Defining the roles of macrophages subsets and NK lymphocytes in silicosis

众所周知，结晶二氧化硅可诱导慢性肺部炎症，可进展为纤维化，即 矽肺。尽管有现有的标准，矽肺在美国仍然是一个普遍的健康问题， 在世界各地。因为它是一种已知的肺纤维化的病原体，所以它经常被用来研究 动物模型中可控条件下的纤维化形成机制。虽然已经学到了很多， 目前关于导致纤维化的分子和细胞机制的信息仍不充分。 有效的治疗方法。一般认为肺泡巨噬细胞是原始细胞。 二氧化硅吸入后的靶点和巨噬细胞参与炎症信号的启动 最有可能的淋巴细胞也参与其中，因为Th1和Th2相关的细胞因子 在纤维化过程中反复牵连。根据我们实验室的最新数据以及 其他，暗示活化的肺巨噬细胞(AM0)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aM0与NK的中心假设 淋巴细胞构成了慢性炎症发展为矽肺的步骤。我们会 使用以下三个目标来检验这一假设：具体目标1：描述暴露于二氧化硅的牙槽骨的特征 巨噬细胞进入间质间隙，获得免疫刺激表型，并发挥 在aM0的产生中起着不可或缺的作用。具体目标2：证明由aM0激活NK是 足以产生肺纤维化所需的炎症。具体目标3：查明性质 和aM0-NK界面的分子组成，导致前纤维化的产生 环境。这一建议是新颖的，因为它将解决aM0和NK之间的复杂相互作用 在呼吸系统的背景下，使用体外和体内模型。在完成后 这些研究，我们期望建立和测试特定亚群的相对贡献 巨噬细胞和NK细胞，并确定这些候选分子和信号通路 这些细胞相互沟通，导致慢性炎症和纤维化。此外，这项工作的主体是 预计将产生指导开发新的治疗靶点的知识 呼吸系统疾病的管理，包括二氧化硅引起的炎症和纤维化。

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 acceptedthat alveolar macrophages are the initial cellular targets following silica inhalation and that macrophagesare 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. Basedon recent data from our laboratory, as well as others, implicating activated lung macrophages (aM0) and NK lymphocytes as being sufficient to set off the inflammatory cycle leading to fibrosis we propose to test the central hypothesis that aM0 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 aM0. Specific Aim 2: Demonstrate that NK activation by the aM0 is sufficient to generatethe inflammatory requirements for lung fibrosis. Specific Aim 3: Ascertain the nature and molecular components of the aM0-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 aM0 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.