CXC chemokines in pathogenesis of pulmonary fibrosis

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(Applicant's Abstract) Few studies have assessed angiogenesis/vascular remodeling in IPF. We hypothesize that neovascularization that promotes pulmonary fibrosis in IPF is due, in part, to angiogenesis, with over-expression of angiogenic CXC chemokines and downregulation of angiostatic interferon (IFN)-inducible CXC chemokines. The imbalance of angiogenic factors in IPF enhances fibrogenesis, and leads to impaired lung function in these patients. This paradigm predicts that treatment of IPF patients with IFN-gamma will lead to reduced expression of angiogenic and augmentation of angiostatic IFN-inducible CXC chemokines, that would inhibit vascular remodeling and fibrogenesis, and result in improved lung function. We will test this postulate in the following specific aims: 1. A) To demonstrate that IPF pulmonary fibroblast interaction with human lung microvascular endothelial cells promotes an angiogenic environment. B) To determine the transcriptional and post-transcnptional molecular mechanism(s) that promotes an angiogenic phenotype of human IPF pulmonary fibroblasts (PF). To ascertain that over-expression of angiostatic IFN-inducible CXC chemokine genes in IPF PF will attenuate the angiogenic phenotype of these cells; 1. A) To establish that the CXC chemokine receptor, CXCR2, is the putative receptor for anglogenic CXC chemokine mediated angiogenesis during the pathogenesis of pulmonary fibrosis. B) To determine in vivo that genetically targeting the endothelium to transgenically overexpress Duffy antigen receptor for chemokines (DARC) will compete with CXCR2 and inhibit CXC chemokine mediated anglogenesis during the pathogenesis of pulmonary fibrosis; 111. To demonstrate in vivo that the angiostatic IFN-inducible CXC chemokines account for the angiostatic effects of IL-18, IL-12 and IFN-gamma in mediating inhibition of anglogenesis and fibrogenesis during the pathogenesis of pulmonary fibrosis; and IV. To correlate the baseline and temporal variation of the expression and biological activity of ancriogenic and anglostatic IFN-inducible CXC chemokines in IPF patients with clinical, chest radiography, physiological, and pathological parameters of disease activity in response to treatment with IFN-gamma prednisone, as compared to conventional therapy with prednisone and azathioprine. Techniques employed in this application will include: genetic, molecular, cellular, whole animal models, and human specimens of IPF. The elucidation of the pathobiology of the imbalance of angiogenic:angiostatic CXC chemokines will permit the development of novel and targeted therapy aimed specifically at attenuating fibrogenesis of IPF.