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: 7185410
• 负责人: Andrij Holian
• 金额: $ 31.4万
• 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/7185410
• 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; base; 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 3 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，结晶二氧化硅会诱发慢性肺部炎症，进而发展为纤维化，即矽肺。尽管有现有标准，矽肺仍然是美国和全世界普遍存在的健康问题。由于它是已知的肺纤维化致病因子，因此通常用于研究动物模型中受控条件下的纤维形成机制。尽管已经了解了很多，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，肺泡巨噬细胞是吸入二氧化硅后的最初细胞靶标，巨噬细胞参与炎症信号的引发，并且很可能淋巴细胞也参与其中，因为 Th1 和 Th2 相关细胞因子反复参与纤维化过程。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 淋巴细胞足以引发导致纤维化的炎症循环，我们建议检验以下中心假设：aMQ 与 NK 淋巴细胞构成慢性炎症进展为硅肺的步骤。我们将使用以下 3 个目标来检验这一假设： 具体目标 1：表征暴露于二氧化硅的肺泡巨噬细胞，这些巨噬细胞通向间质空间，获得免疫刺激表型，并在 aMQ 的生成中发挥不可或缺的作用。具体目标 2：证明 aMQ 激活 NK 足以产生肺纤维化的炎症需求。具体目标 3：确定 aMQ-NK 界面的性质和分子成分，从而产生促纤维化环境。该提案的新颖之处在于它将使用体外和体内模型来解决呼吸系统背景下 aMQ 和 NK 之间复杂的相互作用。完成这些研究后，我们期望建立并测试巨噬细胞和 NK 细胞特定亚群的相对贡献，并确定这些细胞通过哪些候选分子和信号通路进行通讯，从而导致慢性炎症和纤维化。此外，预计这项工作将产生知识，指导开发治疗呼吸系统疾病的新治疗靶点，包括二氧化硅引起的炎症和纤维化。