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

描述(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起重要作用。C/EBP影响出生后肺内稳态的作用和机制目前尚不清楚(S)。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。我们在初步数据中的新发现表明，在以CCSP为启动子的呼吸道上皮细胞中，cre介导的C/EBP(？)(小鼠)使小鼠对高氧高度敏感，伴随着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。CEBP(？/？小鼠生长正常，没有任何肺部疾病，这表明在正常情况下，C/EBP(在出生后肺内稳态中不起关键作用。在CEBPA？/？高氧暴露小鼠BALF中成熟的SP-B显著减少，而SP-B的mRNA或原SP-B的表达没有任何变化，这表明C/EBP(调节高氧期间对肺功能至关重要的蛋白质SP-B的加工或运输)。此外，CEBP(？/？)的恢复明显延迟。我们的初步数据显示，小鼠的细支气管壁上皮细胞被萘注射破坏。重组人(Rh)成纤维细胞生长因子-7对肺高氧有明显的保护作用，可增加培养的II型细胞和大鼠肺的C/EBP。这项赠款申请将确定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角色(S)和机制，并将确定对肺修复至关重要的细胞过程和基因(目标1)。在目标2中，我们将论证重组人成纤维细胞生长因子-7诱导的C/EBP调节在高氧性ALI中的关键作用。了解成纤维细胞生长因子-7治疗ALI的确切分子机制将有助于临床应用重组人成纤维细胞生长因子-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C/EBPA在急性肺损伤中介导肺保护的作用和机制。此外，重组人成纤维细胞生长因子-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.