffusion-weighted MR of the brain:methodology and clinical application. Radiol Med. 109:155-197.2005.
Mazzuero G, Mazzuero A, Pascariello A. Severe acute mountain sickness and suspect high altitude cerebral edema related to nitroglycerin use. High Alt Med Biol. 9:241-243.2008.
Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol. 164:1875-1882.2004.
Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, Sofi F, Savia G, Mancia G, Gensini GF, Parati G. Role of endothelin-1 in exposure to high altitude:Acute Mountain Sickness and Endothelin-1 (ACME-1) study. Circulation.114:1410-1416.2006.
Nagai K, Watanabe M, Seto M, Hisatsune A, Miyata T, Isohama Y. Nitric oxide decreases cell surface expression of aquaporin-5 and membrane water permeability in lung epithelial cells. Biochem Biophys Res Commun. 354:579-584.2007.
Neely JD, Moghaddam MA, Ottersen OP. Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein. Proc Natl Acad Sci U S A 98:14108-14113.2001.
Nicchia GP, Nico B, Camassa LM, Mola MG, Loh N, Dermietzel R, Spray DC, Svelto M, Frigeri A. The role of aquaporin-4 in the blood-brain barrier development and integrity:studies in animal and cell culture models. Neuroscience 129:935-945.2004.
Nielsen S, Nagelhus EA, Moghaddam MA. Specialized Membrane Domains for Water Transport in Glial Cells:High-Resolution Immunogold Cytochemistry of Aquaporin-4 in Rat Brain. J Neurosci.17:171-180.1997.
Ohinata A, Nagai K, Nomura J, Hashimoto K, Hisatsune A, Miyata T, Isohama Y. Lipopolysaccharide changes the subcellular distribution of aquaporin 5 and increases plasma membrane water permeability in mouse lung epithelial cells. Biochem Biophys Res Commun.326:521-526.2005.
Omura A, Roy R, Jennings T. Inhaled nitric oxide improves survival in the rat model of high-altitude pulmonary edema. Wilderness Environ Med.11:251-256.2000.
Panesar NS. High altitude sickness. Is acute cortisol deficiency involved in its pathophysiology? Med Hypotheses.63:507-510.2004.
Papadopoulos MC, Verkman AS. Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis. J Biol Chem. 280:13906-13912.2005.
Papandreou I, Powell A, Lim AL, Denko N. Cellular reaction to hypoxia:sensing and responding to an adverse environment. Mutat Res.569:87-100.2005.
Rodman DM, Stelzner TJ, Zamora MR, Bonvallet ST, Oka M, Sato K, Obrien RF, Mcmurtry IF. Endothelin-1 Increases the Pulmonary Microvascular Pressure and Causes Pulmonary-Edema in Salt Solution but Not Blood-Perfused Rat Lungs. J Cardiovasc Pharmacol.20:658-663.1992.
Rosenblum WI. Cytotoxic edema:monitoring its magnitude and contribution to brain swelling. J Neuropathol Exp Neurol.66:771-778.2007.
Saadoun S, Bell BA, Verkman AS, Papadopoulos MC. Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice. Brain. 131:1087-1098.2008.
Saadoun S, Papadopoulos MC, Davies DC, Krishna S, Bell BA. Aquaporin-4 expression is increased in oedematous human brain tumours. J Neurol Neurosurg Psychiatry.72:262-265.2002.
Sarada S, Himadri P, Mishra C, Geetali P, Ram MS, Ilavazhagan G. Role of oxidative stress and NFkB in hypoxia-induced pulmonary edema. Exp Biol Med. 233:1088-1098.2008.
Scherrer U, Vollenweider L, Delabays A, Savcic M, Eichenberger U, Kleger GR, Fikrle A, Ballmer PE, Nicod P, Bartsch P. Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med.334:624-629.1996.
Schoch HJ, Fischer S, Marti HH. Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain.125:2549-2557.2002.
