Roles for interstitial and airspace macrophages in resolution of pulmonary inflammation

项目摘要/摘要 炎症是一个高度复杂的过程，是大多数形式的肺部疾病的组成部分。它 代表对组织损伤的反应，通常(理想情况下)导致组织内稳的恢复，尽管， 根据激发刺激的不同，修复过程也可能涉及一过性纤维化反应(类似于 皮肤上的“伤口愈合”)。巨噬细胞在这些事件中是必不可少的细胞，在所有步骤中发挥关键作用 协调修复/解决和恢复动态平衡的许多要素的过程； 对这一点的理解是这项提议的主要重点。肺中巨噬细胞可分为两类 类别：1)参与维持体内平衡的常驻巨噬细胞，并充当 检测最初的刺激或损伤，2)从传入的单核细胞中招募成熟的巨噬细胞。我们和 其他人最近在肺内发现了独特的巨噬细胞亚型(常驻和招募)。 空域中的空隙，但在这一点上，他们对或参与， 炎症反应及其消退尚未确定。因此，在这个项目中，我们 将阐明单个巨噬细胞亚群在炎症反应的消退阶段的作用， 最终目标是设计出增强其功能的治疗方法。使用新的方法来 目标，血统追踪和操纵不同的巨噬细胞群我们将确定它们的数量， 功能编程状态，关键是它们在炎症过程中在肺中的特定位置 由四种不相关的刺激诱导--其中两种可导致早期解决(细菌脂多糖和H1N1 流感感染)和两个包括在更长时间的消退期间的一过性纤维化反应的 (博莱霉素或盐酸，后者模拟暴露于胃液中)。在发炎期间，居民 正常肺间质和肺间隙内的巨噬细胞数量增加，但也可通过 大量招募的巨噬细胞。在分解过程中，这些过剩的巨噬细胞 该提案的一个主要重点将是确定清除的方式和影响 故意加强(或推迟)这种去除，以恢复到平衡的肺结构，并 功能。有待探索的关键假说包括：1)巨噬细胞在两个启动过程中的独特性质 炎症，尤其是炎症对间质巨噬细胞亚群的影响(与空气中的细胞相比) 与它们的精确定位有关，例如在支气管血管束内或在胸膜下 区域)。2)巨噬细胞以波的形式被招募到炎症的肺中，表现出独特的编程特性， 后来招募的细胞在炎症消退中发挥关键作用，包括诱导和 一过性纤维化反应的解决。3)募集的巨噬细胞本身，在两个瞬变 在经历外源性细胞凋亡后，延长的炎性环境被移除。

Project Summary/Abstract Inflammation is is a highly complex process that is a component of most forms of pulmonary disease. It represents a response to tissue insult and normally (ideally) leads to return of tissue homeostasis, although, depending on the initating stimulus, the repair process may also involve a transient fibrotic response (akin to “wound heaing” in the skin). Macrophages are essential cells in these events, playing key roles in all steps in the processes, orchestrating many elements of the repair/resolution and return to homeostasis; the understaning of which is the primary focus of this proposal. Macropahges in the lung fall into two general categories: 1) resident macrophages involved in maintaining the homeostasis and serving as sentinels to detect the initial stimulus or injury and 2) recruited macrophages maturing from incoming monocytes. We and others have recently identified unique macrophage subtypes (resident and recruited) within the pulmonary interstitium in addition to those in the airspaces, but at this point, their specific responses to, or participation in, the inflammatory responses and their resolution have not been determined. Accordingly, during this project we will elucidate the roles for individual macrophage subsets in the resolution phase of the inflammatory response, with the ultimate objective of devising therapeutic approaches for its enhancement. Using novel approaches to target, lineage trace and manipulate the different macrophage populations we will determine their numbers, functional programing state, and critically their specific location within the lungs over the course of inflammation induced by four unrelated stimuli – two that lead to early resolution (bacterial lipopolysaccharide and H1N1 influenza infection) and two that include a transient fibrotic response during a more prolonged resolution (bleomycin or HCl, the latter mimicking exposure to gastic contents). During inflammation, the resident macrophages within the normal lung interstitium and airspaces increase in numbers but also are joined by large numbers of recruited macrophages. In the processes of resolution, these excess macrophages are removed and a major focus of the proposal will be determination of the modes of removal and the effects of deliberately enhancing (or delaying) this removal on the desired return to homeostatic lung structure and function. Key hypotheses to be explored include: 1) Unique macrophage properties during both iniation of inflammation and especially its resolution, for subsets of interstitial macrophages (vs. those in the airspaces) relating to their precise localization, for example within the bronchovascular bundles or in the subpleural region). 2) Macrophages are recruited to inflamed lungs in waves, exhibiting unique programing properties, with later recruited cells playing the key roles in inflammation resolution, including both the induction and resolution of the transient fibrotic response. 3) The recruited macrophages themselves, in both the transient and extended inflammatory circumstances are removed after undergoing extrinsic apoptosis.