NMDA受体的激活在高氧暴露后新生大鼠肺损伤和肺泡发育受阻中的作用及机制研究
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摘要
氧疗是临床上抢救治疗各种危重病人的重要措施之一。然而新生儿期长期吸入高浓度氧,可引起以中性粒细胞浸润为特征的弥漫性肺泡损害和以肺泡发育受阻及肺组织纤维化改变为主的慢性肺损伤。NMDA受体是谷氨酸受体的重要亚型,NMDA受体的过度激活可引起神经细胞内Ca~(2+)超载和Na~+蓄积,从而导致神经细胞的急性肿胀、迟发性坏死和凋亡。近年来发现在外周肺组织同样存在NMDA受体的表达,并参与急性肺损伤及弥漫性肺泡炎症反应。本室前期实验采用95%高浓度氧气持续暴露,成功建立了高氧致新生大鼠肺损伤模型。在此模型基础上证实高氧诱导肺组织释放内源性谷氨酸增加及NMDA受体表达增强,MK-801可减轻高氧诱导的新生大鼠肺损伤及炎症浸润程度,减轻持续高氧诱导的肺泡发育受阻及胶原的沉积,提示NMDA受体参与高氧诱导的慢性肺损伤的发生。但是NMDA受体参与高氧暴露后引起的新生大鼠肺泡发育受阻及肺组织纤维化的具体阶段及其机制尚不清楚。本实验将在整体及细胞水平深入探讨NMDA受体在高氧致新生大鼠慢性肺损伤中的作用及其机制。实验分为四部分:
第一章:不同高氧暴露时间对新生大鼠的影响
目的比较不同持续时间高氧暴露对新生大鼠肺组织的影响,选择较为理想的高氧致新生大鼠慢性肺损伤模型。
方法孕22天顺产分娩新生大鼠生后2-4小时内编号并随机分为3组:空气对照组,7天高氧+亚高氧组,3天高氧+空气组。7天高氧+亚高氧组持续维持≥95%高氧暴露7天后改为持续60%亚高氧暴露至生后21天;3天高氧+空气组为持续≥95%高氧暴露3天后接受常压空气;空气对照组置于同一室内,接受常压空气。观察各组一般情况及死亡率,分别在生后3天,7天,14天,21天后在各组随机抽取实验动物处死,进行体重、肺重、肺指数及肺湿重/干重(W/D)的测定;支气管肺泡灌洗检测LDH活性、蛋白含量和白细胞计数;同时检测肺组织HYP含量及肺组织形态检查计算RAC值。
结果
1.高氧7天+亚高氧组生存能力低,发育落后,死亡率高,持续高氧暴露3天时,肺组织W/D,BALF中LDH活性、蛋白含量、白细胞计数均显著升高;持续高氧暴露7天时肺指数开始明显升高,而W/D、蛋白含量、白细胞计数进一步升高,LDH活性虽有所下降但仍然高于空气对照组,第14天肺指数进一步升高,而W/D、LDH活性、蛋白含量、白细胞计数虽有所下降,但仍显著高于空气对照组。持续高氧暴露7天后可以显著增加胶原沉积,14天后更为明显。肺组织形态学检查发现持续高氧暴露3天后可见肺泡内初学及炎症细胞浸润,持续高氧暴露7天时,可见肺泡内出血及肺泡炎症细胞浸润明显增加,肺间隔增宽,肺组织正常结构局灶性破坏,局部肺结构紊乱,终末气腔明显扩张、小肺泡数量减少。持续高氧暴露14天时,肺间隔更宽,肺间质大量血性渗出,肺组织正常结构破坏,终末气腔扩张更为明显、小肺泡数量更少。
2.高氧3天+空气组一般情况与空气对照组比较无明显差别,存活率低于空气对照组但高于持续高氧暴露组,停止高氧暴露4天(生后7天)除肺指数及W/D外,BALF中LDH活性、蛋白含量及白细胞计数均与对照组无显著差异,且均显著低于持续高氧暴露组;停止高氧暴露11天(生后14天),上述所有指标均与空气对照组无明显差异。HYP在停止高氧暴露11天(生后14天)后虽然低于持续高氧组,但开始显著高于空气对照组,在21天后增加更为明显。形态学检查发现停止高氧暴露4天(生后7天)时肺泡内则少见炎性渗出,与空气对照组无明显区别,14天时出现肺泡间隔增宽,21天时形成明显的纤维增生。
结论
1.持续高氧3天可以引起新生大鼠肺组织急性肺损伤及肺泡炎症的发生。随持续高氧暴露时间越长,新生大鼠急性高氧性肺损伤程度越重。
2.在持续高氧7天后改为60%亚高氧继续暴露至生后14天,肺急性损伤及肺泡炎症相对减轻,而胶原沉积、肺泡发育受阻进一步加重。所有动物均不能存活至21天。
3.3天短暂的高氧后,随生后时间延长虽然停止高氧暴露肺脏仍然会逐渐出现肺泡发育受阻及肺纤维化为特点的慢性损伤改变。
第二章:高氧不同阶段应用MK-801对3天高氧暴露所致新生大鼠肺发育受阻及胶原沉积的影响
目的比较在高氧致新生大鼠肺损伤不同阶段应用MK-801对肺损伤的影响,探寻NMDA受体在高氧致新生大鼠慢性肺损伤发生发展中的作用
方法孕22天顺产分娩新生大鼠生后2-4小时内编号并随机分为六组:空气对照组,空气+MK-801 A组(出生1-3天使用MK-801),空气+MK-801 B组(出生8-10天使用MK-801),高氧组,高氧+MK-801A组(高氧暴露同时使用MK-801),高氧+MK-801 B(高氧暴露停止4天后开始使用MK-801)组。其中高氧组、高氧+MK-801A组和高氧+MK-801 B组新生大鼠生后即置于≥95%氧仓中持续高氧暴露3天后接受常压空气;空气+MK-801 A组和高氧+MK-801 A组新生大鼠生后1天开始每日腹腔注射MK-801 0.05mg/kg,连用3天;空气+MK-801 B组和高氧+MK-801 B组在生后8开始每日腹腔注射MK-801 0.05mg/kg,连用3天。分别在生后的第3天,第7天,第14天,第21天处死动物。进行体重、肺重、肺指数及肺湿重/于重(W/D)的测定;支气管肺泡灌洗检测LDH活性、蛋白含量和白细胞计数;同时检测肺组织HYP含量:检测肺组织病理学形态检查,计算RAC值;在在后21天时进行肺功能的检测。
结果
1.高氧暴露1-3d时应用MK-801(高氧+MK-801 A组),可以减轻高氧导致的生后3天及7天肺泡损伤及弥漫性炎症反应,降低生后3天及7天高氧致W/D及肺指数的升高,降低生后14天及21天高氧致HYP含量的升高,改善高氧致肺纤维化程度及肺泡发育受阻,改善高氧所致生后21天时肺顺应性的下降。
2.高氧暴露3d后至生后8-10d应用MK-801(高氧+MK-801 B组),HYP含量、肺顺应性在生后14天和/或21天明显低于高氧组,但高于高氧+MK-801 A组;RAC值高于高氧组,低于高氧+MK-801 A组。
结论首次发现NMDA受体阻断剂MK-801对高氧致新生大鼠肺损伤的保护作用除了减轻早期细胞损伤及炎症反应外,还可以直接抑制高氧诱导的肺组织胶原沉积及肺泡发育受阻。提示NMDA受体的激活参与了高氧诱导的慢性肺损伤的发展。
第三章:NMDA受体的激活对人胎肺成纤维细胞胶原分泌和自身降解的影响
目的:检测NMDA受体在人胎肺成纤维细胞上的表达,并观察其在人胎肺成纤维细胞胶原分泌与自身降解中的作用。
方法
1.免疫组织化学及免疫荧光染色法检测人胎肺成纤维细胞NMDAR1,NR2D表达,实时定量PCR方法(Real Time PCR)检测人胎肺成纤维细胞NR1和NR2A,NR2B、NR2C和NR2D受体亚单位mRNA表达。
2.直接细胞计数法及MTT检测不同浓度谷氨酸或NMDA对人胎肺成纤维细胞增殖的影响。
3.检测不同浓度谷氨酸或NMDA对人胎肺成纤维细胞培养上清液中HYP的影响。
4.ELISA法检测NMDA对人胎肺成纤维细胞培养上清液中Ⅰ,Ⅲ型胶原及MMP-1,TIMP-1分泌的影响
结果
1.正常人胎肺成纤维细胞上存在NMDARs mRNA表达,并且五种受体表达程度并不相同,以NMDAR2A及NMDAR2D表达最强,随后依次为NMDAR2C、NMDA2B和NMDAR1。免疫组化及免疫荧光显人胎肺成纤维细胞存在NMDAR1及NR2D的表达。
