MMP10 Control of Macrophage Activation in COPD

摘要 先天免疫系统在维持健康的肺和塑造 对挑战的反应。对于大多数生物过程，其程度、模式、持续时间和 炎症的后果是由积极和消极之间的平衡控制的 因素我们的初步数据表明，基质分解素-2（MMP 10），基质中的一员， 金属蛋白酶基因家族，其功能是控制浸润的细胞的流入和活化状态。 巨噬细胞，并在香烟烟雾诱导的肺损伤中具有不同的作用。一方面它 缓和炎症的程度，特别是，浸润的细胞的流入和活化状态， 巨噬细胞另一方面，MMP 10促进肺泡破坏。我们建议，这些 表型是由于巨噬细胞活化的差异。具体来说，我们假设， MMP 10调节巨噬细胞向M1表型的活化（经典活化; 促炎性），从而促进更多的M2（或者活化的或未活化的）的分化。 抗炎）巨噬细胞。M2巨噬细胞，已知其在肿瘤中过度表达。 吸烟者的肺被认为是修复性的，并介导基质重塑。然而，在这方面， 在持续炎症的情况下，修复表型将导致过度重塑， 组织破坏因此，我们进一步假设，通过促进M2的分化， 在巨噬细胞中，MMP 10直接或间接地促进肺气肿的发展。到 为了更详细地研究MMP 10在肺泡破坏中的作用，我们建议：1）确定MMP 10在肺泡破坏中的作用， MMP 10在形成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MMP 10;和3）评估MMP 10在调节 巨噬细胞对细菌感染的反应。

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.