钠氢交换体1在内毒素性急性肺损伤中作用的实验研究
摘要
目的建立大鼠内毒素性急性肺损伤实验模型,观察实验模型中大鼠肺组织上钠氢交换体l的表达变化情况及其与炎症的关系。
方法40只雄性清洁级SD大鼠,体重在250-350g之间,随机分成空白对照组(C组)、脂多糖2h组(L-2h组)、脂多糖4h组(L-4h组)和脂多糖6h组(L-6h组),每组各10只。C组大鼠给予股静脉输注生理盐水；L-2h组、L-4h组和L-6h组大鼠均给予股静脉输注6mg/kg脂多糖。实验开始后2h颈动脉放血处死C组和L-2h组大鼠,4小时和6小时后分别处死L-4h组和L-6h组大鼠。监测各组大鼠基本生命体征；光学显微镜下观察大鼠肺组织病理改变；计算急性肺损伤评分和肺组织湿／干重比值；检测支气管肺泡灌洗液中总蛋白、肿瘤坏死因子-α和巨噬细胞炎性蛋白的浓度；测定肺组织髓过氧化物酶活性；EMSA检测肺组织细胞核转录因子-κB的活性；免疫组化、RT-PCR和Western Blot检测肺组织钠氢交换体1 mRNA和蛋白的表达水平。
结果(1)和空白对照组比较,脂多糖各组大鼠平均动脉压明显下降(均P<0.05)、心率和呼吸频率明显上升(均P<0.05)；脂多糖4h组和6h组大鼠动脉血氧分压显著下降(均P<0.05),(2)空白对照组大鼠肺组织肺泡结构正常,肺泡腔无渗出物；脂多糖各组大鼠肺组织病理改变明显,肺泡间隔增厚,肺泡腔内可见较多的炎性细胞,肺泡腔内有血性渗出液。和空白对照组比较,脂多糖各组大鼠肺组织急性肺损伤评分均明显增高(P<0.05)。(3)和空白对照组比较,脂多糖各组大鼠肺组织湿／干重比均明显上升(P<0.05)；支气管肺泡灌洗液中总蛋白、肿瘤坏死因子-α和巨噬细胞炎性蛋白的浓度均明显增高(均P<0.05)。(4)和空白对照组比较,脂多糖各组大鼠肺组织髓过氧化物酶活性均明显增高(P<0.05)。(5)和空白对照组比较,脂多糖各组大鼠肺组织核转录因子-κB的活性均明显增高(P<0.05)。(6)和空白对照组比较,免疫组化检测脂多糖各组大鼠肺组织NHE1的表达水平均明显增高(P<0.05)。(7)和空白对照组比较,脂多糖各组大鼠肺组织钠氢交换体1mRNA的表达水平均明显增高(P<0.05)。(8)和空白对照组比较,脂多糖各组大鼠肺组织钠氢交换体1的蛋白表达水平均明显增高(P<0.05)。
结论以6mg/kg的剂量给予大鼠静脉注射脂多糖后4h就产生了明显的急性肺损伤,表现为大鼠基本生命体征的内毒素休克症状出现；大鼠大体标本组织学炎症病理改变；肺组织含水量增加；肺组织及支气管肺泡灌洗液中相关炎性因子增加；与此同时,脂多糖各组大鼠肺组织钠氢交换体1mRNA和蛋白的表达水平也随着急性肺损伤炎症反应的加重而明显增加。
目的探讨阿米洛利预先给药对脂多糖诱导的大鼠内毒素性急性肺损伤的保护作用及可能机制。
方法40只雄性清洁级SD大鼠,体重在250-350g之间,随机分成空白对照组(C组)、脂多糖组(L组)、阿米洛利组(A组)和阿米洛利预给药组(AL组)。C组静脉输注生理盐水3ml；L组依次静脉输注1ml生理盐水及2ml脂多糖；A组依次静脉输注1ml阿米洛利及2ml生理盐水；AL组先输注1ml阿米洛利再输注2ml脂多糖。静脉注射脂多糖/阿米洛利6小时后颈动脉放血处死大鼠。光学显微镜下观察大鼠肺组织病理改变；计算急性肺损伤评分和肺组织湿／干重比值；测定支气管肺泡灌洗液中总蛋白的浓度；检测肺组织髓过氧化物酶活性、丙二醛浓度和超氧化物歧化酶活力；半定量免疫组化法检测肺组织过氧亚硝酸盐硝基酪氨酸残基的含量；RT-PCR检测肺组织钠氢交换体1mRNA的表达水平；Western blot法检测钠氢交换体1、细胞外信号调节激酶及p38丝裂原活化蛋白激酶的蛋白表达水平。
结果(1)空白对照组和阿米洛利组大鼠肺组织肺泡结构正常,肺泡腔无渗出物；脂多糖组和阿米洛利预给药组大鼠肺组织病理改变明显加重,肺泡间隔增厚,肺泡腔内可见较多炎性细胞渗出。和空白对照组比较,脂多糖组和阿米洛利预给药组大鼠肺组织ALI评分明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织ALI评分显著下降(P<0.05)。(2)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织湿／干重比值明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织湿／干重比值显著下降(P<0.05)。(3)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠BALF中总蛋白浓度明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠BALF中总蛋白浓度显著下降(P<0.05)。(4)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织MPO活性明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织MPO活性显著下降(P<0.05)。(5)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织MDA浓度明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织MDA浓度显著下降(P<0.05)。(6)与空白对照组相比，脂多糖组和阿米洛利预给药组大鼠肺组织湿／干重比明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织湿／干重比显著下降(P<0.05)。(7)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织硝基酪氨酸的含量明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织硝基酪氨酸的含量显著下降(P<0.05)。(8)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织NHE1 mRNA和蛋白的表达水平明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织NHE1 mRNA和蛋白的表达水平显著下降(P<0.05)。(9)与空白对照组相比脂多糖组和阿米洛利预给药组大鼠肺组织ERK的蛋白表达水平明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织ERK的蛋白表达水平显著下降(P<0.05)。(10)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织p38 MAPK的蛋白表达水平明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织p38 MAPK的蛋白表达水平无显著差异(P>0.05)。
