Mechanisms of TNF-alpha Mediated Resolution of Pulmonary Fibrosis

描述（由申请人提供）： 特发性肺纤维化（IPF）是一种严重的纤维化肺实质疾病，发病率和死亡率高，目前尚无有效的治疗方法。因此，它变得越来越重要，以确定分子途径的治疗干预的目标。该提案试图通过使用小鼠中充分表征的博来霉素模型研究TNF-α在肺纤维化消退中的作用来解决这一未满足的需求。在初步研究中，我们已经表明，在博来霉素诱导的纤维化反应的峰值时，腹膜内施用TNF-α加速了纤维化的消退，并且具有遗传性TNF-α缺乏的小鼠具有受损的纤维化消退。这些和其他考虑使我们假设TNF-α通过对巨噬细胞和肌成纤维细胞的作用在肺纤维化的解决中起着不可或缺的作用。我们假设TNF-α改变了这两种细胞群的表型，降低了它们的促纤维化表型，并使它们有助于解决过程。具体目标1将阐述以下假设：TNF-诱导巨噬细胞编程从替代性到经典性的转换，减少促纤维化介质（包括TGF-和IGF-I）的产生，增加促炎细胞因子（TNF-）的产生，并增强基质金属蛋白酶的产生，以启动组织重塑和恢复正常的肺结构。具体目标2的目的是解决TNF-α在两步过程中促进肌成纤维细胞凋亡的假设，首先通过指导肌成纤维细胞去分化为成纤维细胞，其次通过使这些成纤维细胞敏感以经历Fas介导的凋亡。最后，具体目标3将使用IPF衍生的肌成纤维细胞和纤维化的人源化小鼠模型将我们的工作转化为人类疾病。我们提出的研究代表了第一次TNF-α作为肺纤维化解决过程中的关键参与者进行了研究。它也代表了一个新的机会，以确定新的治疗靶点治疗IPF。因此，该提案的长期目标是将我们的预期发现转化为诊断为纤维化肺病（包括IPF）患者的治疗方法的开发。

DESCRIPTION (provided by applicant): Project Summary Idiopathic pulmonary fibrosis (IPF) remains a devastating fibrotic parenchymal lung disease with high morbidity and mortality, for which there are no effective therapies. Consequently, it becomes increasingly important to identify molecular pathways that are targetable for therapeutic intervention. This proposal seeks to address this unmet need by investigating the role of TNF- in the resolution of pulmonary fibrosis using the well- characterized bleomycin model in mice. In preliminary studies we have shown that the intratracheal administration of TNF- at the peak of the bleomycin-induced fibrotic response accelerates resolution and that mice with a genetic TNF- deficiency have impaired resolution of fibrosis. These and other considerations have led us to hypothesize that TNF- plays an integral role in the resolution of pulmonary fibrosis through effects on macrophages and myofibroblasts. We hypothesize that TNF- alters the phenotype of both of these cell populations reducing their pro-fibrogenic phenotype and allowing them to aid in the resolution process. Specific aim 1 will address the hypothesis that TNF- induces a switch in macrophage programming from alternative to classical, reducing the production of pro-fibrotic mediators including TGF- and IGF-I, increasing pro-inflammatory cytokine production (TNF-) and enhancing matrix metalloproteinase production to initiate tissue remodeling and the restoration of normal pulmonary architecture. The goal of specific aim 2 is to address the hypothesis that TNF- promotes myofibroblast apoptosis in a two-step process, first by directing myofibroblasts de-differentiation to fibroblasts, and second by sensitizing these fibroblasts to undergo Fas- mediated apoptosis. Finally, specific aim 3 will translate our work into human disease using IPF-derived myofibroblasts and a humanized mouse model of fibrosis. Our proposed studies represent the first time TNF- has been investigated as a key player in the resolution process of pulmonary fibrosis. It also represents a novel opportunity to identify new therapeutic targets for the treatment of IPF. Thus, a long-term goal of this proposal is to translate our anticipated findings into the development of therapies for patients diagnosed with fibrotic lung diseases, including IPF.