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

 描述（由申请方提供）：长期吸入有机粉尘会导致严重的气道炎症性疾病，包括哮喘、支气管炎和慢性阻塞性肺病，尤其是在农业接触人群中。这一人群也面临着增加的全身不良后果风险，包括肌肉骨骼疾病和骨折的高发生率。为了提供机制的见解，并告知未来的治疗和/或预防策略，我们开发并利用了动物炎症性肺损伤模型暴露于复杂的有机粉尘从大型动物养殖场禁闭。在上一个资助期间，我们通过发现革兰氏阳性细菌， 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（TLR 2）信号传导途径表现出很强的作用。我们还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常见的TLR/IL-1 R衔接蛋白MyD 88，它构成了这种竞争性更新的基础。此外，我们的研究发展到了解这些吸入暴露对骨稳态的全身性后果。重要的是，使用最先进的显微CT成像，我们发现了有机粉尘暴露治疗后的显著骨退化。这是第一次建立了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/MyD 88信号传导和下游IL-6效应通路参与肺-骨炎症轴，这可以有针对性地减少疾病负担。使用这种创新的实验模型系统，结合我们的新观察和初步数据，我们假设TLR/MyD 88依赖性途径是调节肺损伤和全身性骨丢失之间的串扰通过下游细胞因子效应器引起的有机粉尘吸入暴露的核心。我们研究计划的目标是在相关的动物模型中研究机制，生物标志物和治疗方法，这些动物模型可以在以后转化为人类。在目标1中，我们将扩展我们的研究结果，即MyD 88的核心作用，以确定MyD 88依赖的信号通路如何在肺中发挥作用，以控制对有机粉尘暴露的气道炎症反应。了解机制信号和肺细胞生物学调节气道和肺实质病理可能会指导未来的治疗策略。在目标2中，我们将描述肺-骨炎症轴之间串扰的潜在机制，以解释吸入有机粉尘及其微生物成分诱导的肺损伤如何通过重点关注TLR/MyD 88信号通路介导全身性骨丢失。在目标3中，我们将靶向下游TLR/MyD 88介导的全身性IL-6效应器应答，作为临床前可转化的方法，以减少有机粉尘吸入暴露引起的骨退化。

 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.