结论大鼠静脉注射脂多糖产生急性肺损伤的同时伴随有肺组织钠氢交换体1、细胞外信号调节激酶及p38丝裂原活化蛋白激酶的显著激活；钠氢交换体1抑制剂阿米洛利预先给药对大鼠内毒素性急性肺损伤有保护作用,其机制可能与抑制细胞外信号调节激酶的激活有关。
目的探讨丝裂原活化蛋白激酶家族在阿米洛利预先给药防治脂多糖诱导的大鼠内毒素性急性肺损伤中的作用及可能机制。
方法70只雄性清洁级SD大鼠,体重在250-350g之间,随机均分成空白对照组(C组)、脂多糖组(L组)、阿米洛利预给药组(AL组)、PD098059预给药组(PL组)、SB203580预给药组(sL组)、阿米洛利联合PD098059预给药组(APL组)和阿米洛利联合SB203580预给药组(ASL组)。C组静脉输注生理盐水3ml；L组静脉输注脂多糖(6mg/kg)及生理盐水总容积共3ml; AL组先静脉输注阿米洛利(10mg/kg)再输注脂多糖(6mg/kg)及生理盐水总容积共3ml; PL组先静脉输注PD098059(0.3mg/kg)再输注脂多糖(6mg/kg)及生理盐水总容积共3ml; SL组先静脉输注SB203580 (10mg/kg)再输注脂多糖(6mg/kg)及生理盐水总容积共3ml; APL组先静脉输注阿米洛利(10mg/kg)再输注PD098059(0.3mg/kg)及脂多糖(6mg/kg),总容积共3ml; ASL组先静脉输注阿米洛利(10mg/kg)再输注SB203580(10mg/kg)及脂多糖(6mg/kg),总容积共3ml。实验开始6小时后颈动脉放血处死大鼠。光学显微镜下观察大鼠肺组织病理改变；计算急性肺损伤评分和肺组织湿／干重比值；测定支气管肺泡灌洗液中总蛋白、肿瘤坏死因子-α和巨噬细胞炎性蛋白的浓度；检测肺组织髓过氧化物酶活性；RT-PCR检测肺组织钠氢交换体1 mRNA的表达水平；Western blot法检测钠氢交换体1的蛋白表达水平。
结果(1)空白对照组大鼠肺组织肺泡结构正常,肺泡腔无渗出物；其余各组各组大鼠肺组织病理改变明显,肺泡间隔增厚,肺泡腔内可见炎性细胞渗出。(2)与空白对照组相比,其余各组大鼠肺组织ALI评分和肺组织湿／干重比值；BALF中总蛋白、肿瘤坏死因子-α、巨噬细胞炎性蛋白浓度；肺组织髓过氧化物酶活性及钠氢交换体1 mRNA和蛋白的表达水平均明显上升(均P<0.05),其中以脂多糖组上升最显著(均P<0.01)；与脂多糖组相比,阿米洛利预给药组上述各指标显著下降(均P<0.05)；与阿米洛利预给药组相比,PD098059预给药组、阿米洛利联合PD098059预给药组及SB203580预给药组上述各指标均明显下降(均P<0.05)；而PD098059预给药组、阿米洛利联合PD098059预给药组及SB203580预给药组上述各指标之间无明显差别；与这三组相比,阿米洛利联合SB203580预给药组上述各指标明显下降(均P<0.05)。
结论钠氢交换体1抑制剂阿米洛利预先给药对大鼠内毒素性急性肺损伤有保护作用；细胞外信号调节激酶的阻滞剂可以完全取消阿米洛利的作用,说明阿米洛利防治大鼠内毒素性急性肺损伤的作用机制可能与抑制细胞外信号调节激酶的激活有关。
目的观察钠氢交换体1 mRNA和蛋白在脂多糖活化鼠源性巨噬细胞中的表达变化及阿米洛利预先给药对它的影响。
方法传代培养的鼠源性巨噬细胞株(RAW264.7细胞)以1×106个／ml的密度接种于6孔板,培养48 h后,随机分为4组：仅加RPMI 1640培养液的对照组；加300μM阿米洛利的阿米洛利组；加1μg/ml脂多糖的脂多糖组：加300μM阿米洛利干预30min后再加1μg/ml脂多糖的阿米洛利预给药组；实验开始24 h后,ELISA法和Griess法分别检测各组细胞培养上清液中肿瘤坏死因子-α浓度和一氧化氮的水平、应用细胞内活性氧敏感性荧光探针DCFH-DA检测各组细胞内活性氧的水平；实验开始3h后,采用逆转录-聚合酶链反应(RT-PCR)检测各组细胞内钠氢交换体1 mRNA的表达水平；实验开始6h后,应用免疫印迹(Western blotting)技术检测各组细胞内钠氢交换体1蛋白的表达水平。
结果与空白对照组相比,阿米洛利组细胞培养上清液中肿瘤坏死因子-α的浓度和一氧化氮的水平、细胞内活性氧的水平及钠氢交换体1 mRNA和蛋白的表达水平均无显著性差异(均P>0.05)；而脂多糖组和阿米洛利预给药组内上述指标均明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组内上述指标均显著下降(均P<0.05)。
结论脂多糖活化鼠源性巨噬细胞中钠氢交换体1被迅速激活、表达增加；钠氢交换体1抑制剂阿米洛利预先给药干预可以明显抑制这种变化。
PartⅠExpression of Na+/H+ exchanger 1 in endotoxin-induced acute lung injury in rats
Objective To build the model of the acute lung injury(ALI) induced by lipopolysaccharide(LPS) in rats in vivo and to observe the changes of Na+/H+ exchanger 1(NHE1) mRNA and protein expressions in the injurious lungs.
