LYMPHOCYTIC ALVEOLITIS, IL 1B REGULATION AND LUNG INJURY

描述(改编自申请人的摘要) 有几条证据支持这样一种观点，即重要的改变 在肺实质中出现了相当数量的艾滋病毒- 血清阳性者在发病前已被认可 肺部并发症。尽管这些疾病的发病机制 异常现象仍不清楚，最近的证据表明 HIV相关性淋巴细胞性肺泡炎的重要作用和危重 肺泡淋巴细胞-肺泡巨噬细胞相互作用。的目标是 目前的项目是通过严格的研究来扩展这些观察 淋巴细胞性肺泡炎的意义 肺损伤的生理和形态证据以及 关于肺泡巨噬细胞产生细胞因子的失调。 为了实现这一目标，将审查以下具体目标 进球。特定目标1解决了这个问题：活体存在 HIV相关性淋巴细胞性肺泡炎的关键决定因素 肺实质损伤与促炎细胞因子上调？这 AIM将前瞻性地描述淋巴细胞的重要性 生理学、放射学和形态计量学方面的肺泡炎 实质肺损伤的证据以及与活体内的 促炎症细胞因子的诱导。具体目标中的问题2 地址：是体外存在的肺泡细胞毒性T淋巴细胞 肿瘤坏死因子α和白介素1产生的重要调节因素 肺泡巨噬细胞的β？这一目标将考察以下基本机制 促炎症细胞因子的调节，并将主要集中在 CD8细胞毒性淋巴细胞对IL-β处理和释放的影响 通过肺泡巨噬细胞。因为这项研究解决了 最常见的炎性事件之一发生在 在人类免疫缺陷病毒的肺泡环境中，它可能会大大推进对艾滋病的认识-- 相关的肺部疾病。也许更重要的是，它关注的是 肺泡淋巴细胞在协调过程中的中心角色 与肺泡相互作用造成的肺实质损害 巨噬细胞。因此，这个项目代表着一个机会 阐明肺损伤的新机制并更好地了解 对监管具有潜在根本性重要性的因素 发炎。

DESCRIPTION (Adapted from the applicant's abstract) Several lines of evidence support the concept that important alterations in the pulmonary parenchyma occur in a substantial number of HIV- seropositive individuals prior to the development of recognized pulmonary complications. Although the pathogenesis of these abnormalities remains obscure, recent evidence has suggested an important role for an HIV-associated lymphocytic alveolitis and critical alveolar lymphocyte-alveolar macrophage interactions. The goal of the present project is to extend these observations by rigorously examining the significance of a lymphocytic alveolitis both with respect to physiologic and morphologic evidence of lung injury as well as with respect to dysregulation of cytokine production by alveolar macrophages. The following specific aims will be examined in an effort to reach this goal. Specific Aim 1 addresses this question: Is the in vivo presence of an HIV-associated lymphocytic alveolitis a critical determinant of parenchymal lung injury and proinflammatory cytokine upregulation? This aim will prospectively delineate the importance of a lymphocytic alveolitis with respect to physiologic, radiographic, and morphometric evidence of parenchymal lung damage as well as with respect to in vivo proinflammatory cytokine induction. The question in Specific Aim 2 addresses: Is the in vitro presence of alveolar cytoxic T- lymphocytes an important regulatory factor in the production of TNF alpha and IL-1 beta by alveolar macrophages? This aim will examine basic mechanisms of proinflammatory cytokine regulation and will focus primarily on the effects of CD8+ cytotoxic lymphocytes on IL-beta processing and release by alveolar macrophages. Because this study addresses the significance of one of the most common of the inflammatory events occurring in the alveolar environment in HIV, it may greatly advance knowledge of HIV- related lung disease. Perhaps more importantly, it focuses on the role of the alveolar lymphocyte as a central player in orchestrating pulmonary parenchymal damage through interactions with alveolar macrophages. As such, this project represents an opportunity to elucidate novel mechanisms of lung injury and to better understand factors of potentially fundamental importance to the regulation of inflammation.