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)是一种高发病率、高死亡率的破坏性肺纤维化，目前尚无有效的治疗方法。因此，识别可用于治疗干预的分子通路变得越来越重要。这项建议试图通过研究肿瘤坏死因子-α在利用博莱霉素小鼠模型解决肺纤维化中的作用来解决这一未得到满足的需求。在初步研究中，我们已经证明，在博莱霉素诱导的纤维化反应的高峰期，气管内注射肿瘤坏死因子-1可以加速纤维化的消退，而遗传的肿瘤坏死因子缺乏的小鼠已经损害了纤维化的消退。这些和其他方面的考虑使我们假设，通过对巨噬细胞和肌成纤维细胞的影响，肿瘤坏死因子-α在肺纤维化的解决中发挥了不可或缺的作用。我们假设，肿瘤坏死因子改变了这两个细胞群体的表型，减少了它们的促纤维化表型，并允许它们帮助解决过程。具体目标1将解决这一假设，即肿瘤坏死因子诱导巨噬细胞编程从替代转向经典，减少包括转化生长因子-1和胰岛素样生长因子-1在内的促纤维化介质的产生，增加促炎细胞因子的产生，并增强基质金属蛋白酶的产生，以启动组织重塑和正常肺结构的恢复。特异靶向2的目的是解决这一假说，即肿瘤坏死因子通过两个步骤促进肌成纤维细胞的凋亡，第一步是通过引导肌成纤维细胞去分化为成纤维细胞，第二步是通过敏化这些成纤维细胞进行Fas介导的凋亡。最后，特殊目标3将使用IPF来源的肌成纤维细胞和人源化的小鼠纤维化模型将我们的工作转化为人类疾病。我们提出的研究是第一次将肿瘤坏死因子-α作为肺纤维化消退过程中的关键角色进行研究。这也代表了一个新的机会，以确定治疗特发性肺纤维化的新的治疗靶点。因此，这项建议的长期目标是将我们预期的发现转化为对包括IPF在内的纤维化肺部疾病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.