Methods Forty Specific pathogen-free male Sprague-Dawley rats weighing 250-350 g were randomly divided into the following experimental groups (10 rats in each group):control group (C group):rats received iv. injection of normal saline and sacrificed by carotid artery bleeding 2 h after the administration of saline; LPS-2 h group(L-2 h group):rats received iv. injection of 6 mg/kg LPS and sacrificed by carotid artery bleeding 2 h after the administration of LPS; LPS-4 h group(L-4 h group); rats received iv. injection of 6 mg/kg LPS and sacrificed by carotid artery bleeding 4 h after the administration of LPS; LPS-6 h group(L-6 h group):rats received iv. injection of 6 mg/kg LPS and sacrificed by carotid artery bleeding 6 h after the administration of LPS. The samples of pulmonary tissue and lung lavage fluid were collected after experiments. The basic vital signs of rats were monitored and recorded. The pathological changes in lung tissue were examined with optical microscopy. The acute lung injury score and lung tissue wet / dry weight ratio were calculated. The total protein, tumor necrosis factor-a and macrophage inflammatory protein concentration in bronchoalveolar lavage fluid were detected. The myeloperoxidase(MPO) activity of lung tissue were measured. The nuclear factor-KB (NF-κB) activity of lung tissue were assayed with electrophoretic mobility shift assay (EMSA). The NHE1 mRNA and protein expressions in lung tissue were detected by immunohistochemistry、reverse transcriptase-polymerase chain reaction (RT-PCR) and Western Blot.
Results (1) Compared with the control group, the Mean Arterial Pressure(MAP) of rats in LPS-2 h group、LPS-4 h group and LPS-6 h group were decreased significantly (all P<0.05)% Heart Rate (HR) and Respiratory Frequency(RF) of rats in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05); Arterial partial pressure of oxygen(PaO2) of rats in LPS-4 h group and LPS-6 h group were decreased significantly(all P <0.05). (2) The lung tissue in control group rats showed normal alveolar septum and alveolar spaces without exudation; the lung tissue of rats in LPS-2h、LPS-4 h group and LPS-6 h group showed high levels of intra-alveolar exudates, hyaline membrane formation, inflammatory cell infiltration, intra-alveolar hemorrhage, and interstitial edema. Compared with the control group, the lung tissue ALI scores of rats in LPS-2 h、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05), the overall differences between groups were statistically significant (P<0.05). (3) Compared with the control group, the lung tissue wet/ dry weight ratio of rats in LPS-2 h group、LPS-4 h group and LPS-6h group were significantly elevated(all P<0.05), the overall differences between groups were statistically significant (P<0.05); the total protein(TP), tumor necrosis factor-α(TNF-α) and macrophage inflammatory protein(MIP-2) concentration in bronchoalveolar lavage fluid of rats in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05), the overall differences between groups were statistically significant (all P<0.05). (4) Compared with the control group, the MPO activity of lung tissue in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05), the overall differences between groups were statistically significant(P<0.05). (5) Compared with the control group, the NF-κB activity of lung tissue in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05); the overall differences between groups were statistically significant(P<0.05). (6) Compared with the control group, the NHE1 protein immunohistochemistry expressions of lung tissue in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05); the overall differences between groups were statistically significant(P<0.05). (7) Compared with the control group, the NHE1 mRNA expressions of lung tissue in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05); the overall differences between groups were statistically significant(P<0.05). (8) Compared with the control group, the NHE1 protein expressions of lung tissue in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated (all P<0.05); the overall differences between groups were statistically significant(P<0.05).
Conclusion Rats produced significant acute lung injury after intravenous injection of LPS 4 h with 6mg/kg, which includes endotoxin shock symptoms、histological inflammation in rats gross specimen pathology、lung tissue water content increased、inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid increased; at the same time, the NHE1 mRNA and protein expressions of lung tissue in each LPS group were significantly elevated and remarkably increased with the duration of acute lung inflammatory response.
Objective To investigate the effects of amiloride pretreatment on the acute lung injury(ALI) induced by lipopolysaccharide(LPS) in rats and the underlying mechanism.
Methods Forty Specific pathogen-free male Sprague-Dawley rats weighing 250-350g were randomly divided into the following experimental groups (10 rats in each group):control group (C group):rats received iv. injection of normal saline; amiloride group(A group):rats received iv. injection of 10 mg/kg amiloride; LPS group(L group):rats received iv. injection of 6mg/kg LPS; amiloride pretreatment group(AL group):rats received iv. injection of 10 mg/kg amiloride 30 min before the administration of LPS. Degree of ALI were assessed by wet/dry weight ratio(W/D) and lung histological examination. Concentrations of total protien in bronchoalveolar lavage fluid(BALF) were determined. The activity of myeloperoxidase(MPO)、the concentrations of malondialdehyde(MDA) and the Vitality of Superoxide dismutase(SOD) in lung tissue were also measured. The contents of nitrotyrosine(NT) in lung tissue were determined by semi-quantitative immunohistochemistry. The Na+/H+ exchanger 1 (NHE1) mRNA expressions in lung tissue were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). The expression of NHE1、extracellular signal regulated kinase (ERK) and mitogen-activated protein kinase(MAPK) p38 in lung tissue were also determined by Western blot analysis.
Results Lung tissue ALI scores、W/D ratio、MPO activity、MDA concentrations、SOD vitality and NT contents, concentrations of total protienin BALF, the expression of NHE1, MAPK p38 and ERK increased significantly in LPS group as compared with control group(all P<0.05). These increases were significantly reduced in amiloride pretreatment group(all P<0.05) except MAPK p38 expression.
Conclusion NHE1 inhibitor amiloride pretreatment can attenuate ALI induced by LPS in rats. This effect may be related to inhibition of ERK activation.
Part III
Roles of mitogen-activated protein kinases in the protection effects of amiloride on endotoxin-induced acute lung injury in rats
Objective To investigate the roles of mitogen-activated protein kinases(MAPKs) in the protection effects of amiloride pretreatment on the acute lung injury(ALI) induced by lipopolysaccharide(LPS) in rats.
