Regulation of pulmonary inflammation by leukocytes and extracellular matrix

该计划项目资助申请将测试以下假设：基质组织驻留细胞和浸润白细胞之间的通信是指导肺部特异性炎症和炎症反应对感染或损伤的关键。我们认为，这些细胞群之间的相互作用，介导的特定细胞外基质成分的改变，是一个关键方面的发展，对挑战的反应。我们的总体假设是，局部细胞周围环境的变化，如特定细胞外基质成分的沉积或效应分子的产生，作为宿主对气道上皮损伤的反应的结果，为白细胞的募集和激活提供空间信号，最终形成先天性和适应性免疫反应的定性和定量模式。一个重要的，统一的，和新的概念，将在本计划中探讨的是，从先天免疫到适应性免疫在肺部的进展是流体和机械连接。一旦招募，浸润的白细胞诱导局部环境的进一步变化，使炎症反应升级。本提案中的各个项目将探索这一拟议的炎症级联反应的不同但互补和顺序的过程。这些方面包括：（1）间质基质成分多能蛋白聚糖和透明质酸在调节和形成对肺部感染的先天性反应中的作用（Wight），（2）上皮源性细胞因子TSLP的作用（胸腺基质淋巴细胞生成素）在协调肺中的先天性和适应性反应中的作用（齐格勒），（3）基质溶解素-2（MMP-10）在控制急性感染和后期T细胞应答期间巨噬细胞活化中的作用（Parks），和（4）适应性免疫系统的作用，特别是调节性T细胞在控制肺部慢性感染中的作用（坎贝尔）。这些项目中的每一个都有一个共同的主题，即由一种细胞类型产生的效应分子如何控制特定白细胞的活性，总的来说，该计划将提供一种检查肺部炎症的综合方法。

This Program Project Grant application will test the hypothesis that communication between the stroma tissue-resident cells and infiltrating leukocytes is key to directing lung-specific inflammatory and antiinflammatory responses to infection or injury. We believe that the interplay between these cell populations, mediated by alterations in specific extracellular matrix components, is a critical aspect in the development of the response to challenge. Our overall hypothesis is that changes in local pericellular environments, such as deposition of specific extracellular matrix components or the elaboration of effector molecules, as a consequence of the host response to airway epithelial insults, provide spatial signals for recruitment and activation of leukocytes that ultimately shape the qualitative and quantitative patterns of both the innate and adaptive immune responses. An important, unifying, and novel concept that will be explored in this Program is that the progression from innate to adaptive immunity in the lung is fluid and mechanistically linked. Once recruited, infiltrated leukocytes induce further changes in local environments, escalating the inflammatory response. The individual projects in this proposal will probe different, yet complementary and sequential processes of this proposed inflammatory cascade. These aspects include: (1) the role of the interstitial matrix components versican and hyaluronan in regulating and shaping the innate response to lung infection (Wight), (2) the role ofthe epithelial-derived cytokine TSLP (thymic stromal lymphopoietin) in coordinating innate and adaptive responses in the lung (Ziegler), (3) the role of stromelysin-2 (MMP-10) in controlling macrophage activation during acute infection and later T cell responses (Parks), and (4) the role of the adaptive immune system, particularly regulatory T cells, in controlling chronic infection in the lung (Campbell). Each of these projects shares the common theme of how effectors molecules made by one cell type control the activity of specific leukocytes and overall this Program will provide an integrated approach for examining pulmonary inflammation.