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: 9197978
• 负责人: Jill A Poole
• 金额: $ 43.2万
• 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 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197978
• 关键词: Acute; Adaptor Signaling Protein; Agriculture; Animal Model; Animals; Asthma; Biological Markers; Biological Models; Bone Diseases; Bone Marrow; Breathing; Bronchitis; Cells; Cellular biology; Chronic; Chronic Obstructive Airway Disease; Complex; Data; Deterioration; Disease; Dust; Experimental Models; Exposure to; Fracture; Funding; Future; Goals; Homeostasis; Human; Immune; Inflammatory; Inflammatory Response; Inhalant dose form; Interleukin-6; Leukocytes; Lipopolysaccharides; Livestock; Lung; Mediating; Mediator of activation protein; Methodology; Modeling; Modernization; Mus; Musculoskeletal Diseases; Osteoclasts; Pathology; Pathway interactions; Pattern recognition receptor; Peptidoglycan; Persons; Pharmacology; Phenotype; Population; Prevention strategy; Research; Research Proposals; Risk; Role; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; TLR2 gene; Therapeutic; Time; Translating; X-Ray Computed Tomography; airway inflammation; bone; bone loss; burden of illness; clinically translatable; cohort; cytokine; inhibitor/antagonist; injured airway; innovation; insight; lung injury; microCT; microbial; migration; novel; pre-clinical; public health relevance; response; targeted treatment; therapeutic target; translational approach

 DESCRIPTION (provided by applicant): Chronic inhalation of organic dusts causes significant airway inflammatory diseases including asthma, bronchitis, and chronic obstructive pulmonary disease, particularly in agriculture-exposed persons. This population is also at increased risk of adverse systemic consequences including high rates of musculoskeletal disorders and fractures. To provide mechanistic insights and inform future therapeutic and/or prevention strategies, we developed and have utilized an animal inflammatory lung injury model following exposure to complex organic dusts from large animal farm confinements. During the previous funding period, we initiated a paradigm shift in this field by finding that gram-positive bacterial peptidoglycan (PGN), as opposed to gram- negative lipopolysaccharide (LPS), is a predominant driver of lung inflammatory consequences, with a strong role demonstrated for the Toll-like receptor 2 (TLR2) signaling pathway. We also defined roles for other pattern-recognition receptor pathways, but the strongest phenotype discovered was for the common TLR/IL-1R adaptor protein, MyD88, which forms the basis of this competitive renewal. Furthermore, our research evolved to understand the systemic consequences of these inhalant exposures on bone homeostasis. Importantly, using state-of-the-art micro-CT imaging we uncovered significant bone deterioration following treatment with organic dust exposures. This established, for the first time, an animal model connecting inhalant lung injury to bone disease. Importantly, our new preliminary studies support that inhalant organic dust exposures engage the lung-bone inflammatory axis through TLR/MyD88 signaling and downstream IL-6 effector pathways, which could be targeted to reduce disease burden. Using this innovative experimental model systems combined with our novel observations and preliminary data, we hypothesize that TLR/MyD88-dependent pathways are central in regulating the crosstalk between lung injury and systemic bone loss induced by organic dust inhalant exposures via downstream cytokine effectors. The goal of our research proposal is to investigate mechanisms, biomarkers, and therapeutic approaches in a relevant animal model that can be later translated to humans. In Aim 1, we will expand upon our findings of a central role for MyD88 to establish how MyD88- dependent signaling pathways function in the lung to govern airway inflammatory responses to organic dust exposures. Understanding the mechanistic signals and lung cell biology regulating airway and lung parenchyma pathology may guide future therapeutic strategies. In Aim 2, we will delineate the potential mechanisms governing the crosstalk between the lung-bone inflammatory-axis to explain how lung injury induced following inhalation of organic dusts and its microbial components mediate systemic bone loss through focused efforts on key TLR/MyD88 signaling pathway. In Aim 3, we will target the downstream TLR/MyD88- mediated systemic IL-6 effector response as a pre-clinical, translatable approach to reduce bone deterioration induced by organic dust inhalant exposures.

 描述(申请人提供)：长期吸入有机粉尘会导致严重的呼吸道炎症，包括哮喘、支气管炎和慢性阻塞性肺病，特别是在农业接触者中。这一人群还面临着更高的全身不良后果风险，包括肌肉骨骼疾病和骨折的高发病率。为了提供机理上的见解，并为未来的治疗和/或预防策略提供信息，我们开发并利用了一种暴露于大型动物养殖场复杂有机粉尘后的动物炎症性肺损伤模型。在之前的资助期间，我们发现了革兰氏阳性细菌，从而启动了这一领域的范式转变 与革兰氏阴性脂多糖(LPS)相反，肽聚糖(PGN)是肺部炎症后果的主要驱动因素，对Toll样受体2(TLR2)信号通路具有很强的作用。我们也定义了其他模式识别受体途径的作用，但发现的最强表型是共同的TLR/IL-1R适配器蛋白MyD88，它构成了这种竞争性更新的基础。此外，我们的研究逐渐了解了这些吸入剂暴露对骨骼稳态的系统性影响。重要的是，使用最先进的微型CT成像技术，我们发现了有机粉尘暴露治疗后骨骼的显著恶化。这首次建立了一个将吸入性肺损伤与骨骼疾病联系起来的动物模型。重要的是，我们新的初步研究支持吸入性有机粉尘暴露通过TLR/MyD88信号和下游IL-6效应通路参与肺-骨炎轴，这可能是降低疾病负担的靶向。使用这个创新的实验模型系统，结合我们新的观察和初步数据，我们假设TLR/MyD88依赖的通路是通过下游细胞因子效应调节有机粉尘暴露引起的肺损伤和全身骨丢失之间的串扰的中心。我们的研究计划的目标是在相关的动物模型中研究机制、生物标记物和治疗方法，并在以后可以移植到人类身上。在目标1中，我们将扩展我们的发现，即MyD88在肺中发挥核心作用，以确定MyD88依赖的信号通路如何发挥作用，控制对有机粉尘暴露的呼吸道炎症反应。了解调节呼吸道和肺实质病理的机械信号和肺细胞生物学有助于指导未来的治疗策略。在目标2中，我们将描述控制肺-骨-炎症轴之间的潜在机制，以解释吸入有机粉尘所致的肺损伤及其微生物成分如何通过关键的TLR/MyD88信号通路介导全身骨丢失。在目标3中，我们将以下游TLR/MyD88介导的系统性IL-6效应器反应为目标，作为临床前的、可翻译的方法，以减少有机粉尘吸入剂暴露引起的骨骼退化。