Mechanisms of myofibroblast death in pulmonary fibrosis

描述(申请人提供)：特发性肺纤维化(IPF/UIP)是一种纤维化的间质性肺疾病，其特征是肌成纤维细胞在肺实质内积聚和持续存在。经活检证实为IPF/UIP的患者中，有50%在确诊后三年内死亡。目前还没有已知的有效疗法。虽然关于肺纤维化中肌成纤维细胞的起源已经了解很多，但对促进其持续存在的机制(S)知之甚少。我们假设肌成纤维细胞在IPF/UIP中持续存在，部分原因是未能通过凋亡消除这些细胞。初步研究表明，肺成纤维细胞和肌成纤维细胞对凋亡具有基本抵抗力，这种抵抗力可通过暴露于促炎症细胞因子肿瘤坏死因子和干扰素来克服。了解基本的细胞凋亡抵抗及其逆转的分子基础有望为肌成纤维细胞的凋亡如何在IPF/UIP中进行治疗提供新的见解。我们推测，诱导肺成纤维细胞的凋亡包括两个步骤：1)肿瘤坏死因子和干扰素启动的敏化；2)Fas的结扎。在特定的目标1中，我们将验证这样的假设，即肌成纤维细胞对Fas诱导的凋亡的抵抗是由FAP-1介导的，FAP-1是一种抑制蛋白，它与Fas发生碱基相互作用，以防止配体启动的适配蛋白FADD的募集。在具体目标2中，我们将探讨肿瘤坏死因子-(和干扰素-)致敏成纤维细胞和肌成纤维细胞对细胞凋亡的基本抵抗的机制。具体目标3的目的是探讨肿瘤坏死因子-和干扰素-在体内肌成纤维细胞凋亡中的作用，以及在解决发展中和先前已建立的肺纤维化中的作用。总的来说，这些研究有望为肺部炎症和纤维化之间的关系提供新的见解，以及如何操纵这些事件来减缓或逆转这种通常是致命的疾病的无情进展。

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.