Mechanisms of myofibroblast death in pulmonary fibrosis

描述（由申请人提供）：特发性肺纤维化（IPF/UIP）是一种纤维化间质性肺病，其特征是肺实质中肌成纤维细胞的积累和持续存在。活检证实IPF/UIP的患者中有50%在诊断三年内死亡。目前还没有有效的治疗方法。虽然我们对肺纤维化中肌成纤维细胞的起源了解甚多，但对促进其持续存在的机制知之甚少。我们假设肌成纤维细胞在IPF/UIP中持续存在，部分原因是细胞凋亡无法消除这些细胞。初步研究表明，肺成纤维细胞和肌成纤维细胞对细胞凋亡具有基本的抗性，这种抗性可以通过暴露于促炎细胞因子TNF-（和IFN-）来克服。了解细胞凋亡基础抵抗及其逆转的分子基础有望为IPF/UIP中肌成纤维细胞凋亡的治疗操纵提供新的见解。我们假设肺肌成纤维细胞凋亡的诱导包括两个步骤：1)TNF-和IFN-启动致敏和2)fas -结扎。在Specific Aim 1中，我们将验证一个假设，即肌成纤维细胞对Fas诱导的凋亡的抗性是由FAP-1介导的，FAP-1是一种抑制蛋白，它与Fas基本相互作用，以阻止配体启动的接合蛋白FADD的募集。在Specific Aim 2中，我们将探讨TNF-（和IFN-）的致敏作用克服成纤维细胞和肌成纤维细胞对凋亡的基础抵抗的机制。特异性目的3的目标是解决TNF-（和IFN-）在体内肌成纤维细胞凋亡中的作用，以及在发展中和先前建立的肺纤维化的解决中。总的来说，这些研究有望为肺部炎症和纤维化之间的关系以及如何操纵这些事件来减缓或逆转这种通常致命的疾病的无情进展提供新的见解。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF/UIP) is a fibrosing interstitial lung disease characterized by the accumulation and persistence of myofibroblasts in the lung parenchyma. Fifty percent of patients with biopsy proven IPF/UIP die within three years of diagnosis. There is no known effective therapy. While much has been learned about the origin of myofibroblasts in pulmonary fibrosis, little is known about the mechanism(s) that promote their persistence. We hypothesize that myofibroblasts persist in IPF/UIP, in part, by a failure to eliminate these cells by apoptosis. Preliminary studies show that pulmonary fibroblasts and myofibroblasts are basally resistant to apoptosis and that this resistance is overcome by exposure to the pro-inflammatory cytokines, TNF-( and IFN-(. Understanding the molecular basis of the basal resistance to apoptosis and its reversal is expected to provide new insights into how myofibroblast apoptosis may be therapeutically-manipulated in IPF/UIP. We hypothesize that the induction of pulmonary myofibroblast apoptosis involves two steps: 1) TNF-( and IFN-(-initiated sensitization and 2) Fas-ligation. In Specific Aim 1, we will test the hypothesis that the resistance of myofibroblasts to Fas-induced apoptosis is mediated by FAP-1, an inhibitory protein that basally interacts with Fas to prevent ligand-initiated recruitment of the adapter protein, FADD. In Specific Aim 2, we will address the mechanism by which sensitization by TNF-( and IFN-( overcomes the basal resistance of fibroblasts and myofibroblasts to apoptosis. The goal of Specific Aim 3 is to address the role of TNF-( and IFN-( in myofibroblast apoptosis in vivo and in the resolution of developing and previously established pulmonary fibrosis. Collectively, these studies are expected to provide novel insights into the relationship between pulmonary inflammation and fibrosis and how these events may be manipulated to slow or reverse the relentless progression of this usually fatal disorder.