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

急性肺损伤（ALI）是导致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，可能会加剧恢复。先前已经显示了通过信号转导子和转录激活子3（Stat-3）途径发出信号的各种细胞因子和生长因子的强保护作用。Stat-3影响肺稳态的作用和机制目前尚不清楚。我们的初步数据表明，cre介导的肺呼吸道上皮细胞中的Stat-3缺失使小鼠对高氧高度敏感。在Stat-3缺失的小鼠中，表面活性剂稳态被破坏，这证明了Stat-3在氧诱导的损伤期间在呼吸上皮中的信号传导中的关键作用。因此，本申请被设计成辨别Stat-3在肺损伤期间保护肺的机制。 在高氧损伤中，目的1将检验以下假设：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。这些研究将使用在传导气道（CCSP-rtTA）或外周气道上皮细胞（SP-C-rtTA）中选择性缺失Stat-3的条件性Stat-3小鼠（Stat-3 delta/delta小鼠）。目的2将检验上皮细胞Stat-3通过gp 130依赖性途径的配体活化而活化的假设。将在用cre重组酶缺失gp 130的转基因小鼠和呼吸道上皮细胞中评估高氧期间的Stat-3磷酸化和细胞保护。目的3将检验Stat-3调节SP-B和其他表面活性剂组分表达的假设， 高氧。在体内SP-B的遗传和治疗替代后，将评估SP-B在Stat-3 delta/delta小鼠中高氧肺损伤发病机制中的主要作用。目的4将检验Stat-3直接调节对维持上皮细胞稳态至关重要的基因子集的转录的假设。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中应该具有相当大的意义。

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.