MMP10 Control of Macrophage Activation in COPD

MMP10 对 COPD 巨噬细胞激活的控制

• 批准号: 8064157
• 负责人: WILLIAM C PARKS
• 金额: $ 42.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064157
• 关键词: Acute; Alveolar; Anti-Inflammatory Agents; Anti-inflammatory; Bacterial Infections; Bioinformatics; Biological Process; Bleomycin; Cells; Chronic; Chronic Obstructive Airway Disease; Cicatrix; Data; Development; Enzymes; Epithelial; Epithelium; Equilibrium; Exposure to; Gene Family; Immune system; Infection; Inflammation; Inflammatory Response; Injury; Knowledge; Lead; Lung; Macrophage Activation; Matrix Metalloproteinases; Mediating; Metalloproteinase Gene; Modeling; Mus; Pathway interactions; Pattern; Peptide Hydrolases; Phenotype; Play; Population; Pulmonary Emphysema; Relative (related person); Rest; Role; Shapes; Smoke; Smoker; Time; Tissues; Work; alveolar destruction; cell type; cigarette smoke-induced; cigarette smoking; genetic regulatory protein; in vivo; macrophage; member; novel; response; stromelysin 2; tool

DESCRIPTION (provided by applicant): The innate immune system plays critical roles in maintaining a healthy lung and in shaping the responses to challenge. As for most biological processes, the extent, pattern, duration, and consequence of inflammation are controlled by a balance between positive and negative factors. Our preliminary data indicates that stromelysin-2 (MMP10), a member of the matrix metalloproteinase gene family, functions to govern the influx and activation state of infiltrated macrophages and has diverse roles in cigarette smoke-induced lung damage. On one hand, it moderates the extent of inflammation, particularly, the influx and activation state of infiltrated macrophages. On the other, MMP10 promotes alveolar destruction. We propose that these phenotypes are due to differences in macrophage activation. Specifically, we hypothesize that MMP10 moderates macrophage activation towards an M1 phenotype (classically activated; proinflammatory), thereby promoting the differentiation of more M2 (alternatively activated or anti-inflammatory) macrophages. M2 macrophages, which are known to over-represented in the lungs of smokers, are considered to be reparative and to mediate matrix remodeling. However, with sustained inflammation, a reparative phenotype would lead excessive remodeling and tissue destruction. Hence, we further hypothesize that by promoting the differentiation of M2 macrophages, MMP10 contributes-directly or indirectly-to development of emphysema. To study the role of MMP10 in alveolar destruction more detail, we propose to 1) determine the role of MMP10 in shaping macrophage differentiation; 2) determine the relative roles of epithelial- and macrophage-derived MMP10; and 3) assess the role of MMP10 in governing the macrophage response to bacterial infection. PUBLIC HEALTH RELEVANCE: These studies will characterize a novel, fundamental mechanism controlling macrophage activation and tissue destruction in COPD. Knowledge from this work may provide an effective strategy to limit inflammation-associated damage not only in lung, but in all tissues.

描述（由申请人提供）：先天免疫系统在维持肺部健康和形成对挑战的反应方面发挥着关键作用。对于大多数生物过程来说，炎症的程度、模式、持续时间和后果是由积极因素和消极因素之间的平衡控制的。我们的初步数据表明，基质金属蛋白酶基因家族的成员 Stromelysin-2 (MMP10) 具有控制浸润巨噬细胞的流入和激活状态的功能，并且在香烟烟雾引起的肺损伤中发挥多种作用。一方面，它可以减轻炎症的程度，特别是浸润巨噬细胞的流入和激活状态。另一方面，MMP10 促进肺泡破坏。我们认为这些表型是由于巨噬细胞激活的差异造成的。具体来说，我们假设 MMP10 调节巨噬细胞向 M1 表型（经典激活；促炎）的激活，从而促进更多 M2（选择性激活或抗炎）巨噬细胞的分化。众所周知，M2 巨噬细胞在吸烟者肺部过多，被认为具有修复作用并介导基质重塑。然而，随着持续的炎症，修复表型会导致过度重塑和组织破坏。因此，我们进一步假设，通过促进 M2 巨噬细胞的分化，MMP10 直接或间接促进肺气肿的发展。为了更详细地研究 MMP10 在肺泡破坏中的作用，我们建议 1）确定 MMP10 在塑造巨噬细胞分化中的作用； 2)确定上皮细胞和巨噬细胞来源的MMP10的相对作用； 3) 评估 MMP10 在控制巨噬细胞对细菌感染反应中的作用。 公共卫生相关性：这些研究将描述慢性阻塞性肺病中控制巨噬细胞激活和组织破坏的一种新颖的基本机制。这项工作的知识可能提供一种有效的策略来限制炎症相关的损伤，不仅在肺部，而且在所有组织中。