Methods Seventy specific pathogen-free male Sprague-Dawley rats weighing 250-350g were randomly divided into the following experimental groups (10 rats in each group):control group (C group):rats received iv. injection of normal saline; LPS group(L group):rats received iv. injection of 6mg/kg LPS; amiloride pretreatment group(AL group):rats received iv. injection of 10 mg/kg amiloride 30 mins before the administration of LPS; PD098059 pretreatment group(PL group):rats received iv. injection of 0.3mg/kg PD098059 30 mins before the administration of LPS; SB203580 pretreatment group(SL group):rats received iv. injection of 10mg/kg SB203580 30 mins before the administration of LPS; amiloride combined PD098059 pretreatment group(APL group):rats received iv. injection of 10 mg/kg amiloride and 0.3mg/kg PD098059 30 mins before the administration of LPS; amiloride combined SB203580 pretreatment group(ASL group):rats received iv. injection of 10 mg/kg amiloride and 10mg/kg SB203580 30 mins before the administration of LPS. All rats were sacrificed by carotid artery bleeding 6h after the experiment starting. The samples of pulmonary tissue and lung lavage fluid were collected after experiments. The pathological changes in lung tissue were examined with optical microscopy. The acute lung injury scores and lung tissue wet/dry weight ratio were calculated. The total protein, tumor necrosis factor-a and macrophage inflammatory protein concentration in bronchoalveolar lavage fluid were detected. The myeloperoxidase(MPO) activity of lung tissue were also measured; the NHE1 mRNA and protein expressions in lung tissue were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western Blot analysis.
Results (1) The lung tissues in control group rats showed normal alveolar septum and alveolar spaces without exudation; the lung tissues of rats in the other groups showed high levels of intra-alveolar exudates, hyaline membrane formation, inflammatory cell infiltration, intra-alveolar hemorrhage, and interstitial edema. (2) Compared with the control group, concentrations of total protien、tumor necrosis factor-αand macrophage inflammatory protein in bronchoalveolar lavage fluid, lung tissue ALI scores、W/D ratio、MPO activity and NHE1 mRNA and protein expressions in the other groups were significantly increased (all P<0.05), the indicators above-mentioned in LPS group were the most significantly increased (all P<0.05); compared with the LPS group, the indicators above-mentioned in amiloride pretreatment group were decreased significantly (all P<0.05); compared with the amiloride pretreatment group, the indicators above-mentioned in PD098059 pretreatment group、SB203580 pretreatment group and amiloride combined PD098059 pretreatment group were decreased significantly (all P<0.05) however; compared with these three groups, the indicators above-mentioned in amiloride combined SB203580 pretreatment group were significantly decreased (all P<0.05) yet.
Conclusion NHE1 inhibitor amiloride pretreatment can attenuate ALI induced by LPS in rats; extracellular signal-regulated kinase inhibitor can completely abolish this kind of protective effect of amiloride, which illustrated that this effect may be related to inhibition of extracellular signal-regulated kinase activation.
Part IV Expressions of Na+/H+ exchanger 1 in lipopolysaccharide-activated mouse macrophage-like cells and the pretreatment effect of amiloride
Objective To observe the changes of Na+/H+ exchanger 1(NHE1) mRNA and protein expressions in the lipopolysaccharide(LPS)-activated mouse macrophage-like cells and the pretreatment effect of amiloride.
Methods The mouse macrophage-like cell line (RAW 264.7) cells were seeded in 6 well plate with the density of 1×106/ml and cultured in RPMI 1640 medium at 37℃in 5% CO2 incubator for 48 h in vitro, then all cells were randomly divided into 4 groups(n=12):group C:control; amiloride group:RAW 264.7 cells were co-incubated with amiloride 300μM (final concentration); LPS group:RAW 264.7 cells were co-incubated with LPS 1μg/ml (final concentration); amiloride pretreatment group:RAW 264.7 cells were co-incubated with amiloride 300μM (final concentration) for 30 mins before co-incubated with LPS 1μg/ml (final concentration). The concentrations of tumor necrosis factor-α(TNF-α) and the levels of nitric oxide(NO) in cell culture supernatants in each group were detected with enzyme linked immunosorbent assay(ELISA) and the Griess method 24 h after the start of the trial. The levels of intracellular reactive oxygen species(ROS) in each group were detected with the ROS sensitivity DCFH-DA fluorescent probe method 24 h after the start of the trial. The expressions of NHE1 mRNA in each group were measured by reverse transcription-polymerase chain reaction (RT-PCR) 3 h after the start of the trial. The levels of NHE1 protein expressions in each group were also detected with Western blot analysis 6 h after the start of the trial.
Results Compared with the control group, the concentrations of TNF-a and the levels of NO in cell culture supernatants、the levels of intracellular ROS、the expressions of NHE1 mRNA and the levels of NHE1 protein expressions in amiloride group have no statistical difference(all P>0.05); but the indicators above-mentioned in LPS group and amiloride pretreatment group were significantly increased(all P<0.05). Compared with the LPS group, the indicators above-mentioned in amiloride pretreatment group were significantly decreased (all P<0.05).
Conclusion NHE1 can be rapidly activated and the expressions of NHE1 were increased in the LPS-activated mouse macrophage-like cells; pretreatment intervention with NHE 1 inhibitor amiloride can restrain the changes.
