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肺中表达，并在急性肺损伤（ALI）期间被诱导以介导肺修复。C/EBP在正常肺形态发生中起重要作用。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，而高氧会导致细胞损伤，可能会加剧恢复。我们在Preliminary Data中的新发现表明，cre介导的C/EBP缺失（在呼吸道上皮细胞中，使用CCSP作为启动子（Cebp（？/？小鼠）使小鼠对高氧高度敏感，与SP-B降低、严重的肺部炎症、肺泡腔扩大、细支气管上皮细胞损伤和高死亡率相关。Cebp（？/？小鼠正常生长，没有任何肺部疾病，这表明在正常条件下，C/EBP在出生后肺内稳态中不起关键作用。在Cebpa？/？在高氧暴露的小鼠中，BALF中成熟SP-B显著降低，而SP-B mRNA或pro-SP-B表达没有任何变化，表明C/EBP（调节SP-B的加工或运输，SP-B是高氧期间肺功能的关键蛋白。此外，Cebp的恢复显著延迟（？/？小鼠细支气管上皮细胞被萘注射破坏后，在我们的初步数据证明。重组人（rh）FGF-7治疗在保护肺免受高氧方面显示出相当大的功效，并且FGF-7增加C/EBP（在培养的II型细胞和大鼠肺中）。该基金申请将确定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，并将鉴定对肺修复至关重要的细胞过程和基因（目标1）。在目的2中，我们将证明C/EBP的调节（由rhFGF-7治疗诱导）在高氧ALI期间的关键作用。了解FGF-7治疗生存的确切分子机制将有助于临床使用rhFGF-7治疗ALI。公共卫生相关性：急性肺损伤仍然是发病率和死亡率的主要原因。这一建议将确定的作用和机制，C/EBPa介导的保护肺在急性肺损伤。此外，重组人FGF-7治疗急性肺损伤的分子机制，特别是调节Cebpa的信号通路将被确定。

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.