The role TNF-alpha and Macrophages in the Resolution of 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。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。最近在人类IPF/UIP患者和该疾病的动物模型中进行的研究表明：(i)在没有强烈炎症反应的情况下，纤维化可以进展；（ii）在缺乏促炎细胞因子TNF-a的情况下，纤维化和胸膜下蜂窝会恶化。这些发现提出了两个基本问题：1)能否利用肺中TNF-a表达的改变来解决肺纤维化？2)巨噬细胞是肺中参与TNF-a产生的关键细胞类型，是否通过TNF-a的产生参与纤维化的消退？这个F32应用程序的总体目标是调查这些问题。假设：(i)肌成纤维细胞凋亡需要巨噬细胞来源的TNF-a启动的条件信号序列，（ii）纤维化过程中TNF-a产生的恢复将解决纤维化反应。中心假设将通过两个具体目标来解决。目的一是研究巨噬细胞在肺纤维化消退过程中内源性产生TNF-a的潜在作用。目的一是探讨TNF-a在促进肺纤维化消退中的作用。与公共卫生的相关性活检证实IPF/UIP的患者中有50%在诊断后三年内死亡，目前尚无已知的有效治疗方法。拟议的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. While much has been learned about the origin of myofibroblasts in pulmonary fibrosis, little is known about the mechanism(s) that promote their persistence. Recent studies in human IPF/UIP patients and in animal models of this disease have suggested that: (i) fibrosis can progress in the absence of a robust inflammatory response, and (ii) fibrosis and sub-pleural honeycombing are worsened in the absence of the pro-inflammatory cytokine, TNF-a. These findings raise two fundamental questions: 1) Can alterations in pulmonary TNF-a expression be exploited to resolve pulmonary fibrosis? 2) Are macrophages, a key cell type implicated in TNF-a production in the lung, involved in the resolution of fibrosis via the production of TNF-a? The overall goal of this F32 application is to investigate these questions. It is hypothesized that (i) myofibroblast apoptosis requires a conditional sequence of signals initiated by macrophage-derived TNF-a, and (ii) restoration of TNF-a production during fibrosis will resolve the fibrotic response. The central hypotheses will be addressed by two specific aims. The goal of aim one is to investigate the potential role of macrophages in the endogenous production of TNF-a during the resolution of pulmonary fibrosis. The goal of aim one is to investigate the role of TNF-a in promoting the resolution of pulmonary fibrosis. Relevance to Public Health Fifty percent of patients with biopsy proven IPF/UIP die within three years of diagnosis and there is no known effective therapy. The proposed studies are expected to provide novel insights into the relationship between lung inflammation and fibrosis and how these events may be manipulated to slow or reverse the relentless progression of this usually fatal disorder.