CHEMOKINES REGULATE ANGIOGENESIS IN PULMONARY FIBROSIS

间质性肺疾病（ILD）的发病机制， 导致终末期纤维化表现出失调/ 异常修复伴过度新生血管形成，纤维增生， 和细胞外基质（ECM）沉积，导致进行性 纤维化和肺功能丧失。有证据表明， ILD的演变，支持纤维增生的血管生成活性， 依赖于血管生成的不平衡， 肺局部环境中的血管抑制因子。 而利息 一直专注于血管生成因子，目前的研究结果支持了一个曾经 内源性血管生成抑制因子在调节血管生成中的作用增强 净血管生成活性。 最近，人类和小鼠干扰素- γ-诱导蛋白10（IP-10），CXC趋化因子家族的成员， 已经发现是有效的血管抑制因子。 相反， MIP-2，一种人GRO β/γ的结构同源物， 人IL-8的同源物已被证明是血管生成因子。 我们 假设在ILD的发病过程中， 血管抑制性（IP-10）和血管生成性（MIP-2，IL-8）CXC存在 趋化因子 这种生物不平衡的范例将有利于净 血管生成支持纤维增生和细胞外沉积 矩阵 在本提案中，我们将通过以下方式检验这一中心假设： 在以下具体目标进行实验：1）为了 表征表达的时程、幅度和细胞内表达， IP-10和MIP-2在小鼠ILD发病过程中的来源 博莱霉素诱导的肺纤维化模型。2)确定 MIP-2在小鼠肺结核发病机制中的作用 纤维化，通过用中和MIP-2抗体被动免疫。 3)为了证明IP-10的瞬时转基因表达直接 增强肺内血管抑制活性， 纤维化4)为了研究转录和转录后 分子机制，占生产的差异， 人肺成纤维细胞系诱导的血管生成趋化因子IL-8 分离自IPF和对照肺组织。

The pathogenesis of interstitial lung disease (ILD) that ultimately leads to end-stage fibrosis demonstrates features of dysregulated/ abnormal repair with exaggerated neovascularization, fibroproliferation, and deposition of extracellular matrix (ECM), leading to progressive fibrosis and loss of lung function. Evidence suggests that during the evolution of ILD, angiogenic activity that supports fibroplasia is dependent upon an imbalance in the production of angiogenic, as compared to angiostatic factors in the local milieu of the lung. While interest has focused on angiogenic factors, current findings support an ever increasing role for endogenous angiostatic factors in the regulation of net angiogenic activity. Recently both human and murine interferon- gamma-inducible protein 10 (IP-10), members of the CXC chemokine family, have been found to be potent angiostatic factors. In contrast murine MIP-2, a structural homologue of human GRO beta/gamma, and functional homologue of human IL-8 has been shown to be an angiogenic factor. We hypothesize that during the pathogenesis of ILD an imbalance exists in the presence of angiostatic (IP-10) and angiogenic (MIP-2, IL-8) CXC chemokines. This paradigm of biological imbalance will favor net angiogenesis supporting fibroplasia and deposition of extracellular matrix. In this proposal, we will test this central hypothesis by performing experiments in the following Specific Aims: 1) To characterize the time-course, magnitude of expression, and cellular sources of IP-10 and MIP-2 during the pathogenesis of ILD in a murine model of bleomycin-induced pulmonary fibrosis. 2) To determine the specific contribution of MIP-2 to the pathogenesis of murine pulmonary fibrosis, by passive immunization with neutralizing MIP-2 antibodies. 3) To demonstrate that transient transgenic expression of IP-10 directly augments intra-pulmonary angiostatic activity to attenuate pulmonary fibrosis. 4) To study the transcriptional and post-transcriptional molecular mechanisms that account for the disparity of production of the angiogenic CXC chemokine, IL-8, by human pulmonary fibroblast cell lines isolated from IPF and control lung tissue.