Defining the roles of macrophages subsets and NK lymphocytes in silicosis

描述(由申请人提供)：众所周知，结晶二氧化硅可引起慢性肺部炎症，可发展为纤维化，即矽肺。尽管有现有的标准，但在美国和全世界，矽肺仍然是一个普遍的健康问题。因为它是一种已知的肺纤维化的致病因子，所以它经常被用来在动物模型中研究可控条件下的纤维化形成机制。虽然已经了解了很多，但关于导致纤维化的分子和细胞机制的信息仍然不足，无法开发有效的治疗方法。人们普遍认为，肺泡巨噬细胞是二氧化硅吸入后的初始细胞靶点，巨噬细胞参与了炎症信号的启动，最有可能的是淋巴细胞也参与了炎症信号的启动，因为Th1和Th2相关的细胞因子一再参与纤维化过程。根据我们实验室以及其他实验室的最新数据，表明活化的肺巨噬细胞(AMQ)和NK淋巴细胞足以引发炎症循环，导致纤维化，我们建议检验这一中心假设，即AMQ和NK淋巴细胞共同构成了发展为矽肺的慢性炎症的步骤。我们将使用以下三个目标来验证这一假说：特定目标1：表征进入间质的二氧化硅暴露的肺泡巨噬细胞，获得免疫刺激表型，并在AMQ的产生中发挥不可或缺的作用。具体目标2：证明AMQ对NK的激活足以产生肺纤维化所需的炎症。具体目标3：确定导致促纤维化环境产生的AMQ-NK界面的性质和分子组成。这一建议是新颖的，因为它将使用体外和体内模型在呼吸系统的背景下解决AMQ和NK之间的复杂相互作用。在这些研究完成后，我们希望建立和测试特定亚群的巨噬细胞和NK细胞的相对贡献，并确定这些细胞通过哪些候选分子和信号通路进行沟通，从而导致慢性炎症和纤维化。此外，这项工作预计将产生知识，指导开发新的治疗目标，以管理呼吸系统疾病，包括二氧化硅诱导的炎症和纤维化。

DESCRIPTION (provided by applicant): Crystalline silica is well known to induce chronic lung inflammation that can progress to fibrosis, i.e. silicosis. Despite existing standards, silicosis remains a prevalent health problem in the United States and throughout the world. Because it is a known causative agent of lung fibrosis, it is often used to study mechanisms of fibrogenesis under controlled conditions in animal models. While much has been learned, there is still insufficient information on the molecular and cellular mechanisms leading to fibrosis to develop effective therapeutic approaches. It is generally accepted that alveolar macrophages are the initial cellular targets following silica inhalation and that macrophages are involved in the initiation of inflammatory signals and that mostly likely lymphocytes are also involved, since Th1- and Th2- associated cytokines have been repeatedly implicated in the process of fibrosis. Based on recent data from our laboratory, as well as others, implicating activated lung macrophages (aMQ) and NK lymphocytes as being sufficient to set off the inflammatory cycle leading to fibrosis we propose to test the central hypothesis that aMQ with NK lymphocytes constitute steps in the development of chronic inflammation progressing to silicosis. We will use the following three aims to test this hypothesis: Specific Aim 1: Characterize the silica-exposed alveolar macrophages that traffic to the interstitial spaces, acquire an immunostimulatory phenotype, and play an integral role in the generation of the aMQ. Specific Aim 2: Demonstrate that NK activation by the aMQ is sufficient to generate the inflammatory requirements for lung fibrosis. Specific Aim 3: Ascertain the nature and molecular components of the aMQ-NK interface that results in the generation of a pro-fibrotic environment. This proposal is novel in that it will address the complex interactions between aMQ and NK within the context of the respiratory system using both in vitro and in vivo models. Upon completion of these studies, we expect to establish and test the relative contributions of specific subpopulations of macrophages and NK cells and determine those candidate molecules and signaling pathways by which these cells communicate leading to chronic inflammation and fibrosis. Furthermore, this body of work is anticipated to generate knowledge that will direct the development of novel therapeutic targets for the management of respiratory illnesses, including silica-induced inflammation and fibrosis.