PPARβ/δ调节nNOS对肺型氧中毒保护作用的研究

机体持续暴露于氧气中，易导致肺型氧中毒（pulmonary oxygen toxicity，POT），严重影响呼吸衰竭病人的预后。目前对POT缺乏有效防治方法。本课题组在前期通过cDNA芯片对POT小鼠肺组织进行表达谱分析，发现过氧化物酶增殖物激活受体β/δ（PPAR-β/δ）上调。经体内采用激动剂、阻滞剂干预后，证实PPAR-β/δ通路的激活对POT具有保护作用,同时发现PPAR-β/δ激活后可下调肺组织中神经元型一氧化氮合酶（nNOS）的表达。nNOS代谢过程中产生的氧自由基产物是导致POT发病的主要原因之一。因此我们设想nNOS可能是PPAR-β/δ在POT中发挥作用的重要调控因子。我们拟先在体外采用基因敲减技术明确两者在氧中毒肺上皮细胞中的关联，再从转录调控及非基因组效应来探讨PPAR-β/δ对nNOS的调节机制，最后采用基因敲除鼠体内验证。从而为肺型氧中毒提供新的临床治疗靶点。

When administering supplemental oxygen to treat hypoxemia diseases,hyperoxic acute lung injury(HALI) by overexposure may be present. Prolonged exposure to hyperoxia leads to the generation of excessive reactive oxygen species(ROS),which cause acute lung injury. However, until now, there were no effective therapeutic strategies for treat HALI patients. We detected the expression of peroxisome proliferator-activated receptor β/δ(PPAR-β/δ)were up-regulated in lungs of mice which suffered with HALI through gene chip technology.Then we investigated the role of PPAR-beta/delta activation in pulmonary oxygen toxicity, through the use of PPARβ/δ agonist and antagonist in vivo. We found treatment with agonist significantly reduced the (1) Histological evidence of lung injury,(2) MPO activity,(3) proinflammatory cytokines (TNF-α, IL-1β,IFN-γ),(4) PAR formation, and (5) apoptosis (caspase-3, and TUNEL).While PPAR-β/δantagonist,GSK0660 significantly blocked the effect of the agonist and thus abolished the protective .effect. Thus, based on these findings, we propose that PPAR-β/δ may play a role in the pathology of pulmonary type of oxygen toxicity. We also found PPAR-β/δ activation can elevate the expression of nNOS in lung, and when compared with the WT+GSK group, the lung injury in nNOS-/-+GSK was obviously decreased. some studies had proved that nNOS play an important role in the pathogenesis of HALI.So, in this study，we designed this study to explore if PPARβ/δ could protect against oxidative lung injury via up-regulation ..