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.
