Regulation of Pulmonary Fibrosis by CXCR3

描述（由申请人提供）：调节持续肺纤维化的机制尚未完全了解。肺纤维化可发生在患有慢性炎性疾病的患者中，所述慢性炎性疾病例如与结缔组织疾病相关的那些，所述结缔组织疾病例如硬皮病、类风湿性关节炎和多发性肌炎。肺纤维化也发生在不以相同程度的间质性炎症为特征的疾病中，例如特发性肺纤维化。我们已经鉴定了一种新的模型系统，其似乎在调节肺对急性非感染性损伤的反应以及随后的炎症和纤维增生反应中具有独特的作用。我们的初步研究提供了证据表明，CXCR 3和同源趋化因子配体CXCL 10调节肺损伤，炎症和纤维增生的三个基本方面：上皮修复，促纤维化交替激活（M2）巨噬细胞的发育，以及成纤维细胞向肺的运输。CXCR 3缺失小鼠在急性肺损伤后患有进行性纤维化。在肺中过表达CXCL 10的小鼠对急性肺损伤具有显著的抗性。我们提出确定CXCL 10-CXCR 3轴调节肺损伤后肺修复、炎症和纤维化的机制，具体目标如下：1.确定CXCL 10/CXCR 3轴通过募集和扩增祖上皮细胞刺激非感染性肺损伤后肺修复的机制。2.描述CXCL 10通过与蛋白聚糖多配体蛋白聚糖-4相互作用调节成纤维细胞向肺募集的机制。3.研究CXCL 10-CXCR 3相互作用通过调节交替激活的巨噬细胞表型的发展来抑制纤维形成的机制。 公共卫生相关性：这是一个有竞争力的更新的建议，重点是在肺损伤，炎症和纤维化的病理生物学中的趋化因子CXCL 12及其同源受体CXCR 3的作用。我们已经发现，CXCL 10和CXCR 3是肺损伤和修复的关键调节剂，通过对肺上皮细胞修复、成纤维细胞向肺的募集和替代性活化巨噬细胞的发育的影响来响应非感染性肺损伤。了解CXCL 10/CXCR 3轴在肺损伤和修复的病理生物学中的作用可能会导致进行性肺纤维化的新疗法。

DESCRIPTION (provided by applicant): The mechanisms that regulate unrelenting pulmonary fibrosis are incompletely understood. Pulmonary fibrosis can occur in patients with chronic inflammatory diseases such as those associated with connective tissue diseases such as scleroderma, rheumatoid arthritis and polymyositis. Pulmonary fibrosis also occurs in diseases that are not characterized by the same degree of interstitial inflammation such as idiopathic pulmonary fibrosis. We have a identified a novel model system that appears to have a unique role in regulating the lung response to acute non-infectious injury as well as the subsequent inflammatory and fibroproliferative responses. Our preliminary studies have provided evidence that CXCR3 and the cognate chemokine ligand CXCL10 regulates three fundamental aspects of lung injury, inflammation and fibroproliferation: epithelial repair, development of profibrotic alternatively activated (M2) macrophages, and trafficking of fibroblasts to the lung. CXCR3 null mice suffer from progressive fibrosis after acute lung injury. Mice that overexpress CXCL10 in the lung are remarkably resistant to acute lung injury. We propose to determine the mechanisms by which the CXCL10-CXCR3 axis regulates lung repair, inflammation and fibrosis following lung injury in the following specific aims: 1. Determine the mechanisms by which the CXCL10/CXCR3 axis stimulates lung repair following non- infectious lung injury by the recruitment and expansion of progenitor epithelial cells. 2. Characterize the mechanisms by which CXCL10 regulates fibroblast recruitment to the lung through interactions with the proteoglycan syndecan-4. 3. Investigate the mechanisms by which CXCL10-CXCR3 interactions inhibit fibrogenesis by regulating the development of the alternatively activated macrophage phenotype. PUBLIC HEALTH RELEVANCE: This is a competitive renewal of a proposal that focuses on the role of the chemokine CXCL12 and its cognate receptor CXCR3 in the pathobiology of lung injury, inflammation and fibrosis. We have found that CXCL10 and CXCR3 are critical regulators of lung injury and repair in response to non-infectious lung injury through effects on lung epithelial cell repair, fibroblast recruitment to the lung and the development of alternatively activated macrophages. Understanding the roles of the CXCL10/CXCR3 axis in the pathobiology of lung injury and repair could lead to new therapies for progressive pulmonary fibrosis.