2.直接细胞计数显示在试验72小时后1mM谷氨酸及1mM NMDA组与其他组相比明显促进人胎肺成纤维细胞增殖,1mM谷氨酸显著高于1mM NMDA组,10mM谷氨酸组与其他组相比抑制增殖。其余各组无显著差异。MTT法显示1mM谷氨酸组与对照组相比MTT值明显增加,MK-801可抑制1mM谷氨酸引起的MTT增加。1mM NMDA组MTT值明显低于1mM谷氨酸组,并与对照组比无显著差异。单独加入MK-801组与对照组及加入NMDA培养细胞无显著差异。
3.人胎肺成纤维细胞上清液中HYP的测定显示1mM NMDA组与对照组比较显著增高,1mM谷氨酸组与对照组比较显著增高,NMDA组显著高于谷氨酸组。MK-801可以抑制NMDA或谷氨酸诱导的HYP的升高。
4.正常培养人胎肺成纤维细胞存在基础的Ⅰ/Ⅲ型胶原及MMP-1/TIMP-1分泌。NMDA组与对照组比较,Ⅰ/Ⅲ型胶原含量及TIMP-1分泌显著增加,对MMP-1分泌无显著影响。MK-801可以显著抑制NMDA诱导的Ⅰ/Ⅲ型胶原含量及TTMP-1分泌的增加。单独应用MK-801与对照组比较Ⅰ型胶原含量显著降低,对Ⅲ型胶原及MMP-1/TIMP-1的正常分泌无显著影响。
结论
1.人胎肺成纤维细胞存在NMDA受体表达,以NR2A,NR2D表达最强。
2.首次发现谷氨酸可以促进人胎肺成纤维细胞增殖。
3.NMDA受体激活可以促进人胎肺成纤维细胞胶原分泌增加和自身降解的减少
第四章:NMDA受体激活促进人胎肺成纤维细胞胶原和TIMP-1分泌的细胞内信号转导途径
目的:研究NMDAR在人胎肺成纤维细胞胶原分泌及降解中的细胞信号转导通路,论证NMDAR在人胎肺成纤维细胞细胞外基质分泌与自身降解中的作用机制。
方法
1.Western Blot法观察NMDA对人胎肺成纤维细胞pERK的影响,
2.ELISA法观察阻断ERK_(1/2)磷酸化及PKC后对NMDA促人胎肺成纤维细胞Ⅰ/Ⅲ型胶原,MMP1/TIMP1释放的影响。
3.定量PCR方法(Real Time PCR)检测NMDA对人胎肺成纤维细胞NMDARs mRNA表达的影响。
结果
1.正常人胎肺成纤维细胞存在ERK_(1/2)磷酸化,1mM NMDA可以促进ERK_(1/2)磷酸化增强,MK-801可以降低1mM NMDA诱导的ERK磷酸化增强。ERK磷酸化抑制剂U0126可以显著降低细胞正常ERK_(1/2)磷酸化水平,阻断NMDA诱导的ERK_(1/2)磷酸化增强。PKC抑制剂H7也可以显著降低细胞正常ERK_(1/2)磷酸化水平,阻断NMDA诱导的ERK_(1/2)磷酸化增强。
2.U0126组与对照组比较Ⅰ/Ⅲ型胶原分泌显著降低,对TIMP-1、MMP-1分泌无显著影响。U0126可以显著抑制NMDA诱导的Ⅰ/Ⅲ型胶原含量及TIMP-1分泌的增加。H7组与对照组比较Ⅰ型胶原分泌显著降低,对Ⅲ型胶原含量及TIMP-1、MMP-1分泌无显著影响。H7可以显著抑制NMDA诱导的Ⅰ/Ⅲ型胶原含量及TIMP-1分泌的增加。
3.1mM NMDA作用372小时后,NR1 mRNA表达无显著改变。NR2D mRNA对表达显著增强六倍以上,NR2B/NR2C mRNA表达也较对照组显著增强。NR2A mRNA表达显著下降。
结论
1.NMDA可以通过NMDA受体介导ERK_(1/2)磷酸化影响人胎肺成纤维细胞胶原的分泌与自身降解。
2.NMDAR-PKC-ERR_(1/2)途径是NMDA促人胎肺成纤维细胞胶原分泌与降解的细胞信号转导通路之一。
3.NMDA可以引起人胎肺成纤维细胞NMDA受体各亚基表达改变,其生物学意义有待进一步研究。
Background
Oxygen therapy is an important measure to improve the state of hypoxia.But prolonged inhalation of high concentrations of oxygen (hyperoxia) will lead to varying degrees of acute and chronic lung injury. Neonatal period is alveolar mature critical period,long-term inhalation of high concentrations of oxygen could lead to diffuse alveolar damage associated with infiltration of inflammatory cells characterized by acute lung injury and alveolization impairment and fibrosis mainly characterized chronic lung injury.
Glutamate is one of the major excitatory neurotransmitters and is abundantly present in the mammalian central nervous system(CNS).It plays key roles in brain development,learning and memory,and synaptic plasticity.On the other hand,glutamate may also be lethal to neurons, through over-activation of N-methyl-D-aspartate receptors (NMDAR).This results in an influx of a large quantity of calcium,which triggers a series of toxic events and ultimately leads to cell death. Over-stimulation of NMDA receptors can lead to neuronal cell death under many acute and chronic conditions,and has been found responsible for neural loss in ischemia,epilepsy,Parkinson's disease,Alzheimer's disease,Huntington's chorea,and AIDS encephalopathy.
The earlier stage of our examination had found that hyperoxia can induce a high level of the releasing of Glu and the expressing of NMDAR, and MK-801 could decrease the hyperoxia-associated lung injury.For the first time,we conclude that Glu may play an important role in hyperoxia-induced lung injury by activation of NMDA receptor. However,it remains indistinct of the NMDA receptor effects on the alveolar development and lung collagen deposition after hyperoxic exposure,and also unclear that the relationship between NMDA receptor and lung fibroblasts.Our investigation could provide a new way to solve this contradictive clinical trouble.
