Regulation of pulmonary inflammation by leukocytes and extracellular matrix

本项目资助申请将验证基质组织驻留细胞和浸润性白细胞之间的交流是指导肺部特异性炎症和抗炎反应的关键。我们认为，这些细胞群之间的相互作用，由特定细胞外基质成分的改变介导，是对挑战反应发展的关键方面。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精细化，作为宿主对气道上皮损伤的反应的结果，为白细胞的招募和激活提供了空间信号，最终形成了先天和适应性免疫反应的定性和定量模式。本课程将探讨一个重要的、统一的和新颖的概念，即肺部从先天免疫到适应性免疫的进展是流体的和机械相关的。一旦招募，浸润的白细胞会引起局部环境的进一步变化，使炎症反应升级。本提案中的单个项目将探索不同的，但互补的和顺序的炎症级联过程。这些方面包括：(1)间质基质成分versican和透明质酸在调节和塑造肺部感染先天反应中的作用（Wight），(2)上皮源性细胞因子TSLP（胸腺基质淋巴生成素）在协调肺部先天和适应性反应中的作用（Ziegler），(3)基质溶素-2 （MMP-10）在急性感染和随后的T细胞反应中控制巨噬细胞活化的作用（Parks），以及(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方面（Campbell）。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，这个项目将为检查肺部炎症提供一个综合的方法。

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.