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，其可进展为纤维化，即肺纤维化。 矽肺病尽管有现有的标准，硅肺仍然是美国普遍存在的健康问题， 在全世界都有。因为它是一种已知的肺纤维化的病原体，它经常被用来研究 在动物模型中控制条件下的纤维化机制。虽然已经学到了很多， 关于导致纤维化发展的分子和细胞机制的信息仍然不足 有效的治疗方法。一般认为肺泡巨噬细胞是最初的细胞， 目标后二氧化硅吸入和巨噬细胞参与启动炎症信号 而且最有可能的是淋巴细胞也参与其中，因为Th 1和Th 2相关的细胞因子已经被发现， 反复参与纤维化过程。根据我们实验室的最新数据， 另一些人认为，激活的肺巨噬细胞（aM 0）和NK淋巴细胞足以引发 我们提出，通过研究导致纤维化的炎性周期，我们可以检验中心假设，即aM 0与NK 淋巴细胞构成了慢性炎症发展到矽肺的步骤。我们将 使用以下三个目标来检验这一假设：具体目标1：表征二氧化硅暴露的肺泡 巨噬细胞运输到间质空间，获得免疫刺激表型，并发挥免疫调节作用。 在aM 0的生成中起着不可或缺的作用。具体目标2：证明aM 0的NK活化是 足以产生肺纤维化的炎症需求。具体目标3：确定性质 以及导致促纤维化蛋白生成的aM 0-NK界面的分子组分 环境该提议是新颖的，因为它将解决aM 0和NK之间的复杂相互作用 在使用体外和体内模型的呼吸系统的情况下。完成后 这些研究，我们希望建立和测试特定亚群的相对贡献， 巨噬细胞和NK细胞，并确定那些候选分子和信号通路， 这些细胞相互交流导致慢性炎症和纤维化。此外，这项工作是 预计将产生的知识，将指导新的治疗目标的发展， 呼吸道疾病的管理，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.