ChapterⅠEffect of Different Prolong Hyperoxia Exposure Days on Newborn Rat
Objective
To establish more reasonable animal model of CLD in newborn rats by comparing the effect of different prolong hyperoxia exposure days on hyperoxia-induced lung injury.
Methods
The 22-day gestation full term rats in 2-4 hours after birth were randomly marked with a diferent number and assigned to three groups:air control group,hyperoxia group with 95%O_2 for 7 days,followed by 60%O_2 14 days and hyperoxia group with 95%O_2 for 3 days,followed by air condition 14 days.Postnatal 3,7,14 and 21 days,the neonatal rats were sacrificed with an overdose of intra-peritoneal pentobarbital,and exsanguinated by severing the abdominal aorta.The counts of inflammatory cell,the content of protein,LDH in bronchoalveolar lavage fluid(BALF);body weight,lung weight,lung dry weight,lung index,the ratio of lung wet weight to lung dry weight(W/D),the content of hydroxyproline in the Lung homogenates and histological changes, including staining of HE,and radical alveolar count(RAC) were measured respectively.All data were expressed as means±SD and analyzed by one-way ANOVA and LSD-t test with SPSS 13.0 statistical software.Values at P＜0.05 were considered statistical significant.
Result
1.Lung index,lung W/D and BALF analyse:After having 3days of exposure,the hyperoxia group has been saw a significant increase in lung W/D and BALF inflammatory cell counts,protein and LDH.If stopping hyperoxia exposure at this time,above-mentioned index decline to normal except W/D and lung index,and no obvious change in the next days.After having 7 days of exposure,above-mentioned index further increase compared with 3~(rd) day and air control group. Postnatal 14 day,they have declined and lower than the 7~(th) day,but still higher than air control group.
2.The content of HYP in lung homogenates have increased after 7days of exposure compared with the air control group,with the days of exposure increasing,the content continue increased and much higher than air control group.If stopping hyperoxia exposure at postnatal 3 day,it does not increase significantly until postnatal 14 day,and going further at 21 day.
3.Lung histology and RAC:The hyperoxia group showed dilated and congestive capillary vessels,erythrocyte extravasation,and leukocyte infiltration in alveolar,pulmonary interstitial inflammation cell infiltration and a little collagen deposition.The pathologic changes were more and more severe with days of exposure increasing that broadened pulmonary interstitial tissue and disruption of the alveolar structure were saw in the lung tissures.At the same time,RAC has decreased dramatically in the hyperoxia group.If stopping hyperoxia exposure at postnatal 3 day,pulmonary alveolus inflammation cell infiltrations disappear at 7 day.At 14 and 21 day,fibroelastosis and fewer RAC were found compared with the control group.
Conclusion
1.High concentration of≥95%oxygen can cause acute inflammatory lung injury in newborn rats after 3 days exposure,and aggravated with the prolong of exposure days.Lung injury change from early alveolitis acute damage to the alveolization impairment and lung tissue fibrosis with a lot of collagen deposition.