方法40只雄性清洁级SD大鼠,体重在250-350g之间,随机分成空白对照组(C组)、脂多糖2h组(L-2h组)、脂多糖4h组(L-4h组)和脂多糖6h组(L-6h组),每组各10只。C组大鼠给予股静脉输注生理盐水；L-2h组、L-4h组和L-6h组大鼠均给予股静脉输注6mg/kg脂多糖。实验开始后2h颈动脉放血处死C组和L-2h组大鼠,4小时和6小时后分别处死L-4h组和L-6h组大鼠。监测各组大鼠基本生命体征；光学显微镜下观察大鼠肺组织病理改变；计算急性肺损伤评分和肺组织湿／干重比值；检测支气管肺泡灌洗液中总蛋白、肿瘤坏死因子-α和巨噬细胞炎性蛋白的浓度；测定肺组织髓过氧化物酶活性；EMSA检测肺组织细胞核转录因子-κB的活性；免疫组化、RT-PCR和Western Blot检测肺组织钠氢交换体1 mRNA和蛋白的表达水平。
结果(1)和空白对照组比较,脂多糖各组大鼠平均动脉压明显下降(均P<0.05)、心率和呼吸频率明显上升(均P<0.05)；脂多糖4h组和6h组大鼠动脉血氧分压显著下降(均P<0.05),(2)空白对照组大鼠肺组织肺泡结构正常,肺泡腔无渗出物；脂多糖各组大鼠肺组织病理改变明显,肺泡间隔增厚,肺泡腔内可见较多的炎性细胞,肺泡腔内有血性渗出液。和空白对照组比较,脂多糖各组大鼠肺组织急性肺损伤评分均明显增高(P<0.05)。(3)和空白对照组比较,脂多糖各组大鼠肺组织湿／干重比均明显上升(P<0.05)；支气管肺泡灌洗液中总蛋白、肿瘤坏死因子-α和巨噬细胞炎性蛋白的浓度均明显增高(均P<0.05)。(4)和空白对照组比较,脂多糖各组大鼠肺组织髓过氧化物酶活性均明显增高(P<0.05)。(5)和空白对照组比较,脂多糖各组大鼠肺组织核转录因子-κB的活性均明显增高(P<0.05)。(6)和空白对照组比较,免疫组化检测脂多糖各组大鼠肺组织NHE1的表达水平均明显增高(P<0.05)。(7)和空白对照组比较,脂多糖各组大鼠肺组织钠氢交换体1mRNA的表达水平均明显增高(P<0.05)。(8)和空白对照组比较,脂多糖各组大鼠肺组织钠氢交换体1的蛋白表达水平均明显增高(P<0.05)。
结论以6mg/kg的剂量给予大鼠静脉注射脂多糖后4h就产生了明显的急性肺损伤,表现为大鼠基本生命体征的内毒素休克症状出现；大鼠大体标本组织学炎症病理改变；肺组织含水量增加；肺组织及支气管肺泡灌洗液中相关炎性因子增加；与此同时,脂多糖各组大鼠肺组织钠氢交换体1mRNA和蛋白的表达水平也随着急性肺损伤炎症反应的加重而明显增加。
目的探讨阿米洛利预先给药对脂多糖诱导的大鼠内毒素性急性肺损伤的保护作用及可能机制。
方法40只雄性清洁级SD大鼠,体重在250-350g之间,随机分成空白对照组(C组)、脂多糖组(L组)、阿米洛利组(A组)和阿米洛利预给药组(AL组)。C组静脉输注生理盐水3ml；L组依次静脉输注1ml生理盐水及2ml脂多糖；A组依次静脉输注1ml阿米洛利及2ml生理盐水；AL组先输注1ml阿米洛利再输注2ml脂多糖。静脉注射脂多糖/阿米洛利6小时后颈动脉放血处死大鼠。光学显微镜下观察大鼠肺组织病理改变；计算急性肺损伤评分和肺组织湿／干重比值；测定支气管肺泡灌洗液中总蛋白的浓度；检测肺组织髓过氧化物酶活性、丙二醛浓度和超氧化物歧化酶活力；半定量免疫组化法检测肺组织过氧亚硝酸盐硝基酪氨酸残基的含量；RT-PCR检测肺组织钠氢交换体1mRNA的表达水平；Western blot法检测钠氢交换体1、细胞外信号调节激酶及p38丝裂原活化蛋白激酶的蛋白表达水平。
结果(1)空白对照组和阿米洛利组大鼠肺组织肺泡结构正常,肺泡腔无渗出物；脂多糖组和阿米洛利预给药组大鼠肺组织病理改变明显加重,肺泡间隔增厚,肺泡腔内可见较多炎性细胞渗出。和空白对照组比较,脂多糖组和阿米洛利预给药组大鼠肺组织ALI评分明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织ALI评分显著下降(P<0.05)。(2)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织湿／干重比值明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织湿／干重比值显著下降(P<0.05)。(3)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠BALF中总蛋白浓度明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠BALF中总蛋白浓度显著下降(P<0.05)。(4)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织MPO活性明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织MPO活性显著下降(P<0.05)。(5)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织MDA浓度明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织MDA浓度显著下降(P<0.05)。(6)与空白对照组相比，脂多糖组和阿米洛利预给药组大鼠肺组织湿／干重比明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织湿／干重比显著下降(P<0.05)。(7)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织硝基酪氨酸的含量明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织硝基酪氨酸的含量显著下降(P<0.05)。(8)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织NHE1 mRNA和蛋白的表达水平明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织NHE1 mRNA和蛋白的表达水平显著下降(P<0.05)。(9)与空白对照组相比脂多糖组和阿米洛利预给药组大鼠肺组织ERK的蛋白表达水平明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织ERK的蛋白表达水平显著下降(P<0.05)。(10)与空白对照组相比,脂多糖组和阿米洛利预给药组大鼠肺组织p38 MAPK的蛋白表达水平明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组大鼠肺组织p38 MAPK的蛋白表达水平无显著差异(P>0.05)。
结论大鼠静脉注射脂多糖产生急性肺损伤的同时伴随有肺组织钠氢交换体1、细胞外信号调节激酶及p38丝裂原活化蛋白激酶的显著激活；钠氢交换体1抑制剂阿米洛利预先给药对大鼠内毒素性急性肺损伤有保护作用,其机制可能与抑制细胞外信号调节激酶的激活有关。
目的探讨丝裂原活化蛋白激酶家族在阿米洛利预先给药防治脂多糖诱导的大鼠内毒素性急性肺损伤中的作用及可能机制。
