Defining the roles of macrophages subsets and NK lymphocytes in silicosis

定义巨噬细胞亚群和 NK 淋巴细胞在矽肺中的作用

• 批准号: 7422552
• 负责人: Andrij Holian
• 金额: $ 0.75万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-12 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7422552
• 关键词: Address; Adoptive Transfer; Alveolar Macrophages; Animal Model; Biological Models; Breathing; Cells; Chronic; Complex; Condition; Data; Developed Countries; Developing Countries; Development; Elements; Environment; Event; Exposure to; Fibrosis; Fluorescence Microscopy; Generations; Health; Immune response; In Vitro; Inflammation; Inflammatory; Knockout Mice; Knowledge; Laboratories; Learning; Lung; Lung Inflammation; Lymphocyte; Lymphocyte Activation; Maintenance; Modeling; Molecular; Mus; Natural Killer Cells; Nature; Occupational; Personal Satisfaction; Phenotype; Play; Population; Process; Relative (related person); Respiratory System; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Silicon Dioxide; Silicosis; Standards of Weights and Measures; Synapses; Testing; Therapeutic; United States; Work; Workplace; cellular targeting; cytokine; fibrogenesis; in vivo Model; interstitial; macrophage; novel; novel therapeutics; respiratory; therapeutic target; tool; trafficking

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.

描述（由申请人提供）：众所周知，结晶二氧化硅可诱导慢性肺部炎症，并可进展为纤维化，即矽肺。尽管有现有的标准，矽肺仍然是美国和世界各地普遍存在的健康问题。因为它是已知的肺纤维化的病原体，所以它经常被用于在动物模型中在受控条件下研究纤维化发生的机制。虽然已经了解了很多，但仍然没有足够的关于导致纤维化的分子和细胞机制的信息来开发有效的治疗方法。人们普遍认为，肺泡巨噬细胞是吸入二氧化硅后的初始细胞靶点，巨噬细胞参与炎症信号的启动，淋巴细胞也很可能参与其中，因为Th 1和Th 2相关细胞因子反复参与纤维化过程。基于我们实验室以及其他实验室的最新数据，涉及活化的肺巨噬细胞（aMQ）和NK淋巴细胞足以引发导致纤维化的炎症周期，我们建议测试中心假设，即aMQ与NK淋巴细胞构成慢性炎症进展为矽肺的发展步骤。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，其运输到间质空间，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的NK活化足以产生肺纤维化的炎症要求。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分。该提议是新颖的，因为它将使用体外和体内模型解决在呼吸系统背景下aMQ和NK之间的复杂相互作用。在完成这些研究后，我们希望建立和测试巨噬细胞和NK细胞的特定亚群的相对贡献，并确定这些细胞沟通导致慢性炎症和纤维化的候选分子和信号通路。此外，这项工作预计将产生知识，指导开发用于管理呼吸系统疾病的新型治疗靶点，包括二氧化硅诱导的炎症和纤维化。