2.3 days of hyperoxia exposure can induced CLD characteristiced by alveolization impairment,lung collagen deposition and fibroelastosis.
ChapterⅡEffect of MK-801on 3 Days Hyperoxia Induced Alveolization Impairment and Lung Injury inNewborn Rat at Different Stages of Hyperoxia Exposure
Ojective
To research the direct role of NMDAR in hyperoxia induced BPD by comparing the effect of applications of MK-801 at different times.
Methods
The 22-day gestation full term rats in 2-4 hours after birth were randomly marked with a diferent number and assigned to six groups:air control group,air +MK-801 group with injection MK-801 at postnatal 1-3 days, air +MK-801 group with injection MK-801 at postnatal 8-10 days, hyperoxia group with 95%O_2 for 3 days,hyperoxia +MK-801 group with injection MK-801 at postnatal 1-3 days and hyperoxia +MK-801 group with injection MK-801 at postnatal 8-10-3 days.At postnatal 3,7,14 and 21 days,the neonatal rats were sacrificed with an overdose of intra-peritoneal pentobarbital,and exsanguinated by severing the abdominal aorta.The counts of inflammatory cell,the content of protein, LDH in bronchoalveolar lavage fluid(BALF);body weight,lung weight, lung dry weight,lung index,the ratio of lung wet weight to lung dry weight(W/D),the content of hydroxyproline in the Lung homogenates and histological changes,including staining of HE,and radical alveolar count(RAC) were measured respectively.Pulmonary respiratory function was measure too at 21st day.All data were expressed as means±SD and analyzed by one-way ANOVA and LSD-t test with SPSS 13.0 statistical software.Values at P＜0.05 were considered statistical significant.
Result
1.Application of MK-801 in hyperoxia exposure days,W/D and BALF inflammatory cell counts,protein and LDH were significantly decreased at postnatal 3 day.HYP and RAC were lower than air control at postnatal 14 and 21 day.Cdyn was declined compared with air control at postnatal 21 day.The degree of pulmonary fibrosis and alveolization impairment were reduced.
2.Application of MK-801 in post hyperoxia exposure,HYP,Cdyn and RAC were lower than air control at postnatal 21 day although their higher than use of MK-801 in hyperoxia exposure days.The degree of pulmonary fibrosis and alveolization impairment were also reduced.
Conclusion
The role of NMDAR on hyperoxia-induced CLD is not only the inhibition of early cell injury and inflammation,but also the direct relationship between the NMDAR and the progress of chronic lung injury. Which suggest that NMDAR may immediacy take part in the alveolar development of newborn rat and fibroelastosis induced by hyperoxia.
ChapterⅢCollagen Secretion and Self-degradation Mediated by NMDR Activation in Human Fetal Lung Fibroblasts
Objective
To detect the expression of NMDA receptors in human fetal lung fibroblasts,and observe the role of NMDAR in the secretion and self-degradation of collagen.
Methods
1.NMDAR1 and NR2D expression was analyzed by Immunohistochemistry and immunofluorescence,
2.Expression of NMDAR1 and four NR2 subunit(NR2A,NR2B,NR2C and N2D) mRNA were examined by real-time PCR.
3.Cell proliferations were measured by cell counting and MTT in different concentrations of glutamate or NMDA.
4.Detection of HYP in cell supernatant at different concentrations of glutamate or NMDA.
5.Ⅰ,Ⅲcollagen and MMP-1,TIMP-1 secretion in cell supematant were measured by ELISA.
Result
1.Immunohistochemistry and immunofluorescence indicated the expression of NR1 and NR2D.
2.real time PCR detected the expression of NR1 and four NR2D subtypes(A,B,C and D) mRNA,the strongest two subtypes are NR2A and NR2D,followed by N2C,N2B and NAR1.
3.1mM glutamate and NMDA can promote cell proliferation,1mM glutamate was significantly higher than 1mM NMDA group,10mM glutamate group inhibit the proliferation.
4.1mM glutamate and NMDA can promote the secretion of HYP,1mM NMDA was significantly higher than 1mM glutamate group,MK-801 can inhibit the NMDA or glutamate-induced increase in HYP.
5.1mM NMDA induced secretion increase inⅠ/Ⅲcollagen and TIMP-1, secretion of MMP-1 have no significant effect.0.5mM MK-801 could significantly inhibit the NMDA-induced increase ofⅠ/Ⅲcollagen and TIMP- 1.
Conclusion
1.We found Glutamate can promote human fetal lung fibroblasts proliferation for the first time.
2.NR1 and four NR2D subtypes(A,B,C and D) all express in human fetal lung fibroblasts.
3.NMDA can promote the secretion of collagen,and inhibit collagen self-degradation in human fetal lung fibroblasts.
ChapterⅣCell Signaling Pathways of NMDA-mediated Collagen Secretion and Self-degradation in Human Fetal Lung Fibroblasts
Objective To study the cell signaling pathways in human fetal lung fibroblast collagen secretion and self-degradation though NMDAR.
Methods
1.Measurement of phosphorylated ERK by Western Blot in human fetal lung fibroblasts
2.Detection ofⅠ/Ⅲcollagen,MMP1/TIMP1 by ELISA after inhibiting NMDAR,ERK phosphorylation and PKC.
3.Change of expression for NMDAR1 and four NR2 subunits(NR2A, NR2B,NR2C and N2D ) rnRNA after being induced by NMDA were examined by real-time PCR.
Result
1.NMDA can enhance ERK phosphorylation;MK-801 can reduce NMDA-induced phosphorylation of ERK.Phosphorylated ERK inhibitor U0126 significantly reduced ERK phosphorylation in normal cells,and blocks the increase of NMDA-induced phosphorylation of ERK.PKC inhibitor H7 show a significant reduction in the normal cells,and block the increase of NMDA-induced phosphorylation of ERK.
