CXC chemokines in pathogenesis of pulmonary fibrosis

（申请人的摘要）很少有研究评估了血管生成/血管生成 IPF的重塑。我们假设新血管形成促进 IPF中的肺纤维化部分是由于血管生成， 血管生成CXC趋化因子和血管生成抑制因子的下调 干扰素（IFN）诱导的CXC趋化因子。血管生成因子失衡 在IPF患者中， 患者这种模式预测了用IFN-γ治疗IPF患者 将导致血管生成的表达减少和血管抑制的增强， IFN-诱导的CXC趋化因子，可以抑制血管重塑， 纤维形成，并导致改善的肺功能。我们将测试这个 假设在以下具体目标：1. A.证明IPF 肺成纤维细胞与人肺微血管内皮细胞的相互作用 细胞促进血管生成环境。B）为了确定转录水平， 和促进血管生成的转录后分子机制 人IPF肺成纤维细胞（PF）的表型。为了确定这种过度表达 IPF PF中血管抑制性IFN诱导的CXC趋化因子基因的表达将 减弱这些细胞的血管生成表型; 1.（一）确定 CXC趋化因子受体CXCR 2是血管生成性CXC的假定受体 趋化因子在肺纤维化发病中介导的血管生成。 B）为了在体内确定基因靶向内皮以 转基因过表达Duffy抗原趋化因子受体（DARC）将 与CXCR 2竞争并抑制CXC趋化因子介导的血管生成， 肺纤维化的发病机制; 111.为了在体内证明， 抑制血管生成的IFN诱导型CXC趋化因子解释了抑制血管生成的作用 IL-18、IL-12和IFN-γ介导的血管生成抑制， 肺纤维化发病过程中的纤维形成;和IV.到 将表达和生物学特性的基线和时间变化关联起来， IPF中促炎性和血管生成抑制性IFN诱导的CXC趋化因子的活性 患者的临床、胸部X线摄影、生理和病理检查 响应IFN-γ治疗的疾病活动性参数 泼尼松，与常规泼尼松治疗相比， 硫唑嘌呤。本申请中采用的技术将包括：遗传， IPF的分子、细胞、整体动物模型和人类标本。的 血管生成失衡的病理生物学解释：血管抑制性CXC 趋化因子将允许开发新的靶向治疗， 特别是减弱IPF的纤维化。

(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.