MODULATION OF OXIDANT INJURY BY FGF-10

肺泡上皮细胞（AEC）的损伤和修复在氧化性肺损伤的发病机制中起重要作用。最近的研究表明，生长因子在预防氧化剂诱导的肺损伤中具有关键作用。然而，所涉及的机制是多种的，并且没有很好地定义。生长因子可能通过防止AEC中DNA损伤（氧化应激的早期指标）、细胞凋亡和Na，K-ATP酶下调来减轻氧化诱导的肺损伤。促分裂原活化蛋白激酶级联反应是由生长因子触发的，导致细胞增殖和分化。成纤维细胞生长因子-10（Fibroblast growth factor-10，FGF-10）是一种对大鼠肺泡Ⅱ型细胞（AtII cell，AII cell）有促进作用的生长因子。成纤维细胞生长因子-10（FGF-10）主要在肺中表达，并且是肺发育所需的。这种新型FGF的生物学作用尚未阐明。我们的初步数据显示FGF-10减弱H202诱导的A549细胞DNA损伤和细胞死亡。本发明的具体目的是1）确定FGF-10是否防止H 202诱导的ATII细胞DNA损伤和凋亡。2)确定FGF-10是否改善AEC中H2 O2诱导的Na，K-ATP酶下调。3)确定FGF-10是否通过激活MAPK信号通路减弱H2 O2诱导的AEC DNA损伤和Na，K-ATP酶下调。我的工作将使我了解急性呼吸窘迫综合征和肺纤维化的病理生理学的分子和生物学基础。

Alveolar epithelial cell (AEC) injury and repair are important in the pathogenesis of oxidant-induced lung damage. Recent investigations have demonstrated that growth factors have a critical role in preventing oxidant-induced lung injury. However the mechanisms involved are multiple and not well defined. Growth factors may decrease oxidant-- induced lung injury by preventing DNA damage (an early indicator of oxidant stress), apoptosis, and down regulation o Na, K-ATPase in AEC. Mitogen-activated protein kinase cascade is triggered by growth factors resulting in cell proliferation and differentiation. The recently described growth factor Fibroblast growth factor-10, is a potent mitogen for rat ATII cell (alveolar Type II cells). Fibroblast Growth Factor-10 (FGF-10) is predominantly expressed in the lung and is required for the lung development. The biological role of this novel FGF is yet to be elucidated. Our preliminary data show that FGF-10 attenuates H202- induced A549 cells DNA damage and cell death. The Specific aims of this proposal are 1) To determine whether FGF-10 prevents H202- induced ATII cells DNA damage and apoptosis. 2) To determine whether FGF-10 improves H202-induced Na,K-ATPase downregulation in AEC. 3) To determine whether FGF-10 attenuates H202-induced AEC DNA damage and Na,K-ATPase downregulation by activation of the MAPK signaling pathways. My proposed work will enable me to understand the molecular and biological basis of the pathophysiology of acute respiratory distress syndrome and pulmonary fibrosis.