2.NMDA induced the increase ofⅠ/Ⅲcollagen and TIMP-1 secretion were significantly inhibited by ERK inhibitor U0126 and PKC inhibitor H7
3.NR1 no signifcant change in expression after application of NMDA. NR2D expression markedly increased more than six-fold,NR2B and NR2C expression was signifcantly enhanced compared with the control group.NR2A expression decreased significantly.
Conclusion.
1.The secretion and self-degradation of collagen induced by NMDA in human fetal lung fibroblasts was through NMDA-mediated ERK phosphorylation.
2.NMDAR-PKC-ERK_(1/2) pathway was one of the cell signaling pathways in NMDA-mediated collagen secretion and self degradation of human fetal lung fibroblasts.
3.NR2D may play an important role in NMDAR-mediated collagen secretion and self-degradation in human fetal lung fibroblasts.
第一章:不同高氧暴露时间对新生大鼠的影响
目的比较不同持续时间高氧暴露对新生大鼠肺组织的影响,选择较为理想的高氧致新生大鼠慢性肺损伤模型。
方法孕22天顺产分娩新生大鼠生后2-4小时内编号并随机分为3组:空气对照组,7天高氧+亚高氧组,3天高氧+空气组。7天高氧+亚高氧组持续维持≥95%高氧暴露7天后改为持续60%亚高氧暴露至生后21天;3天高氧+空气组为持续≥95%高氧暴露3天后接受常压空气;空气对照组置于同一室内,接受常压空气。观察各组一般情况及死亡率,分别在生后3天,7天,14天,21天后在各组随机抽取实验动物处死,进行体重、肺重、肺指数及肺湿重/干重(W/D)的测定;支气管肺泡灌洗检测LDH活性、蛋白含量和白细胞计数;同时检测肺组织HYP含量及肺组织形态检查计算RAC值。
结果
1.高氧7天+亚高氧组生存能力低,发育落后,死亡率高,持续高氧暴露3天时,肺组织W/D,BALF中LDH活性、蛋白含量、白细胞计数均显著升高;持续高氧暴露7天时肺指数开始明显升高,而W/D、蛋白含量、白细胞计数进一步升高,LDH活性虽有所下降但仍然高于空气对照组,第14天肺指数进一步升高,而W/D、LDH活性、蛋白含量、白细胞计数虽有所下降,但仍显著高于空气对照组。持续高氧暴露7天后可以显著增加胶原沉积,14天后更为明显。肺组织形态学检查发现持续高氧暴露3天后可见肺泡内初学及炎症细胞浸润,持续高氧暴露7天时,可见肺泡内出血及肺泡炎症细胞浸润明显增加,肺间隔增宽,肺组织正常结构局灶性破坏,局部肺结构紊乱,终末气腔明显扩张、小肺泡数量减少。持续高氧暴露14天时,肺间隔更宽,肺间质大量血性渗出,肺组织正常结构破坏,终末气腔扩张更为明显、小肺泡数量更少。
2.高氧3天+空气组一般情况与空气对照组比较无明显差别,存活率低于空气对照组但高于持续高氧暴露组,停止高氧暴露4天(生后7天)除肺指数及W/D外,BALF中LDH活性、蛋白含量及白细胞计数均与对照组无显著差异,且均显著低于持续高氧暴露组;停止高氧暴露11天(生后14天),上述所有指标均与空气对照组无明显差异。HYP在停止高氧暴露11天(生后14天)后虽然低于持续高氧组,但开始显著高于空气对照组,在21天后增加更为明显。形态学检查发现停止高氧暴露4天(生后7天)时肺泡内则少见炎性渗出,与空气对照组无明显区别,14天时出现肺泡间隔增宽,21天时形成明显的纤维增生。
结论
1.持续高氧3天可以引起新生大鼠肺组织急性肺损伤及肺泡炎症的发生。随持续高氧暴露时间越长,新生大鼠急性高氧性肺损伤程度越重。
2.在持续高氧7天后改为60%亚高氧继续暴露至生后14天,肺急性损伤及肺泡炎症相对减轻,而胶原沉积、肺泡发育受阻进一步加重。所有动物均不能存活至21天。
3.3天短暂的高氧后,随生后时间延长虽然停止高氧暴露肺脏仍然会逐渐出现肺泡发育受阻及肺纤维化为特点的慢性损伤改变。
第二章:高氧不同阶段应用MK-801对3天高氧暴露所致新生大鼠肺发育受阻及胶原沉积的影响
目的比较在高氧致新生大鼠肺损伤不同阶段应用MK-801对肺损伤的影响,探寻NMDA受体在高氧致新生大鼠慢性肺损伤发生发展中的作用
方法孕22天顺产分娩新生大鼠生后2-4小时内编号并随机分为六组:空气对照组,空气+MK-801 A组(出生1-3天使用MK-801),空气+MK-801 B组(出生8-10天使用MK-801),高氧组,高氧+MK-801A组(高氧暴露同时使用MK-801),高氧+MK-801 B(高氧暴露停止4天后开始使用MK-801)组。其中高氧组、高氧+MK-801A组和高氧+MK-801 B组新生大鼠生后即置于≥95%氧仓中持续高氧暴露3天后接受常压空气;空气+MK-801 A组和高氧+MK-801 A组新生大鼠生后1天开始每日腹腔注射MK-801 0.05mg/kg,连用3天;空气+MK-801 B组和高氧+MK-801 B组在生后8开始每日腹腔注射MK-801 0.05mg/kg,连用3天。分别在生后的第3天,第7天,第14天,第21天处死动物。进行体重、肺重、肺指数及肺湿重/于重(W/D)的测定;支气管肺泡灌洗检测LDH活性、蛋白含量和白细胞计数;同时检测肺组织HYP含量:检测肺组织病理学形态检查,计算RAC值;在在后21天时进行肺功能的检测。
结果
1.高氧暴露1-3d时应用MK-801(高氧+MK-801 A组),可以减轻高氧导致的生后3天及7天肺泡损伤及弥漫性炎症反应,降低生后3天及7天高氧致W/D及肺指数的升高,降低生后14天及21天高氧致HYP含量的升高,改善高氧致肺纤维化程度及肺泡发育受阻,改善高氧所致生后21天时肺顺应性的下降。
