Effects of maresin-1 & organic dust on lung inflammation

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是美国第三大致死原因，估计有15%的COPD病例与职业接触有关。在农业工人中，有机粉尘暴露会导致破坏性的急性和慢性呼吸道炎症，现有的治疗方法不足以治疗由此产生的呼吸道疾病。因此，迫切需要新的预防或治疗方案来对抗这些暴露的有害炎症影响。富含欧米茄-3脂肪酸(？-3 FA)的饮食对健康的益处已经被很好地认识到了，但还不完全清楚。最近的研究表明，某些？-3FA衍生物可以减轻和消退炎症。这些“亲解”介质(PRM)可能是？-3 FA有益效果的关键。在预防和治疗方案中利用PRM的抗炎和促分解特性可能会彻底改变我们抗击炎症性疾病过程的方式。然而，PRM在治疗有机粉尘相关的呼吸道疾病方面的潜力以及它们对关键的呼吸道炎症启动者--支气管上皮细胞(BECs)的影响尚未被研究。因此，这项拟议研究的目标是确定一种PRM-MAREINE-1(MAR1)在限制有机粉尘暴露的炎症效应方面的效用。据推测，在有机粉尘暴露过程中，MaR1可以减轻呼吸道炎症，增加BECs的抗炎和促分解作用。为了验证这一假设，本文提出了两个具体目标。目的1将重点描述在单次和重复暴露的临床前小鼠模型中，MaR1对有机粉尘引起的呼吸道炎症的影响。目的2重点研究MaR1如何通过以下途径降低BECs对有机粉尘的促炎反应：(A)确定MaR1对粉尘提取物刺激的BECs的促炎反应；(B)明确MaR1诱导粉尘提取物处理的BECs的促炎反应的机制。综上所述，这些目标的结果预计将产生重要的积极影响；它们将证明MaR1在治疗有机粉尘引起的呼吸道疾病方面的有效性，并揭示PRM作为炎症性呼吸道疾病的主要或辅助治疗的潜力。因此，这些实验具有重大的翻译意义，可能会改变预防和治疗急性和慢性炎症性呼吸道疾病的方式。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and an estimated 15% of COPD cases are related to occupational exposures. In agricultural workers, organic dust exposures lead to damaging acute and chronic airway inflammation, and existing therapeutics do not adequately treat the resulting airway disease. Thus, novel preventative or treatment schemes are vitally needed to combat the deleterious inflammatory effects of these exposures. The health benefits of diets high in omega-3 fatty acids (?-3 FA) are well recognized, but incompletely understood. Recent studies reveal certain ?-3 FA derivatives attenuate and resolve inflammation. These "pro-resolving" mediators (PRM) may be key to the beneficial effects of ?-3 FA. Harnessing the anti-inflammatory and pro-resolving properties of PRM in preventative and treatment regimens could revolutionize the way we combat inflammatory disease processes. However, the potential for PRM in treating organic dust-related airway disease, as well as their effects on key airway inflammation initiators, the bronchial epithelial cells (BECs), have not yet been studied. Therefore, the objective for the proposed research is to determine the utility of a PRM, maresin-1 (MaR1), at limiting the inflammatory effects of organic dust exposures. It is hypothesized that MaR1 will reduce airway inflammation and increase the anti-inflammatory and pro-resolving actions of BECs during organic dust exposures. To test this hypothesis, two specific aims are proposed. Aim 1 will focus on delineating the effects of MaR1 on organic dust-induced airway inflammation in a preclinical murine model of single and repetitive exposures. Aim 2 will focus on establishing how MaR1 decreases the pro-inflammatory responses of BECs to organic dust by (a) determining what pro-inflammatory responses in dust extract-stimulated BECs are modified by MaR1, and (b) defining the mechanisms of MaR1-induced changes in dust extract-treated BECs. Taken together, the results of these aims are expected to have important positive impacts; they will demonstrate the utility of MaR1 in treating organic dust-induced airway disease, and expose the potential for PRM as primary or adjunct therapies in inflammatory airway diseases. These experiments are therefore of great translational significance, potentially transforming the way acute and chronic inflammatory airway diseases are prevented and treated.