方法70只雄性清洁级SD大鼠,体重在250-350g之间,随机均分成空白对照组(C组)、脂多糖组(L组)、阿米洛利预给药组(AL组)、PD098059预给药组(PL组)、SB203580预给药组(sL组)、阿米洛利联合PD098059预给药组(APL组)和阿米洛利联合SB203580预给药组(ASL组)。C组静脉输注生理盐水3ml；L组静脉输注脂多糖(6mg/kg)及生理盐水总容积共3ml; AL组先静脉输注阿米洛利(10mg/kg)再输注脂多糖(6mg/kg)及生理盐水总容积共3ml; PL组先静脉输注PD098059(0.3mg/kg)再输注脂多糖(6mg/kg)及生理盐水总容积共3ml; SL组先静脉输注SB203580 (10mg/kg)再输注脂多糖(6mg/kg)及生理盐水总容积共3ml; APL组先静脉输注阿米洛利(10mg/kg)再输注PD098059(0.3mg/kg)及脂多糖(6mg/kg),总容积共3ml; ASL组先静脉输注阿米洛利(10mg/kg)再输注SB203580(10mg/kg)及脂多糖(6mg/kg),总容积共3ml。实验开始6小时后颈动脉放血处死大鼠。光学显微镜下观察大鼠肺组织病理改变；计算急性肺损伤评分和肺组织湿／干重比值；测定支气管肺泡灌洗液中总蛋白、肿瘤坏死因子-α和巨噬细胞炎性蛋白的浓度；检测肺组织髓过氧化物酶活性；RT-PCR检测肺组织钠氢交换体1 mRNA的表达水平；Western blot法检测钠氢交换体1的蛋白表达水平。
结果(1)空白对照组大鼠肺组织肺泡结构正常,肺泡腔无渗出物；其余各组各组大鼠肺组织病理改变明显,肺泡间隔增厚,肺泡腔内可见炎性细胞渗出。(2)与空白对照组相比,其余各组大鼠肺组织ALI评分和肺组织湿／干重比值；BALF中总蛋白、肿瘤坏死因子-α、巨噬细胞炎性蛋白浓度；肺组织髓过氧化物酶活性及钠氢交换体1 mRNA和蛋白的表达水平均明显上升(均P<0.05),其中以脂多糖组上升最显著(均P<0.01)；与脂多糖组相比,阿米洛利预给药组上述各指标显著下降(均P<0.05)；与阿米洛利预给药组相比,PD098059预给药组、阿米洛利联合PD098059预给药组及SB203580预给药组上述各指标均明显下降(均P<0.05)；而PD098059预给药组、阿米洛利联合PD098059预给药组及SB203580预给药组上述各指标之间无明显差别；与这三组相比,阿米洛利联合SB203580预给药组上述各指标明显下降(均P<0.05)。
结论钠氢交换体1抑制剂阿米洛利预先给药对大鼠内毒素性急性肺损伤有保护作用；细胞外信号调节激酶的阻滞剂可以完全取消阿米洛利的作用,说明阿米洛利防治大鼠内毒素性急性肺损伤的作用机制可能与抑制细胞外信号调节激酶的激活有关。
目的观察钠氢交换体1 mRNA和蛋白在脂多糖活化鼠源性巨噬细胞中的表达变化及阿米洛利预先给药对它的影响。
方法传代培养的鼠源性巨噬细胞株(RAW264.7细胞)以1×106个／ml的密度接种于6孔板,培养48 h后,随机分为4组：仅加RPMI 1640培养液的对照组；加300μM阿米洛利的阿米洛利组；加1μg/ml脂多糖的脂多糖组：加300μM阿米洛利干预30min后再加1μg/ml脂多糖的阿米洛利预给药组；实验开始24 h后,ELISA法和Griess法分别检测各组细胞培养上清液中肿瘤坏死因子-α浓度和一氧化氮的水平、应用细胞内活性氧敏感性荧光探针DCFH-DA检测各组细胞内活性氧的水平；实验开始3h后,采用逆转录-聚合酶链反应(RT-PCR)检测各组细胞内钠氢交换体1 mRNA的表达水平；实验开始6h后,应用免疫印迹(Western blotting)技术检测各组细胞内钠氢交换体1蛋白的表达水平。
结果与空白对照组相比,阿米洛利组细胞培养上清液中肿瘤坏死因子-α的浓度和一氧化氮的水平、细胞内活性氧的水平及钠氢交换体1 mRNA和蛋白的表达水平均无显著性差异(均P>0.05)；而脂多糖组和阿米洛利预给药组内上述指标均明显上升(均P<0.05)；与脂多糖组相比,阿米洛利预给药组内上述指标均显著下降(均P<0.05)。
结论脂多糖活化鼠源性巨噬细胞中钠氢交换体1被迅速激活、表达增加；钠氢交换体1抑制剂阿米洛利预先给药干预可以明显抑制这种变化。
PartⅠExpression of Na+/H+ exchanger 1 in endotoxin-induced acute lung injury in rats
Objective To build the model of the acute lung injury(ALI) induced by lipopolysaccharide(LPS) in rats in vivo and to observe the changes of Na+/H+ exchanger 1(NHE1) mRNA and protein expressions in the injurious lungs.
Methods Forty Specific pathogen-free male Sprague-Dawley rats weighing 250-350 g were randomly divided into the following experimental groups (10 rats in each group):control group (C group):rats received iv. injection of normal saline and sacrificed by carotid artery bleeding 2 h after the administration of saline; LPS-2 h group(L-2 h group):rats received iv. injection of 6 mg/kg LPS and sacrificed by carotid artery bleeding 2 h after the administration of LPS; LPS-4 h group(L-4 h group); rats received iv. injection of 6 mg/kg LPS and sacrificed by carotid artery bleeding 4 h after the administration of LPS; LPS-6 h group(L-6 h group):rats received iv. injection of 6 mg/kg LPS and sacrificed by carotid artery bleeding 6 h after the administration of LPS. The samples of pulmonary tissue and lung lavage fluid were collected after experiments. The basic vital signs of rats were monitored and recorded. The pathological changes in lung tissue were examined with optical microscopy. The acute lung injury score and lung tissue wet / dry weight ratio were calculated. The total protein, tumor necrosis factor-a and macrophage inflammatory protein concentration in bronchoalveolar lavage fluid were detected. The myeloperoxidase(MPO) activity of lung tissue were measured. The nuclear factor-KB (NF-κB) activity of lung tissue were assayed with electrophoretic mobility shift assay (EMSA). The NHE1 mRNA and protein expressions in lung tissue were detected by immunohistochemistry、reverse transcriptase-polymerase chain reaction (RT-PCR) and Western Blot.