Schoonman GG, Sandor PS, Nirkko AC, Lange T, Jaermann T, Dydak U, Kremer C, Ferrari MD, Boesiger P, Baumgartner RW. Hypoxia-induced acute mountain sickness is associated with intracellular cerebral edema:a 3 T magnetic resonance imaging study. J Cereb Blood Flow Metab.28:198-206.2008.
Senger DR, Connolly DT, Van de Water L, Feder J, Dvorak HF. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res.50:1774-1778.1990.
Shimoda LA, Sham JS, Liu Q, Sylvester JT. Acute and chronic hypoxic pulmonary vasoconstriction:a central role for endothelin-1? Respir Physiol Neurobiol. 132:93-106.2002.
Sidhaye V, Hoffert JD, King LS. cAMP has distinct acute and chronic effects on aquaporin-5 in lung epithelial cells. J Biol Chem.280:3590-3596.2005.
Sidhaye VK, Schweitzer KS, Caterina MJ, Shimoda L, King LS. Shear stress regulates aquaporin-5 and airway epithelial barrier function. Proc Natl Acad Sci U S A. 105:3345-3350.2008.
Smith EM, Baillie JK, Thompson AA, Irving JB, Porteous D, Webb DJ. Endothelial nitric oxide synthase polymorphisms do not influence pulmonary artery systolic pressure at altitude. High Alt Med Biol.7:221-227.2006.
Song Y, Fukuda N, Bai C, Ma T, Matthay MA, Verkman AS. Role of aquaporins in alveolar fluid clearance in neonatal and adult lung, and in oedema formation following acute lung injury:studies in transgenic aquaporin null mice. J Physiol. 3:771-779.2000.
Sotak CH. Nuclear magnetic resonance (NMR) measurement of the apparent diffusion coefficient (ADC) of tissue water and its relationship to cell volume changes in pathological states. Neurochem Int.45:569-582.2004.
Stelzner TJ, O'Brien RF, Sato K, Weil JV. Hypoxia-induced increases in pulmonary transvascular protein escape in rats. Modulation by glucocorticoids. J Clin Invest. 82:1840-1847.1988.
Swenson ER, Maggiorini M, Mongovin S, Gibbs JS, Greve I, Mairbaurl H, Bartsch P. Pathogenesis of high-altitude pulmonary edema:inflammation is not an etiologic factor. JAMA.287:2228-2235.2002.
Taniguchi M, Yamashita T, Kumura E, Tamatani M, Kobayashi A, Yokawa T, Maruno M, Kato A, Ohnishi T, Kohmura E, Tohyama M, Yoshimine T. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Brain Res. 78:131-137.2000.
Tissot van Patot MC, Leadbetter G, Keyes LE, Bendrick-Peart J, Beckey VE, Christians U, Hackett P. Greater free plasma VEGF and lower soluble VEGF receptor-1 in acute mountain sickness. J Appl Physiol.98:1626-1629.2005.
Trang AJ, Teoh H, Ward ME. Inhibition of prostanoid-mediated contraction to endothelin-1 after hypoxia in rat aorta. Eur J Pharmacol.423:57-61.2001.
Vajda Z, Promeneur D, Doczi T, Sulyok E, Frokiaer J, Ottersen OP, Nielsen S. Increased aquaporin-4 immunoreactivity in rat brain in response to systemic hyponatremia. Biochem Biophys Res Commun.270:495-503.2000.
Van Osta A, Moraine JJ, Melot C, Mairbaurl H, Maggiorini M, Naeije R. Effects of high altitude exposure on cerebral hemodynamics in normal subjects. Stroke. 36:557-560.2005.
Verkman AS, Mitra AK. Structrue and function of aquaporin water channels. Am J Physiol Renal Physiol 278:13-28.2000.
Verkman AS. More than just water channels:unexpected cellular roles of aquaporins. J Cell Sci.118:3225-3232.2005.
Verkman AS, Binder DK, Bloch O, Auguste K, Papadopoulos MC. Three distinct roles of aquaporin-4 in brain function revealed by knockout mice. Biochim Biophys Acta.1758:1085-1093.2006.
