Role of Stat-3 in Protection of the Lung During Hyperoxia

急性肺损伤(ALI)仍然是发病率和死亡率的主要原因。ALI患者需要高氧才能生存，而高氧会导致细胞损伤，从而加剧康复。多种细胞因子和生长因子通过信号转导和转录激活子3(Stat-3)途径发出信号，具有很强的保护作用。Stat-3影响肺内稳态的作用(S)和机制目前尚不清楚。我们的初步数据表明，cre介导的肺上皮细胞中Stat-3的缺失使小鼠对高氧高度敏感。在缺失Stat-3的小鼠中，表面活性物质的动态平衡被破坏，这表明在氧气诱导的损伤过程中，Stat-3在呼吸道上皮细胞信号转导中起着关键作用。因此，本申请旨在辨别Stat-3保护肺的机制 高氧性损伤，目标1将验证这样的假设，即Stat-3调节细胞保护反应以限制O2诱导的损伤，和/或Stat-3是氧损伤后修复所需的上皮细胞基因表达和增殖所必需的。条件Stat-3小鼠(Stat-3 Delta/Delta小鼠)将用于这些研究，其中Stat-3选择性地在传导气道(CCSP-RTTA)或外周气道上皮细胞(SP-C-RTTA)中缺失。目的2验证上皮细胞Stat-3被gp130依赖通路的配体激活所激活的假说。在用cre重组酶和呼吸道上皮细胞缺失gp130的转基因小鼠中，将评估高氧期间STAT-3的磷酸化和细胞保护作用。目的3将验证Stat-3调节SP-B和其他表面活性物质成分在 高氧症。在体内对SP-B进行遗传和治疗替代后，将评估SP-B在Stat-3 Delta/Delta小鼠高氧性肺损伤发病机制中的主要作用。目的4将验证这样的假设，即Stat-3直接调节对维持上皮细胞内环境平衡至关重要的基因亚群的转录。这项拟议的研究将确定Stat-3及其相关途径在急性肺损伤期间介导肺保护的作用和机制，并将确定对肺修复至关重要的细胞处理器和基因。这些途径在设计治疗或预防急性肺损伤的治疗策略时应引起相当大的兴趣。

Acute lung injury (ALI) remains a major cause of morbidity and mortality. Patients with ALI require high oxygen for survival and hyperoxia contributes to cellular injury that may exacerbate recovery. Strong protective role of various cytokines and growth factors that signal through the signal transducers and activators of transcription3 (Stat-3) pathway has been shown previously. The role(s) and mechanisms by which Stat-3 influences pulmonary homeostasis are presently unknown. Our preliminary data demonstrated that cre-mediated deletion of Stat-3 in respiratory epithelial cells of the lung render the mice highly susceptible to hyperoxia. Surfactant homeostasis was disrupted in the Stat-3 deleted mice demonstrating a critical role for Stat-3 in signaling in the respiratory epithelium during oxygen induced injury. The present application is therefore designed to discern the mechanisms by which Stat-3 protects the lung during hyperoxic injury, Aim 1 will test the hypothesis that Stat-3 modulates cytoprotective responses to limit O2 induced damage, and/or Stat-3 is required for epithelial cell gene expression and proliferation required for repair following oxygen injury. Conditional Stat-3 mice (Stat-3 delta/delta mice) in which Stat-3 is selectively deleted in conducting airway (CCSP-rtTA) or peripheral airway epithelial cells (SP-C-rtTA) will be utilized for these studies. Aim 2 will test the hypothesis that epithelial cell Stat-3 is activated by ligand activation of gp130 dependent pathways. Stat-3 phosphorylation and cytoprotection during hyperoxia will be assessed in transgenic mice in which gp130 is deleted with cre-recombinase and respiratory epithelial cells. Aim 3 will test the hypothesis that Stat-3 regulates the expression of SP-B and other surfactant components during hyperoxia. The primary role of SP-B in the pathogenesis of hyperoxic lung injury in the Stat-3 delta/delta mice will be assessed after genetic and therapeutic replacement of SP-B in vivo. Aim 4 will test the hypothesis that Stat-3 directly regulates the transcription of subsets of genes critical to the maintenance of epithelial cell homeostasis. The proposed studies will determine the effects and mechanisms by which Stat-3 and its associated pathways mediate protection of the lung during acute lung injury and will identify the cellular processors and genes critical for repair of the lung. These pathways should be of considerable interest in the design of therapeutic strategies for the treatment or prevention of acute lung injury.