Results (1) Compared with the control group, the Mean Arterial Pressure(MAP) of rats in LPS-2 h group、LPS-4 h group and LPS-6 h group were decreased significantly (all P<0.05)% Heart Rate (HR) and Respiratory Frequency(RF) of rats in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05); Arterial partial pressure of oxygen(PaO2) of rats in LPS-4 h group and LPS-6 h group were decreased significantly(all P <0.05). (2) The lung tissue in control group rats showed normal alveolar septum and alveolar spaces without exudation; the lung tissue of rats in LPS-2h、LPS-4 h group and LPS-6 h group showed high levels of intra-alveolar exudates, hyaline membrane formation, inflammatory cell infiltration, intra-alveolar hemorrhage, and interstitial edema. Compared with the control group, the lung tissue ALI scores of rats in LPS-2 h、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05), the overall differences between groups were statistically significant (P<0.05). (3) Compared with the control group, the lung tissue wet/ dry weight ratio of rats in LPS-2 h group、LPS-4 h group and LPS-6h group were significantly elevated(all P<0.05), the overall differences between groups were statistically significant (P<0.05); the total protein(TP), tumor necrosis factor-α(TNF-α) and macrophage inflammatory protein(MIP-2) concentration in bronchoalveolar lavage fluid of rats in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05), the overall differences between groups were statistically significant (all P<0.05). (4) Compared with the control group, the MPO activity of lung tissue in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05), the overall differences between groups were statistically significant(P<0.05). (5) Compared with the control group, the NF-κB activity of lung tissue in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05); the overall differences between groups were statistically significant(P<0.05). (6) Compared with the control group, the NHE1 protein immunohistochemistry expressions of lung tissue in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05); the overall differences between groups were statistically significant(P<0.05). (7) Compared with the control group, the NHE1 mRNA expressions of lung tissue in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated(all P<0.05); the overall differences between groups were statistically significant(P<0.05). (8) Compared with the control group, the NHE1 protein expressions of lung tissue in LPS-2 h group、LPS-4 h group and LPS-6 h group were significantly elevated (all P<0.05); the overall differences between groups were statistically significant(P<0.05).
Conclusion Rats produced significant acute lung injury after intravenous injection of LPS 4 h with 6mg/kg, which includes endotoxin shock symptoms、histological inflammation in rats gross specimen pathology、lung tissue water content increased、inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid increased; at the same time, the NHE1 mRNA and protein expressions of lung tissue in each LPS group were significantly elevated and remarkably increased with the duration of acute lung inflammatory response.
Objective To investigate the effects of amiloride pretreatment on the acute lung injury(ALI) induced by lipopolysaccharide(LPS) in rats and the underlying mechanism.
Methods Forty Specific pathogen-free male Sprague-Dawley rats weighing 250-350g were randomly divided into the following experimental groups (10 rats in each group):control group (C group):rats received iv. injection of normal saline; amiloride group(A group):rats received iv. injection of 10 mg/kg amiloride; LPS group(L group):rats received iv. injection of 6mg/kg LPS; amiloride pretreatment group(AL group):rats received iv. injection of 10 mg/kg amiloride 30 min before the administration of LPS. Degree of ALI were assessed by wet/dry weight ratio(W/D) and lung histological examination. Concentrations of total protien in bronchoalveolar lavage fluid(BALF) were determined. The activity of myeloperoxidase(MPO)、the concentrations of malondialdehyde(MDA) and the Vitality of Superoxide dismutase(SOD) in lung tissue were also measured. The contents of nitrotyrosine(NT) in lung tissue were determined by semi-quantitative immunohistochemistry. The Na+/H+ exchanger 1 (NHE1) mRNA expressions in lung tissue were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). The expression of NHE1、extracellular signal regulated kinase (ERK) and mitogen-activated protein kinase(MAPK) p38 in lung tissue were also determined by Western blot analysis.
Results Lung tissue ALI scores、W/D ratio、MPO activity、MDA concentrations、SOD vitality and NT contents, concentrations of total protienin BALF, the expression of NHE1, MAPK p38 and ERK increased significantly in LPS group as compared with control group(all P<0.05). These increases were significantly reduced in amiloride pretreatment group(all P<0.05) except MAPK p38 expression.
Conclusion NHE1 inhibitor amiloride pretreatment can attenuate ALI induced by LPS in rats. This effect may be related to inhibition of ERK activation.
Part III
Roles of mitogen-activated protein kinases in the protection effects of amiloride on endotoxin-induced acute lung injury in rats
Objective To investigate the roles of mitogen-activated protein kinases(MAPKs) in the protection effects of amiloride pretreatment on the acute lung injury(ALI) induced by lipopolysaccharide(LPS) in rats.