Vizuete ML, Venero JL, Vargas C, Ilundain AA, Echevarria M, Machado A, Cano J. Differential upregulation of aquaporin-4 mRNA expression in reactive astrocytes after brain injury:potential role in brain edema. Neurobiol Dis.6:245-258.1999.
Vock P, Fretz C, Franciolli M, Bartsch P. High-Altitude Pulmonary-Edema-Findings at High-Altitude Chest Radiography and Physical-Examination. Radiology. 170:661-666.1989.
Wagner PD. The biology of oxygen. Eur Respir J.31:887-890.2008.
Wang ML, Huang XJ, Fang SH, Yuan YM, Zhang WP, Lu YB, Ding Q, Wei EQ. Leukotriene D4 induces brain edema and enhances CysLT2 receptor-mediated aquaporin 4 expression. Biochem Biophys Res Commun.350:399-404.2006.
West JB. The physiologic basis of high-altitude diseases. Ann Intern Med. 141:789-800.2004.
West JB, Colice GL, Lee YJ, Namba Y, Kurdak SS, Fu Z, Ou LC, Mathieu-Costello O. Pathogenesis of high-altitude pulmonary oedema:direct evidence of stress failure of pulmonary capillaries. Eur Respir J.8:523-529.1995.
Wu T, Ding S, Liu J, Jia J, Dai R, Liang B, Zhao J, Qi D. Ataxia:an early indicator in high altitude cerebral edema. High Alt Med Biol.7:275-280.2006.
Wu TY, Ding SQ, Liu JL, Yu MT, Jia JH, Chai ZC, Dai RC, Zhang SL, Li BY, Pan L, Liang BZ, Zhao JZ, Qi de T, Sun YF, Kayser B. Who should not go high: chronic disease and work at altitude during construction of the Qinghai-Tibet railroad. High Alt Med Biol.8:88-107.2007.
Xu F, Severinghaus JW. Rat brain VEGF expression in alveolar hypoxia:possible role in high-altitude cerebral edema. J Appl Physiol.85:53-57.1998.
Yamamoto N, Sobue K, Miyachi T, Inagaki M, Miura Y, Katsuya H, Asai K. Differential regulation of aquaporin expression in astrocytes by protein kinase C. Brain Res Mol Brain Res.95:110-116.2001.
Yang B, Zador Z, Verkman AS. Glial cell aquaporin-4 overexpression in transgenic mice accelerates cytotoxic brain swelling. J Biol Chem.283:15280-15286.2008.
Yao X, Hrabetova S, Nicholson C, Manley GT. Aquaporin-4-deficient mice have increased extracellular space without tortuosity change. J Neurosci. 28:5460-5464.2008.
Zelenina M, Zelenin S, Bondar AA, Brismar H, Aperia A. Water permeability of aquaporin-4 is decreased by protein kinase C and dopamine. Am J Physiol Renal Physiol.283:F309-318.2002.
Zelenina M. Regulation of brain aquaporins. Neurochem Int. doi:10.1016/j.neuint. 2010.03.022
Zeynalov E, Chen CH, Froehner SC, Adams ME, Ottersen OP, Amiry-Moghaddam M, Bhardwaj A. The perivascular pool of aquaporin-4 mediates the effect of osmotherapy in postischemic cerebral edema. Crit Care Med. 36:2634-2640.2008.
Zhao J, Moore AN, Clifton GL, Dash PK. Sulforaphane enhances aquaporin-4 expression and decreases cerebral edema following traumatic brain injury. J Neurosci Res.82:499-506.2005.
Zhou G, Dada LA, Chandel NS, Iwai K, Lecuona E, Ciechanover A, Sznajder JI. Hypoxia-mediated Na-K-ATPase degradation requires von Hippel Lindau protein. FASEB J.22:1335-1342.2008a.
Zhou J, Kong H, Hua X, Xiao M, Ding J, Hu G. Altered blood-brain barrier integrity in adult aquaporin-4 knockout mice. Neuroreport 19:1-5.2008b.
江晓波.中国山地范围界定的初步意见.山地学报.26：129.2008.
邓伟,程根伟,文安邦.中国山地科学发展构想.中国科学院院刊23：156-161.2008.