2.高氧暴露3d后至生后8-10d应用MK-801(高氧+MK-801 B组),HYP含量、肺顺应性在生后14天和/或21天明显低于高氧组,但高于高氧+MK-801 A组;RAC值高于高氧组,低于高氧+MK-801 A组。
结论首次发现NMDA受体阻断剂MK-801对高氧致新生大鼠肺损伤的保护作用除了减轻早期细胞损伤及炎症反应外,还可以直接抑制高氧诱导的肺组织胶原沉积及肺泡发育受阻。提示NMDA受体的激活参与了高氧诱导的慢性肺损伤的发展。
第三章:NMDA受体的激活对人胎肺成纤维细胞胶原分泌和自身降解的影响
目的:检测NMDA受体在人胎肺成纤维细胞上的表达,并观察其在人胎肺成纤维细胞胶原分泌与自身降解中的作用。
方法
1.免疫组织化学及免疫荧光染色法检测人胎肺成纤维细胞NMDAR1,NR2D表达,实时定量PCR方法(Real Time PCR)检测人胎肺成纤维细胞NR1和NR2A,NR2B、NR2C和NR2D受体亚单位mRNA表达。
2.直接细胞计数法及MTT检测不同浓度谷氨酸或NMDA对人胎肺成纤维细胞增殖的影响。
3.检测不同浓度谷氨酸或NMDA对人胎肺成纤维细胞培养上清液中HYP的影响。
4.ELISA法检测NMDA对人胎肺成纤维细胞培养上清液中Ⅰ,Ⅲ型胶原及MMP-1,TIMP-1分泌的影响
结果
1.正常人胎肺成纤维细胞上存在NMDARs mRNA表达,并且五种受体表达程度并不相同,以NMDAR2A及NMDAR2D表达最强,随后依次为NMDAR2C、NMDA2B和NMDAR1。免疫组化及免疫荧光显人胎肺成纤维细胞存在NMDAR1及NR2D的表达。
2.直接细胞计数显示在试验72小时后1mM谷氨酸及1mM NMDA组与其他组相比明显促进人胎肺成纤维细胞增殖,1mM谷氨酸显著高于1mM NMDA组,10mM谷氨酸组与其他组相比抑制增殖。其余各组无显著差异。MTT法显示1mM谷氨酸组与对照组相比MTT值明显增加,MK-801可抑制1mM谷氨酸引起的MTT增加。1mM NMDA组MTT值明显低于1mM谷氨酸组,并与对照组比无显著差异。单独加入MK-801组与对照组及加入NMDA培养细胞无显著差异。
3.人胎肺成纤维细胞上清液中HYP的测定显示1mM NMDA组与对照组比较显著增高,1mM谷氨酸组与对照组比较显著增高,NMDA组显著高于谷氨酸组。MK-801可以抑制NMDA或谷氨酸诱导的HYP的升高。
4.正常培养人胎肺成纤维细胞存在基础的Ⅰ/Ⅲ型胶原及MMP-1/TIMP-1分泌。NMDA组与对照组比较,Ⅰ/Ⅲ型胶原含量及TIMP-1分泌显著增加,对MMP-1分泌无显著影响。MK-801可以显著抑制NMDA诱导的Ⅰ/Ⅲ型胶原含量及TTMP-1分泌的增加。单独应用MK-801与对照组比较Ⅰ型胶原含量显著降低,对Ⅲ型胶原及MMP-1/TIMP-1的正常分泌无显著影响。
结论
1.人胎肺成纤维细胞存在NMDA受体表达,以NR2A,NR2D表达最强。
2.首次发现谷氨酸可以促进人胎肺成纤维细胞增殖。
3.NMDA受体激活可以促进人胎肺成纤维细胞胶原分泌增加和自身降解的减少
第四章:NMDA受体激活促进人胎肺成纤维细胞胶原和TIMP-1分泌的细胞内信号转导途径
目的:研究NMDAR在人胎肺成纤维细胞胶原分泌及降解中的细胞信号转导通路,论证NMDAR在人胎肺成纤维细胞细胞外基质分泌与自身降解中的作用机制。
方法
1.Western Blot法观察NMDA对人胎肺成纤维细胞pERK的影响,
2.ELISA法观察阻断ERK_(1/2)磷酸化及PKC后对NMDA促人胎肺成纤维细胞Ⅰ/Ⅲ型胶原,MMP1/TIMP1释放的影响。
3.定量PCR方法(Real Time PCR)检测NMDA对人胎肺成纤维细胞NMDARs mRNA表达的影响。
结果
1.正常人胎肺成纤维细胞存在ERK_(1/2)磷酸化,1mM NMDA可以促进ERK_(1/2)磷酸化增强,MK-801可以降低1mM NMDA诱导的ERK磷酸化增强。ERK磷酸化抑制剂U0126可以显著降低细胞正常ERK_(1/2)磷酸化水平,阻断NMDA诱导的ERK_(1/2)磷酸化增强。PKC抑制剂H7也可以显著降低细胞正常ERK_(1/2)磷酸化水平,阻断NMDA诱导的ERK_(1/2)磷酸化增强。
2.U0126组与对照组比较Ⅰ/Ⅲ型胶原分泌显著降低,对TIMP-1、MMP-1分泌无显著影响。U0126可以显著抑制NMDA诱导的Ⅰ/Ⅲ型胶原含量及TIMP-1分泌的增加。H7组与对照组比较Ⅰ型胶原分泌显著降低,对Ⅲ型胶原含量及TIMP-1、MMP-1分泌无显著影响。H7可以显著抑制NMDA诱导的Ⅰ/Ⅲ型胶原含量及TIMP-1分泌的增加。
3.1mM NMDA作用372小时后,NR1 mRNA表达无显著改变。NR2D mRNA对表达显著增强六倍以上,NR2B/NR2C mRNA表达也较对照组显著增强。NR2A mRNA表达显著下降。
结论
1.NMDA可以通过NMDA受体介导ERK_(1/2)磷酸化影响人胎肺成纤维细胞胶原的分泌与自身降解。
2.NMDAR-PKC-ERR_(1/2)途径是NMDA促人胎肺成纤维细胞胶原分泌与降解的细胞信号转导通路之一。
3.NMDA可以引起人胎肺成纤维细胞NMDA受体各亚基表达改变,其生物学意义有待进一步研究。
Background
Oxygen therapy is an important measure to improve the state of hypoxia.But prolonged inhalation of high concentrations of oxygen (hyperoxia) will lead to varying degrees of acute and chronic lung injury. Neonatal period is alveolar mature critical period,long-term inhalation of high concentrations of oxygen could lead to diffuse alveolar damage associated with infiltration of inflammatory cells characterized by acute lung injury and alveolization impairment and fibrosis mainly characterized chronic lung injury.
