Regulation of Pulmonary Fibrosis by CXCR3

CXCR3 对肺纤维化的调节

• 批准号: 8268397
• 负责人: Carol Jiurong Liang
• 金额: $ 38.86万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268397
• 关键词: Acute; Acute Lung Injury; Alveolar; Architecture; Area; Biological Models; Biopsy; Bleomycin; CXC Chemokines; CXC chemokine receptor 3; CXCL10 gene; CXCL11 gene; CXCL12 gene; CXCL9 gene; CXCR3 gene; Cell Proliferation; Cells; Characteristics; Chronic; Collagen; Collection; Connective Tissue Diseases; Deposition; Development; Disease; Distal; Epithelial; Epithelial Cells; Evaluation; Extracellular Matrix; Fibroblasts; Fibrosis; Funding; Gases; Hamman-Rich syndrome; Host Defense; Human; Immune response; Immunity; Infiltration; Inflammation; Inflammatory; Injury; Knockout Mice; Lead; Ligands; Lung; Lung diseases; Lymphocyte; Macrophage Activation; Mesenchymal; Microscopic; Morbidity - disease rate; Mus; Nonspecific Interstitial Pneumonia; Pathologic; Patients; Pattern; Phenotype; Polymyositis; Proteoglycan; Pulmonary Fibrosis; Regulation; Resistance; Rheumatoid Arthritis; Role; Scleroderma; Site; Smooth Muscle; Source; Stem cells; System; Testing; Time; Tissues; alveolar epithelium; cell behavior; cell injury; chemokine; chemokine receptor; fibrogenesis; interstitial; lung development; lung injury; lung repair; macrophage; migration; mortality; novel; overexpression; prevent; progenitor; public health relevance; receptor; repaired; response; syndecan-4; trafficking

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.

描述（由申请人提供）：调节持续性肺纤维化的机制尚不完全清楚。肺纤维化可发生在患有慢性炎症性疾病的患者中，例如与硬皮病、类风湿性关节炎和多发性肌炎等结缔组织疾病相关的患者。肺纤维化也发生在不以相同程度的间质炎症为特征的疾病中，例如特发性肺纤维化。我们已经确定了一种新的模型系统，它似乎在调节肺部对急性非感染性损伤的反应以及随后的炎症和纤维增殖反应方面具有独特的作用。我们的初步研究提供的证据表明，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、促纤维化替代激活 (M2) 巨噬细胞的发育以及成纤维细胞向肺部的运输。 CXCR3缺失小鼠在急性肺损伤后出现进行性纤维化。肺部过度表达 CXCL10 的小鼠对急性肺损伤具有显着的抵抗力。我们建议确定 CXCL10-CXCR3 轴在肺损伤后调节肺修复、炎症和纤维化的机制，具体目标如下： 1. 确定 CXCL10/CXCR3 轴在非感染性肺损伤后通过祖上皮细胞的募集和扩张刺激肺修复的机制。 2. 描述 CXCL10 通过与蛋白聚糖 syndecan-4 相互作用来调节成纤维细胞募集至肺部的机制。 3. 研究 CXCL10-CXCR3 相互作用通过调节替代激活巨噬细胞表型的发展来抑制纤维形成的机制。 公共健康相关性：这是一项提案的竞争性更新，重点关注趋化因子 CXCL12 及其同源受体 CXCR3 在肺损伤、炎症和纤维化病理学中的作用。我们发现CXCL10和CXCR3是肺损伤和修复的关键调节因子，通过影响肺上皮细胞修复、肺成纤维细胞募集以及替代活化巨噬细胞的发育来响应非感染性肺损伤。了解 CXCL10/CXCR3 轴在肺损伤和修复病理学中的作用可能会导致进行性肺纤维化的新疗法。