MMP10 Control of Macrophage Activation in COPD

摘要 先天免疫系统在维持健康的肺部和塑造身体方面起着至关重要的作用。 对挑战的回应。至于大多数生物过程，范围、模式、持续时间和 炎症的后果由积极和消极之间的平衡控制 各种因素。我们的初步数据表明基质分解素-2(MMP10)是基质中的一员 金属蛋白酶基因家族调控浸润性血管内流激活状态的研究进展 巨噬细胞，在香烟烟雾引起的肺损伤中起着不同的作用。一方面，它 减轻炎症的程度，特别是炎症的渗入和激活状态。 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不同所致。具体地说，我们假设 MMP10调节巨噬细胞向M1表型的激活(经典激活； 促炎)，从而促进更多M2的分化(交替激活或 抗炎)巨噬细胞。M2巨噬细胞，已知在 吸烟者的肺被认为是修复性的，并介导基质重塑。然而， 对于持续性炎症，修复表型会导致过度的重塑和 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，MMP10直接或间接参与肺气肿的发生。至 更详细地研究MMP10在肺泡破坏中的作用，我们建议1)确定其作用 MMP10在形成巨噬细胞分化中的作用；2)确定上皮细胞-巨噬细胞分化的相对作用。 和巨噬细胞来源的MMP10；以及3)评估MMP10在调控 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.