CHEMOKINES REGULATE ANGIOGENESIS IN PULMONARY FIBROSIS

间质性肺病(ILD)的发病机制最终 导致终末期纤维化表现出调控失调的特点 异常修复，夸大新生血管，纤维增生， 和细胞外基质(ECM)的沉积，导致进行性 纤维化和肺功能丧失。有证据表明，在 ILD的演变，支持纤维增生的血管生成活性是 依赖于血管生成的产生不平衡，与 对肺局部环境中的血管抑制因子有影响。在兴趣的同时 一直专注于血管生成因子，目前的发现支持 内源性血管抑制因子在血管紧张素转换酶调节中的作用 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趋化因子家族成员， 已被发现是有效的血管抑制因子。相比之下，小鼠 MIP-2，人Groβ/γ的结构同源物，功能 人IL-8的同系物已被证明是一种血管生成因子。我们 假设在ILD的发病过程中， 血管抑制性(IP-10)和新生血管(MIP-2、IL-8)CXC的存在 趋化因子。这种生物失衡的范例将有利于网络 支持纤维增生和细胞外沉积的血管生成 矩阵。在本提案中，我们将通过以下方式验证这一中心假设 进行以下具体目标的实验：1) 描述时间进程、表达的大小和细胞 IP-10和MIP-2在小鼠ILD发病中的来源 博莱霉素性肺纤维化模型。2)确定 MIP-2在小鼠肺损伤发病机制中的特异性作用 纤维化，通过中和MIP-2抗体被动免疫。 3)直接证明IP-10的瞬时转基因表达 增强肺内血管抑制活性以减轻肺活量 纤维化症。4)转录和转录后研究 解释大豆产量差异的分子机制 人肺成纤维细胞系血管生成CXC趋化因子IL-8的表达 从IPF和对照肺组织中分离得到。

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.