Regulation of Pulmonary Fibrosis by CXCR3

描述(申请人提供)：调节顽固性肺纤维化的机制尚不完全清楚。患有慢性炎症性疾病的患者可发生肺纤维化，如硬皮病、类风湿性关节炎和多发性肌炎等结缔组织疾病。肺纤维化也发生在不是以相同程度的间质炎症为特征的疾病中，如特发性肺纤维化。我们已经确定了一种新的模型系统，它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性反应中具有独特的作用。我们的初步研究提供了证据，证明CXCR3和同源趋化因子配体CXCL10调节肺损伤、炎症和纤维增殖的三个基本方面：上皮修复，促纤维化交替激活的(M2)巨噬细胞的发育，以及成纤维细胞向肺的运输。CXCR3基因缺失的小鼠在急性肺损伤后出现进行性纤维化。在肺中过度表达CXCL10的小鼠对急性肺损伤具有显著的抵抗力。我们从以下几个方面探讨CXCL10-CXCR3轴调节肺损伤后肺修复、炎症和纤维化的机制：1.确定CXCL10/CXCR3轴通过募集和扩增祖细胞促进非感染性肺损伤后肺修复的机制。2.研究CXCL10通过与蛋白多糖Syndecan-4的相互作用调节成纤维细胞向肺内募集的机制。3.研究CXCL10-CXCR3相互作用通过调节交替激活的巨噬细胞表型的发育来抑制纤维化形成的机制。 公共卫生相关性：这是一项提案的竞争性更新，该提案侧重于趋化因子CXCL12及其同源受体CXCR3在肺损伤、炎症和纤维化的病理生物学中的作用。我们发现，CXCL10和CXCR3通过影响肺上皮细胞修复、成纤维细胞向肺内募集和发展交替激活的巨噬细胞，是非感染性肺损伤反应中肺损伤和修复的关键调节因子。了解CXCL10/CXCR3轴在肺损伤和修复的病理生物学中的作用可能会导致对进行性肺纤维化的新治疗。

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.