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MMP10 Control of Macrophage Activation in COPD

MMP10 对 COPD 巨噬细胞激活的控制

基本信息

批准号：
8584308
负责人：
WILLIAM C PARKS
金额：
$ 40.92万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-02-28
项目状态：
已结题

项目摘要

ABSTRACT 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.

抽象的先天免疫系统在维持肺部健康和塑造肺部健康方面发挥着关键作用对挑战的回应。对于大多数生物过程来说，其程度、模式、持续时间和炎症的后果由正负平衡控制因素。我们的初步数据表明基质溶素 2 (MMP10)，基质的成员金属蛋白酶基因家族，负责控制渗透的流入和激活状态巨噬细胞在香烟烟雾引起的肺损伤中发挥多种作用。一方面，它缓和炎症的程度，特别是浸润的流入和激活状态巨噬细胞。另一方面，MMP10 促进肺泡破坏。我们建议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 表型激活（经典激活；促炎），从而促进更多 M2（或者激活或抗炎）巨噬细胞。 M2 巨噬细胞，已知在吸烟者的肺部，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的分化巨噬细胞中，MMP10 直接或间接导致肺气肿的发生。到为了更详细地研究 MMP10 在肺泡破坏中的作用，我们建议 1) 确定作用 MMP10 在塑造巨噬细胞分化中的作用。 2）确定上皮细胞的相对作用和巨噬细胞衍生的 MMP10； 3) 评估 MMP10 在治理方面的作用巨噬细胞对细菌感染的反应。