Role of C/EBPalpha in Cytoprotection and Recovery from Lung Injury

描述（由申请人提供）：许多参与肺形态发生的转录途径在出生后的肺中表达，并在急性肺损伤（ALI）期间被诱导以介导肺的修复。 C/EBP( 在正常肺形态发生中发挥着重要作用。C/EBP( 影响出生后肺稳态的作用和机制目前尚不清楚。ALI 患者需要高氧才能生存，高氧血症会导致细胞损伤，从而可能加剧恢复。我们在初步数据中的新发现表明，使用 CCSP 作为启动子（Cebp(?/? 小鼠）的呼吸道上皮细胞中 cre 介导的 C/EBP( 缺失）使小鼠高度易受高氧影响，与 SP-B 减少、严重肺部炎症、肺泡腔扩大、细支气管上皮细胞损伤和高死亡率有关。表明 C/EBP( 调节 SP-B 的加工或运输，SP-B 是高氧期间对肺功能至关重要的蛋白质。此外，我们的初步数据证明，在通过萘注射破坏细支气管上皮细胞后，Cebp( ?/? 小鼠的恢复显着延迟。重组人 (rh) FGF-7 治疗在保护肺免受高氧影响方面显示出相当大的功效，并且 FGF-7 在培养的 II 型细胞和大鼠肺中增加了 C/EBP( )。这项拨款申请将确定C/EBP( 及其相关途径在肺泡和细支气管上皮细胞损伤期间介导肺保护的新作用和机制，并将识别对肺修复至关重要的细胞过程和基因（目标 1)。在目标 2 中，我们将证明在高氧 ALI 期间由 rhFGF-7 治疗诱导的 C/EBP( 调节的关键作用。了解 FGF-7 治疗生存的精确分子机制将有助于临床使用rhFGF-7 用于治疗 ALI。急性肺损伤仍然是发病和死亡的主要原因。该提案将确定 C/EBPα 在急性肺损伤期间介导的肺保护作用和机制。此外，还将确定重组人 FGF-7 治疗急性肺损伤的分子机制，特别是调节 Cebpa 的信号通路。

DESCRIPTION (provided by applicant): Many of the transcriptional pathways involved in lung morphogenesis are expressed in the postnatal lung and induced during acute lung injury (ALI) to mediate repair of the lung. C/EBP( plays an important role in normal lung morphogenesis. The role(s) and mechanisms by which C/EBP( influences postnatal pulmonary homeostasis are presently unknown. Patients with ALI require high oxygen for survival and hyperoxia contributes to cellular injury that may exacerbate recovery. Our novel findings in Preliminary Data demonstrated that cre-mediated deletion of C/EBP( in respiratory epithelial cells using CCSP as promoter (Cebp(?/? mice) render the mice highly susceptible to hyperoxia, associated with decreased SP-B, severe lung inflammation, enlarged alveolar space, bronchiolar epithelial cell injury, and high mortality. Cebp( ?/? mice grow normally without any pulmonary disorder, suggesting that C/EBP( does not play a critical role in postnatal pulmonary homeostasis under normal conditions. In Cebpa?/? mice exposed to hyperoxia, mature SP-B in BALF was significantly decreased without any changes in SP-B mRNA or pro-SP-B expression, indicating that C/EBP( regulates the processing or trafficking of SP-B, a protein critical for lung function during hyperoxia. Furthermore, significantly delayed recovery of Cebp( ?/? mice after destruction of bronchiolar epithelial cells by naphthalene injection was demonstrated in our Preliminary Data. Recombinant human (rh) FGF-7 treatment showed considerable efficacy in protecting lung from hyperoxia and FGF-7 increased C/EBP( in cultured type II cells and rat lung. This grant application will determine the novel role(s) and mechanisms by which C/EBP( and its associated pathways mediate protection of the lung during alveolar and bronchiolar epithelial cell injury, and will identify the cellular processes and genes critical for repair of the lung (Aim 1). In Aim 2, we will demonstrate the critical role of regulation of C/EBP( induced by rhFGF-7 treatment during hyperoxia ALI. Understanding the precise molecular mechanisms of FGF-7 treatment for survival would help in the clinical use of rhFGF-7 for treatment of ALI. PUBLIC HEALTH RELEVANCE: Acute lung injury remains a major cause of morbidity and mortality. This proposal will determine the role and mechanisms by which C/EBPa mediates protection of the lung during acute lung injury. Furthermore, the molecular mechanisms, in particular the signaling pathways regulating Cebpa, of recombinant human FGF-7 treatment for acute lung injury will be determined.