Mechanisms of alveolar epithelial apoptosis during acute lung injury

美国约有15万人患上急性肺损伤(ALL)和急性呼吸系统疾病 每年发生的窘迫综合征(ARDS)(1)。尽管研究推动了治疗的进步，但其中约40% 病人会死的。ALL和ARDS通常表现为系统性炎症过程的一部分，导致 弥漫性肺泡上皮损伤和毛细血管损伤伴富含蛋白质液体渗出 进入牙槽间隙。作为肺泡-毛细血管修复的一部分，ALI/ARDS患者发展为 以间充质细胞增殖、分化为特征的纤维增殖过程 间充质细胞转化为肌成纤维细胞和细胞外基质沉积。分子和细胞 ALI和ARDS期间纤维增殖的机制尚不完全清楚。转型 生长因子-β1(TGF-31)是成纤维细胞激活和组织修复所必需的。的多个报告 近10年来，早期成纤维细胞激活在决定急性髓细胞白血病患者预后中的作用已有报道 ARDS。转化生长因子-31如何诱导上皮损伤后的肺纤维化尚不完全清楚。到目前为止 没有遗传证据表明上皮细胞凋亡是否足够和启动所需。 肺损伤继发肺纤维化。我们认为，转化生长因子-31通过以下途径诱导肺损伤和纤维化 激活肺泡上皮细胞的内源性凋亡途径。固有的细胞凋亡途径是 受Bc l-2家族成员调控。为了支持我们的假设，我们已经报道了促凋亡素的丢失 Bcl-2家族成员Bid可预防转化生长因子-31诱导的小鼠肝纤维化。这笔赠款的目的是 转化生长因子-31诱导BID依赖性上皮细胞死亡致肺损伤的机制 损伤和纤维化。目前的建议将利用小鼠模型中的遗传学来解决这些问题 肺损伤和纤维化。

Approximately 150,000 people in the United States develop acute lung injury (All) and the acute respiratory distress syndrome (ARDS) annually (1). Despite research driven advances in therapy, ~40% of these patients will die. All and ARDS often manifest as a part of a systemic inflammatory process resulting in the development of diffuse alveolar epithelial damage and capillary injury with the exudation of protein rich fluid into the alveolar space. As part of the alveolar-capillary repair ALI/ARDS patients develop a fibroproliferative process that is characterized by the proliferation of mesenchymal cells, differentiation of mesenchymal cells into myofibroblasts and deposition of extracellular matrix. The molecular and cellular mechanisms underlying fibroproliferation during ALI and ARDS are not fully understood. Transforming growth factor-beta 1 (TGF-31) is integral for fibroblast activation and tissue repair. Multiple reports over the last 10 years have described a role for early fibroblast activation in determining the outcome of patients with the ARDS. How TGF-31 induces lung fibrosis following epithelial injury is not fully understood. To date there is no genetic evidence to indicate whether epithelial apoptosis is sufficient and required for the initiation of lung injury followed by pulmonary fibrosis. We propose that TGF-31 induces lung injury and fibrosis by activating the intrinsic apoptotic pathway in alveolar epithelial cells. The intrinsic apoptotic pathway is regulated by the Bcl-2 family members. In support of our hypothesis, we have reported that loss of the proapoptotic Bcl-2 family member Bid prevents TGF-31 induced fibrosis in mice. The purpose of this grant is to elucidate the mechanisms by which TGF-31 induces Bid dependent epithelial cell death resulting in lung injury and fibrosis. The current proposal will address these questions utilizing genetics in mouse models of lung injury and fibrosis.