Glutamate is one of the major excitatory neurotransmitters and is abundantly present in the mammalian central nervous system(CNS).It plays key roles in brain development,learning and memory,and synaptic plasticity.On the other hand,glutamate may also be lethal to neurons, through over-activation of N-methyl-D-aspartate receptors (NMDAR).This results in an influx of a large quantity of calcium,which triggers a series of toxic events and ultimately leads to cell death. Over-stimulation of NMDA receptors can lead to neuronal cell death under many acute and chronic conditions,and has been found responsible for neural loss in ischemia,epilepsy,Parkinson's disease,Alzheimer's disease,Huntington's chorea,and AIDS encephalopathy.
The earlier stage of our examination had found that hyperoxia can induce a high level of the releasing of Glu and the expressing of NMDAR, and MK-801 could decrease the hyperoxia-associated lung injury.For the first time,we conclude that Glu may play an important role in hyperoxia-induced lung injury by activation of NMDA receptor. However,it remains indistinct of the NMDA receptor effects on the alveolar development and lung collagen deposition after hyperoxic exposure,and also unclear that the relationship between NMDA receptor and lung fibroblasts.Our investigation could provide a new way to solve this contradictive clinical trouble.
ChapterⅠEffect of Different Prolong Hyperoxia Exposure Days on Newborn Rat
Objective
To establish more reasonable animal model of CLD in newborn rats by comparing the effect of different prolong hyperoxia exposure days on hyperoxia-induced lung injury.
Methods
The 22-day gestation full term rats in 2-4 hours after birth were randomly marked with a diferent number and assigned to three groups:air control group,hyperoxia group with 95%O_2 for 7 days,followed by 60%O_2 14 days and hyperoxia group with 95%O_2 for 3 days,followed by air condition 14 days.Postnatal 3,7,14 and 21 days,the neonatal rats were sacrificed with an overdose of intra-peritoneal pentobarbital,and exsanguinated by severing the abdominal aorta.The counts of inflammatory cell,the content of protein,LDH in bronchoalveolar lavage fluid(BALF);body weight,lung weight,lung dry weight,lung index,the ratio of lung wet weight to lung dry weight(W/D),the content of hydroxyproline in the Lung homogenates and histological changes, including staining of HE,and radical alveolar count(RAC) were measured respectively.All data were expressed as means±SD and analyzed by one-way ANOVA and LSD-t test with SPSS 13.0 statistical software.Values at P＜0.05 were considered statistical significant.
Result
1.Lung index,lung W/D and BALF analyse:After having 3days of exposure,the hyperoxia group has been saw a significant increase in lung W/D and BALF inflammatory cell counts,protein and LDH.If stopping hyperoxia exposure at this time,above-mentioned index decline to normal except W/D and lung index,and no obvious change in the next days.After having 7 days of exposure,above-mentioned index further increase compared with 3~(rd) day and air control group. Postnatal 14 day,they have declined and lower than the 7~(th) day,but still higher than air control group.
2.The content of HYP in lung homogenates have increased after 7days of exposure compared with the air control group,with the days of exposure increasing,the content continue increased and much higher than air control group.If stopping hyperoxia exposure at postnatal 3 day,it does not increase significantly until postnatal 14 day,and going further at 21 day.
3.Lung histology and RAC:The hyperoxia group showed dilated and congestive capillary vessels,erythrocyte extravasation,and leukocyte infiltration in alveolar,pulmonary interstitial inflammation cell infiltration and a little collagen deposition.The pathologic changes were more and more severe with days of exposure increasing that broadened pulmonary interstitial tissue and disruption of the alveolar structure were saw in the lung tissures.At the same time,RAC has decreased dramatically in the hyperoxia group.If stopping hyperoxia exposure at postnatal 3 day,pulmonary alveolus inflammation cell infiltrations disappear at 7 day.At 14 and 21 day,fibroelastosis and fewer RAC were found compared with the control group.
Conclusion
1.High concentration of≥95%oxygen can cause acute inflammatory lung injury in newborn rats after 3 days exposure,and aggravated with the prolong of exposure days.Lung injury change from early alveolitis acute damage to the alveolization impairment and lung tissue fibrosis with a lot of collagen deposition.
2.3 days of hyperoxia exposure can induced CLD characteristiced by alveolization impairment,lung collagen deposition and fibroelastosis.
ChapterⅡEffect of MK-801on 3 Days Hyperoxia Induced Alveolization Impairment and Lung Injury inNewborn Rat at Different Stages of Hyperoxia Exposure
Ojective
To research the direct role of NMDAR in hyperoxia induced BPD by comparing the effect of applications of MK-801 at different times.
