Mechanisms of alveolar epithelial apoptosis during acute lung injury

在美国大约有150，000人发生急性肺损伤（All）和急性呼吸道损伤（ALL）。 急性呼吸窘迫综合征（ARDS）每年（1）。尽管研究推动了治疗的进步，但其中约40%的人 病人会死。ALL和ARDS通常表现为全身性炎症过程的一部分， 弥漫性肺泡上皮损伤和毛细血管损伤的发展，伴有富含蛋白质的液体渗出 进入肺泡腔作为肺泡-毛细血管修复的一部分，ALI/ARDS患者发展为 纤维增殖过程的特征在于间充质细胞的增殖、间充质细胞的分化、间充质细胞的分化、间充质细胞的增殖、间充质细胞的分化、间充质细胞的增殖、间充质细胞的分化、间充质细胞的增殖、间充质细胞的分化、间充质细胞的增殖、间充质细胞的增殖、间充质细胞的分化、间充质细胞的增殖、间充质细胞的分化、间充质细胞的增殖、间充质细胞的分化、间充质细胞的增殖、间充质细胞的分化、间充质细胞的增殖和间充质细胞的增殖。 间充质细胞转化成肌成纤维细胞和细胞外基质沉积。分子和细胞 ALI和ARDS期间纤维增生的潜在机制尚未完全了解。转化 生长因子-β 1（TGF-β 1）是成纤维细胞活化和组织修复所必需的。多份报告显示， 过去10年来，已经描述了早期成纤维细胞活化在确定患有糖尿病的患者的结果中的作用。 ARDS。TGF-31如何诱导上皮损伤后的肺纤维化尚不完全清楚。迄今 没有遗传学证据表明上皮细胞凋亡是否是足够的，并且是启动所需的， 肺损伤后肺纤维化我们认为TGF-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在凋亡途径。内源性凋亡途径是 由Bcl-2家族成员调控。为了支持我们的假设，我们已经报道了前凋亡蛋白的丢失， Bcl-2家族成员Bid预防TGF-31诱导的小鼠纤维化。该补助金的目的是 阐明TGF-31诱导Bid依赖性上皮细胞死亡的机制， 损伤和纤维化。目前的建议将利用遗传学在小鼠模型中解决这些问题， 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.