Role of pattern recognition receptors in organic dust-induced airway inflammation

模式识别受体在有机粉尘引起的气道炎症中的作用

• 批准号: 7984990
• 负责人: Jill A Poole
• 金额: $ 30.38万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-23 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7984990
• 关键词: Agricultural Workers; Agriculture; Alveolar Macrophages; Animals; Antigen-Presenting Cells; Asthma; Attenuated; Automobile Driving; Breathing; Bronchitis; Cell Culture Techniques; Cell Wall; Cell surface; Chemicals; Chronic; Chronic Bronchitis; Clinical; Data; Development; Disease; Dust; Endotoxins; Environment; Epidemiology; Exhibits; Exposure to; Family suidae; Farming environment; Gram-Negative Bacteria; Gram-Positive Bacteria; Human; Immune; Immune response; Impairment; In Vitro; Individual; Industry; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Laboratories; Laboratory Study; Lead; Link; Livestock; Lung; Lung Inflammation; Lung diseases; Mediating; Muramic Acid; Mus; Nuclear; Obstructive Lung Diseases; Occupational Asthma; Pattern recognition receptor; Peptidoglycan; Persons; Phenotype; Predisposition; Prevention; Regulation; Reporting; Respiratory physiology; Risk; Role; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; System; Testing; Time; Toll-Like Receptor 2; Toxin; adaptive immunity; airway inflammation; base; in vivo; macrophage; microbial; monocyte; mouse model; novel; peptidoglycan receptor; prevent; public health relevance; research study; respiratory; response; sensor; treatment strategy

DESCRIPTION (provided by applicant): Organic dust exposure in the agricultural industry, particularly from large animal farming, results in significant airway disease including bronchitis, exacerbation of asthma, and obstructive lung disease. Initial exposure to organic dust induces an intense airway inflammatory response that wanes over time; however, persons repetitively exposed to these environments exhibit an increased risk of lung function decline, persistent inflammation and progressive respiratory impairment. We have demonstrated in our newly developed murine model that mice adapt to repetitive organic dust exposure, yet manifest evidence of chronic lung tissue inflammation and impaired alveolar macrophage function. We have also established in vitro that repetitive organic dust exposure profoundly impairs antigen presenting cell (APC) phenotype and function. As APCs function to recognize, respond, and clear inhaled agents/toxins while mediating adaptive immunity, a functionally impaired APC due to repetitive dust exposure would likely contribute to worsening respiratory disease. The mechanisms underlying these observations are not clear and could lead to the development of novel treatments to prevent and manage organic dust-induced airway disease in agriculture workers. The inherent complexity of the dust is a challenge in defining mechanisms of organic dust-induced inflammatory responses. One established inflammatory component in organic dusts is endotoxin; however, epidemiologic and laboratory-based studies have failed to link endotoxin exposure to disease manifestations. Our recent analysis has revealed a strong predominance of Gram-positive (rather than Gram-negative) bacteria and chemical analysis demonstrated a high concentration of muramic acid, a component of peptidoglycan (PGN) from the bacterial cell wall, in large animal farming environments. Our studies also support that non-endotoxin components, such as PGN, are driving the innate immune inflammatory responses to large animal farming dusts. Gram-positive PGN and its degradation products can act through several pattern-recognition receptors including cell surface Toll-like receptor 2 (TLR2) and the cytosolic nuclear oligomerization domain molecule (NOD2). Our preliminary data suggest that TLR2 and NOD2 are important signal transduction molecules key to the regulation of organic dust-induced inflammation. These novel observations led us to hypothesize that pattern recognition receptors responsible for recognizing Gram-positive peptidoglycan regulate the chronic inflammatory response to large animal organic dust exposure. To test this hypothesis we will perform experiments outlined in three specific aims: 1) determine the time course and reversibility of NOD2 expression by antigen presenting cells with organic dust exposure and the signaling pathways responsible for its expression; 2) define the functional role of NOD2 and TLR2 in modulating APC response to activation following organic dust exposure in knock-out mice in vitro and in vivo; and 3) investigate whether mice deficient in either NOD2 or TLR2 exhibit altered susceptibility to organic dust exposure induced airway disease. PUBLIC HEALTH RELEVANCE: The significance of this proposal lies in identifying mechanisms by which the Gram-positive microbial components present in organic dust mediate inflammation, which represents a paradigm shift from the current dogma focused on endotoxin-driven mechanisms. This project will help identify novel inflammatory targets that could lead to new prevention and treatment strategies of individuals subjected to repeated organic dust exposure.

描述（由申请人提供）：农业中的有机粉尘暴露，特别是大型动物养殖中的有机粉尘暴露，会导致严重的气道疾病，包括支气管炎、哮喘加重和阻塞性肺病。最初暴露于有机粉尘会引起强烈的气道炎症反应，随着时间的推移而减弱;然而，反复暴露于这些环境的人表现出肺功能下降，持续性炎症和进行性呼吸障碍的风险增加。我们已经在我们新开发的小鼠模型中证明，小鼠适应重复的有机粉尘暴露，但表现出慢性肺组织炎症和肺泡巨噬细胞功能受损的证据。我们还建立了在体外，反复接触有机粉尘深刻损害抗原呈递细胞（APC）的表型和功能。由于APC在介导适应性免疫的同时具有识别、响应和清除吸入的试剂/毒素的功能，因此由于重复粉尘暴露而导致的功能受损的APC可能会导致呼吸道疾病恶化。这些观察结果的机制尚不清楚，可能导致开发新的治疗方法来预防和管理农业工人中有机粉尘引起的气道疾病。粉尘的固有复杂性是确定有机粉尘诱导的炎症反应机制的挑战。有机粉尘中的一种既定炎症成分是内毒素;然而，流行病学和实验室研究未能将内毒素暴露与疾病表现联系起来。我们最近的分析表明，革兰氏阳性（而不是革兰氏阴性）细菌和化学分析表明，在大型动物养殖环境中，高浓度的胞壁酸，肽聚糖（PGN）的一个组成部分，从细菌细胞壁。我们的研究还支持非内毒素成分，如PGN，正在驱动对大型动物养殖粉尘的先天免疫炎症反应。革兰氏阳性PGN及其降解产物可以通过几种模式识别受体起作用，包括细胞表面Toll样受体2（TLR 2）和胞质核寡聚化结构域分子（NOD 2）。我们的初步数据表明，TLR 2和NOD 2是重要的信号转导分子的关键调节有机粉尘诱导的炎症反应。这些新的观察使我们假设，负责识别革兰氏阳性肽聚糖的模式识别受体调节大型动物有机粉尘暴露的慢性炎症反应。为了验证这一假设，我们将进行三个具体目标的实验：1）确定暴露于有机粉尘的抗原呈递细胞表达NOD 2的时间过程和可逆性以及负责其表达的信号通路; 2）在体外和体内确定NOD 2和TLR 2在敲除小鼠中调节APC对暴露于有机粉尘后的活化的应答中的功能作用;和3）研究NOD 2或TLR 2缺陷的小鼠是否表现出对有机粉尘暴露诱导的气道疾病的易感性改变。 公共卫生相关性：这一提议的意义在于确定有机粉尘中存在的革兰氏阳性微生物组分介导炎症的机制，这代表了从目前专注于内毒素驱动机制的教条的范式转变。该项目将有助于确定新的炎症靶点，从而为反复接触有机粉尘的个体提供新的预防和治疗策略。