Methods
The 22-day gestation full term rats in 2-4 hours after birth were randomly marked with a diferent number and assigned to six groups:air control group,air +MK-801 group with injection MK-801 at postnatal 1-3 days, air +MK-801 group with injection MK-801 at postnatal 8-10 days, hyperoxia group with 95%O_2 for 3 days,hyperoxia +MK-801 group with injection MK-801 at postnatal 1-3 days and hyperoxia +MK-801 group with injection MK-801 at postnatal 8-10-3 days.At postnatal 3,7,14 and 21 days,the neonatal rats were sacrificed with an overdose of intra-peritoneal pentobarbital,and exsanguinated by severing the abdominal aorta.The counts of inflammatory cell,the content of protein, LDH in bronchoalveolar lavage fluid(BALF);body weight,lung weight, lung dry weight,lung index,the ratio of lung wet weight to lung dry weight(W/D),the content of hydroxyproline in the Lung homogenates and histological changes,including staining of HE,and radical alveolar count(RAC) were measured respectively.Pulmonary respiratory function was measure too at 21st day.All data were expressed as means±SD and analyzed by one-way ANOVA and LSD-t test with SPSS 13.0 statistical software.Values at P＜0.05 were considered statistical significant.
Result
1.Application of MK-801 in hyperoxia exposure days,W/D and BALF inflammatory cell counts,protein and LDH were significantly decreased at postnatal 3 day.HYP and RAC were lower than air control at postnatal 14 and 21 day.Cdyn was declined compared with air control at postnatal 21 day.The degree of pulmonary fibrosis and alveolization impairment were reduced.
2.Application of MK-801 in post hyperoxia exposure,HYP,Cdyn and RAC were lower than air control at postnatal 21 day although their higher than use of MK-801 in hyperoxia exposure days.The degree of pulmonary fibrosis and alveolization impairment were also reduced.
Conclusion
The role of NMDAR on hyperoxia-induced CLD is not only the inhibition of early cell injury and inflammation,but also the direct relationship between the NMDAR and the progress of chronic lung injury. Which suggest that NMDAR may immediacy take part in the alveolar development of newborn rat and fibroelastosis induced by hyperoxia.
ChapterⅢCollagen Secretion and Self-degradation Mediated by NMDR Activation in Human Fetal Lung Fibroblasts
Objective
To detect the expression of NMDA receptors in human fetal lung fibroblasts,and observe the role of NMDAR in the secretion and self-degradation of collagen.
Methods
1.NMDAR1 and NR2D expression was analyzed by Immunohistochemistry and immunofluorescence,
2.Expression of NMDAR1 and four NR2 subunit(NR2A,NR2B,NR2C and N2D) mRNA were examined by real-time PCR.
3.Cell proliferations were measured by cell counting and MTT in different concentrations of glutamate or NMDA.
4.Detection of HYP in cell supernatant at different concentrations of glutamate or NMDA.
5.Ⅰ,Ⅲcollagen and MMP-1,TIMP-1 secretion in cell supematant were measured by ELISA.
Result
1.Immunohistochemistry and immunofluorescence indicated the expression of NR1 and NR2D.
2.real time PCR detected the expression of NR1 and four NR2D subtypes(A,B,C and D) mRNA,the strongest two subtypes are NR2A and NR2D,followed by N2C,N2B and NAR1.
3.1mM glutamate and NMDA can promote cell proliferation,1mM glutamate was significantly higher than 1mM NMDA group,10mM glutamate group inhibit the proliferation.
4.1mM glutamate and NMDA can promote the secretion of HYP,1mM NMDA was significantly higher than 1mM glutamate group,MK-801 can inhibit the NMDA or glutamate-induced increase in HYP.
5.1mM NMDA induced secretion increase inⅠ/Ⅲcollagen and TIMP-1, secretion of MMP-1 have no significant effect.0.5mM MK-801 could significantly inhibit the NMDA-induced increase ofⅠ/Ⅲcollagen and TIMP- 1.
Conclusion
1.We found Glutamate can promote human fetal lung fibroblasts proliferation for the first time.
2.NR1 and four NR2D subtypes(A,B,C and D) all express in human fetal lung fibroblasts.
3.NMDA can promote the secretion of collagen,and inhibit collagen self-degradation in human fetal lung fibroblasts.
ChapterⅣCell Signaling Pathways of NMDA-mediated Collagen Secretion and Self-degradation in Human Fetal Lung Fibroblasts
Objective To study the cell signaling pathways in human fetal lung fibroblast collagen secretion and self-degradation though NMDAR.
Methods
1.Measurement of phosphorylated ERK by Western Blot in human fetal lung fibroblasts
2.Detection ofⅠ/Ⅲcollagen,MMP1/TIMP1 by ELISA after inhibiting NMDAR,ERK phosphorylation and PKC.
3.Change of expression for NMDAR1 and four NR2 subunits(NR2A, NR2B,NR2C and N2D ) rnRNA after being induced by NMDA were examined by real-time PCR.
Result
1.NMDA can enhance ERK phosphorylation;MK-801 can reduce NMDA-induced phosphorylation of ERK.Phosphorylated ERK inhibitor U0126 significantly reduced ERK phosphorylation in normal cells,and blocks the increase of NMDA-induced phosphorylation of ERK.PKC inhibitor H7 show a significant reduction in the normal cells,and block the increase of NMDA-induced phosphorylation of ERK.
2.NMDA induced the increase ofⅠ/Ⅲcollagen and TIMP-1 secretion were significantly inhibited by ERK inhibitor U0126 and PKC inhibitor H7
3.NR1 no signifcant change in expression after application of NMDA. NR2D expression markedly increased more than six-fold,NR2B and NR2C expression was signifcantly enhanced compared with the control group.NR2A expression decreased significantly.
Conclusion.
1.The secretion and self-degradation of collagen induced by NMDA in human fetal lung fibroblasts was through NMDA-mediated ERK phosphorylation.
2.NMDAR-PKC-ERK_(1/2) pathway was one of the cell signaling pathways in NMDA-mediated collagen secretion and self degradation of human fetal lung fibroblasts.
3.NR2D may play an important role in NMDAR-mediated collagen secretion and self-degradation in human fetal lung fibroblasts.
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