CXC chemokines in pathogenesis of pulmonary fibrosis

(申请人摘要)很少有研究评估血管生成/血管 IPF的重塑。我们假设促进新生血管形成的 IPF中的肺纤维化部分是由于过度表达的血管生成。 血管生成CXC趋化因子与血管抑素的下调 干扰素诱导的CXC趋化因子。血管生成因子的失衡 在IPF促进了纤维化的形成，并导致这些患者的肺功能受损 病人。这一范式预测，干扰素-γ治疗特发性肺功能衰竭患者 会导致新生血管表达减少，血管抑素表达增强 干扰素诱导的CXC趋化因子，可抑制血管重塑和 促进肝纤维化，改善肺功能。我们将对此进行测试 假定有以下具体目标：1.a)证明森林小组 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)确定转录本 和促进血管生成的转化后分子机制(S) 人肺成纤维细胞(PF)的表型。为了确定这种过度表达 血管抑制性干扰素诱导的CXC趋化因子基因在IPF PF中的表达 减弱这些细胞的血管生成表型；1.a)建立 CXC趋化因子受体CXCR2可能是致血管生成CXC的受体 趋化因子在肺纤维化发病机制中介导的血管生成。 B)在体内确定通过基因靶向内皮细胞 转基因过表达趋化因子达菲抗原受体(DARC) 与CXCR2竞争抑制CXC趋化因子介导的血管形成 肺纤维化的发病机制；111。为了在体内证明 血管抑制性干扰素诱导的CXC趋化因子解释了血管抑制性作用 IL-18、IL-12和干扰素-γ在抑制血管生成和血管生成中的作用 肺纤维化发病过程中的纤维化形成； 将表达的基线和时间变化与生物学相关 干扰素诱导的CXC趋化因子在IPF中的活性 患者的临床、胸片、生理和病理 干扰素-γ治疗后的疾病活动性参数 泼尼松与泼尼松的常规治疗和 硫唑嘌呤。本申请中采用的技术将包括：遗传， IPF的分子、细胞、全动物模型和人体标本。这个 血管生成失衡的病理生物学阐明：血管抑制性CXC 趋化因子将使新的靶向治疗的发展成为可能 特别是在减轻IPF的纤维化方面。

(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.