Regulation of pulmonary inflammation by leukocytes and extracellular matrix

这项计划项目拨款申请将检验这一假设，即基质组织驻留细胞和渗透的白细胞之间的通信是引导肺部特异性炎症和抗炎反应以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，由特定的细胞外基质成分的改变所介导，是发展对挑战的反应的关键方面。我们的总体假设是，由于宿主对呼吸道上皮损伤的反应，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器分子的形成，为白细胞的招募和激活提供了空间信号，最终塑造了先天性和获得性免疫反应的定性和定量模式。在这个项目中将探索的一个重要的、统一的和新的概念是，从先天免疫到肺内获得性免疫的过程是流动的和机械联系的。一旦被招募，渗入的白细胞会在局部环境中引起进一步的变化，加剧炎症反应。本提案中的个别项目将探讨这一拟议的炎症性级联的不同、但互补和顺序的过程。这些方面包括：(1)间质基质成分通俗易懂和透明质酸在调节和塑造肺部感染的先天反应中的作用(鬼魂)，(2)上皮源性细胞因子胸腺间质淋巴生成素(TSLP)在协调肺部的先天和适应性反应中的作用(Ziegler)，(3)基质分解素-2(MMP2)在控制急性感染期间巨噬细胞激活和后来的T细胞反应(PARKS)中的作用，以及(4)适应性免疫系统，尤其是调节性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，即由一种细胞类型制造的效应器分子如何控制特定白细胞的活动，总体而言，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.