Effects of maresin-1 & organic dust on lung inflammation

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是美国第三大死亡原因，估计15%的COPD病例与职业暴露有关。在农业工人中，有机粉尘暴露导致急性和慢性气道炎症，现有的治疗方法不能充分治疗由此产生的气道疾病。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作用。富含omega-3脂肪酸的饮食对健康的好处（？- 3 FA）是公认的，但不完全理解。最近的研究表明，某些？3 FA衍生物减轻和解决炎症。这些“促消退”介质（PRM）可能是？- 3 FA。在预防和治疗方案中利用PRM的抗炎和促消退特性可以彻底改变我们对抗炎症性疾病过程的方式。然而，PRM在治疗有机粉尘相关气道疾病中的潜力，以及它们对关键气道炎症引发剂支气管上皮细胞（BEC）的影响尚未研究。因此，拟议研究的目的是确定PRM maresin-1（MaR 1）在限制有机粉尘暴露的炎症效应方面的效用。 据推测，MaR 1将减少气道炎症，并增加BEC的抗炎和促分解作用在有机粉尘暴露。为了检验这一假设，提出了两个具体目标。目的1将集中于描绘MaR 1对有机粉尘诱导的气道炎症的作用，在临床前小鼠模型的单次和重复暴露。目的2将集中于确定MaR 1如何降低BEC对有机粉尘的促炎反应，方法是：（a）确定MaR 1修饰了粉尘提取物刺激的BEC中的哪些促炎反应，以及（B）定义MaR 1诱导的粉尘提取物处理的BEC变化的机制。总之，这些目标的结果预计将产生重要的积极影响;它们将证明MaR 1在治疗有机粉尘诱导的气道疾病中的效用，并揭示PRM作为炎症性气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转化意义，可能改变急性和慢性炎症性气道疾病的预防和治疗方式。

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.