RvD1-FPR2 signaling ameliorates alcoholic liver disease

酒精性肝炎(AH)是一种预后不佳的病态疾病，主要由酒精性肝炎引起 免疫细胞功能对内毒素血症的反应，但其机制尚不完全清楚 明白了。分解蛋白D_1(RvD_1)是一种促进分解的脂质介质，通过甲酰基传递信号 小鼠肽受体2(FPR2)引起巨噬细胞M2极化及抗菌作用 中性粒细胞的功能。急性脑出血患者血浆RvD1水平和肝脏FPR2表达降低 提示此通路在急性肝炎中受阻的患者。动物模型建议Rvd1治疗 改善Fpr2-/-小鼠酒精性肝损伤、炎症、纤维化和内毒素血症 出现加重的肝损伤、炎症、纤维化和内毒素血症。研究的特点 RvD1-FPR2信号通路在酒精性肝病(ALD)中是不存在的 根据初步数据是有根据的。目标1：这一目标将决定Rvd1是否仅通过 FPR2诱导对酒精性肝病(ALD)动物的保护作用。目标2：目标2a将决定 RvD1-FPR2信号通路对Kupffer细胞M2极化是必不可少的。目标2b将 确定中性粒细胞介导的防御反应是否需要RvD1-FPR2信号转导 致病威胁。目的3：获得性中性粒细胞和单核细胞 将接受或不接受RvD1的体外治疗，随后进行流式细胞仪和蛋白质组学和 磷蛋白质组学分析测量受体激活并表征信号转导 途径，分别为。总而言之，这项研究将产生可以识别Rvd1或FPR2的数据 激动剂作为ALD的一种治疗方法。由于急性呼吸窘迫的严重性和对急性呼吸暂停的分析 患者对这项研究进行了抽样，它立即产生了影响，并为未来的治疗提供了信息 战略。新的生物标记物和治疗干预有望来自 拟议研究的结论。RvD1-FPR2信号通路的基础生物学研究 中性粒细胞和单核细胞也有望从这项工作中获得。

Alcoholic hepatitis (AH) is a morbid condition with poor prognosis that is primarily driven by altered immune cell function in response to endotoxemia, but the mechanisms are not fully known or understood. Resolvin D1 (RvD1) is a pro-resolution lipid mediator that signals through formyl peptide receptor 2 (FPR2) in mice eliciting M2 polarization in macrophages and antibacterial functions in neutrophils. Plasma RvD1 levels and hepatic FPR2 expression are decreased in AH patients suggesting this pathway is impeded in AH. Animal models suggest RvD1 treatment ameliorates alcohol induced liver injury, inflammation, fibrosis, and endotoxemia while Fpr2-/- mice develop exacerbated liver injury, inflammation, fibrosis, and endotoxemia. Studies characterizing the RvD1-FPR2 signaling pathway in alcoholic liver disease (ALD) are nonexistent but are warranted based on preliminary data. Aim 1: This aim will determine if RvD1 acts solely through FPR2 to elicit protection in an animal of alcoholic liver disease (ALD). Aim 2: Aim 2a will determine if the RvD1-FPR2 signaling pathway is essential for M2 polarization of Kupffer cells. Aim 2b will establish if RvD1-FPR2 signaling is required for neutrophil-mediated defense responses against pathogenic threats. Aim 3: AH patient and healthy control acquired neutrophils and monocytes will be treated with or without RvD1 ex vivo followed by flow cytometry and proteomic and phosphoproteomic analysis to measure receptor activation and to characterize the signaling pathway, respectively. Collectively this study will generate data that could identify RvD1 or FPR2 agonists as a therapeutic approach for ALD. Due to the severity of AH and the analysis of AH patient samples this study it is immediately impactful and informative for future treatment strategies. Novel biomarkers and therapeutic interventions are expected to come from the conclusion of the proposed study. Basic biology of the RvD1-FPR2 signaling pathway in neutrophils and monocytes is expected from this work as well.