Methods Seventy specific pathogen-free male Sprague-Dawley rats weighing 250-350g were randomly divided into the following experimental groups (10 rats in each group):control group (C group):rats received iv. injection of normal saline; LPS group(L group):rats received iv. injection of 6mg/kg LPS; amiloride pretreatment group(AL group):rats received iv. injection of 10 mg/kg amiloride 30 mins before the administration of LPS; PD098059 pretreatment group(PL group):rats received iv. injection of 0.3mg/kg PD098059 30 mins before the administration of LPS; SB203580 pretreatment group(SL group):rats received iv. injection of 10mg/kg SB203580 30 mins before the administration of LPS; amiloride combined PD098059 pretreatment group(APL group):rats received iv. injection of 10 mg/kg amiloride and 0.3mg/kg PD098059 30 mins before the administration of LPS; amiloride combined SB203580 pretreatment group(ASL group):rats received iv. injection of 10 mg/kg amiloride and 10mg/kg SB203580 30 mins before the administration of LPS. All rats were sacrificed by carotid artery bleeding 6h after the experiment starting. The samples of pulmonary tissue and lung lavage fluid were collected after experiments. The pathological changes in lung tissue were examined with optical microscopy. The acute lung injury scores and lung tissue wet/dry weight ratio were calculated. The total protein, tumor necrosis factor-a and macrophage inflammatory protein concentration in bronchoalveolar lavage fluid were detected. The myeloperoxidase(MPO) activity of lung tissue were also measured; the NHE1 mRNA and protein expressions in lung tissue were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western Blot analysis.
Results (1) The lung tissues in control group rats showed normal alveolar septum and alveolar spaces without exudation; the lung tissues of rats in the other groups showed high levels of intra-alveolar exudates, hyaline membrane formation, inflammatory cell infiltration, intra-alveolar hemorrhage, and interstitial edema. (2) Compared with the control group, concentrations of total protien、tumor necrosis factor-αand macrophage inflammatory protein in bronchoalveolar lavage fluid, lung tissue ALI scores、W/D ratio、MPO activity and NHE1 mRNA and protein expressions in the other groups were significantly increased (all P<0.05), the indicators above-mentioned in LPS group were the most significantly increased (all P<0.05); compared with the LPS group, the indicators above-mentioned in amiloride pretreatment group were decreased significantly (all P<0.05); compared with the amiloride pretreatment group, the indicators above-mentioned in PD098059 pretreatment group、SB203580 pretreatment group and amiloride combined PD098059 pretreatment group were decreased significantly (all P<0.05) however; compared with these three groups, the indicators above-mentioned in amiloride combined SB203580 pretreatment group were significantly decreased (all P<0.05) yet.
Conclusion NHE1 inhibitor amiloride pretreatment can attenuate ALI induced by LPS in rats; extracellular signal-regulated kinase inhibitor can completely abolish this kind of protective effect of amiloride, which illustrated that this effect may be related to inhibition of extracellular signal-regulated kinase activation.
Part IV Expressions of Na+/H+ exchanger 1 in lipopolysaccharide-activated mouse macrophage-like cells and the pretreatment effect of amiloride
Objective To observe the changes of Na+/H+ exchanger 1(NHE1) mRNA and protein expressions in the lipopolysaccharide(LPS)-activated mouse macrophage-like cells and the pretreatment effect of amiloride.
Methods The mouse macrophage-like cell line (RAW 264.7) cells were seeded in 6 well plate with the density of 1×106/ml and cultured in RPMI 1640 medium at 37℃in 5% CO2 incubator for 48 h in vitro, then all cells were randomly divided into 4 groups(n=12):group C:control; amiloride group:RAW 264.7 cells were co-incubated with amiloride 300μM (final concentration); LPS group:RAW 264.7 cells were co-incubated with LPS 1μg/ml (final concentration); amiloride pretreatment group:RAW 264.7 cells were co-incubated with amiloride 300μM (final concentration) for 30 mins before co-incubated with LPS 1μg/ml (final concentration). The concentrations of tumor necrosis factor-α(TNF-α) and the levels of nitric oxide(NO) in cell culture supernatants in each group were detected with enzyme linked immunosorbent assay(ELISA) and the Griess method 24 h after the start of the trial. The levels of intracellular reactive oxygen species(ROS) in each group were detected with the ROS sensitivity DCFH-DA fluorescent probe method 24 h after the start of the trial. The expressions of NHE1 mRNA in each group were measured by reverse transcription-polymerase chain reaction (RT-PCR) 3 h after the start of the trial. The levels of NHE1 protein expressions in each group were also detected with Western blot analysis 6 h after the start of the trial.
Results Compared with the control group, the concentrations of TNF-a and the levels of NO in cell culture supernatants、the levels of intracellular ROS、the expressions of NHE1 mRNA and the levels of NHE1 protein expressions in amiloride group have no statistical difference(all P>0.05); but the indicators above-mentioned in LPS group and amiloride pretreatment group were significantly increased(all P<0.05). Compared with the LPS group, the indicators above-mentioned in amiloride pretreatment group were significantly decreased (all P<0.05).
Conclusion NHE1 can be rapidly activated and the expressions of NHE1 were increased in the LPS-activated mouse macrophage-like cells; pretreatment intervention with NHE 1 inhibitor amiloride can restrain the changes.
引文
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1. Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European Consensus conference on acute respiratory distress syndrome:definitions, mechanisms, relevant outcomes, and clinical trial coordination:consensus Committee. J Crit Care,1994,9:72-81.
2. Glassberg AE, Luce JM, Matthay MA, et al.. Reasons for nonenrollment in a clinical trial of acute lung injury. Chest,2008,134:719-23.
3. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS:definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med,1994,149:818-24.
4. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med,2000,342: 1334-1349.
5. Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol,2004,202:145-156.
6. Abraham E. Neutrophils and acute lung injury. Crit Care Med 2003,31:S195-199.
7. Slepkov ER,Rainey JK,Sykes BD, et al. Structural and functional analysis of the Na+/H+exchanger. Biochem J,2007,401(Pt3):623-633.
8. Orlowski J, Grinstein S. Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflugers Arch,2004,447:549-565.
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19. Podrez E A,Poliakov E, Shen Z, et al. A novel family of atherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptor CD36 and is enriched in atherosclerotic lesions. J Biol Chem,2002,277:38517-38523.
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24. Kaba NK, Schultz J, Law FY, et al. Inhibition of Na+/H+ exchanger enhances low pH-induced L-selectin shedding and β2-integrin surface expression in human neutrophils. Am J Physiol Cell Physiol,2008,295:C1454-1463.
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