Gao Ye, Zhang Huawei, Luo Lingchun, Lin Jing, Li Dan, Zheng Sisi, Huang Hua, Yan Songfan, Yang Jingxiang, Hao Yu, Li Hui, Gao Smith Fang, Jin Shengwei
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang 325027, China; and.
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang 325027, China; and
J Immunol. 2017 Sep 15;199(6):2043-2054. doi: 10.4049/jimmunol.1700315. Epub 2017 Aug 9.
Acute respiratory distress syndrome (ARDS) is a severe illness characterized by uncontrolled inflammation. The resolution of inflammation is a tightly regulated event controlled by endogenous mediators, such as resolvin D1 (RvD1). Cyclooxygenase-2 (COX-2) has been reported to promote inflammation, along with PGE, in the initiation of inflammation, as well as in prompting resolution, with PGD acting in the later phase of inflammation. Our previous work demonstrated that RvD1 enhanced COX-2 and PGD expression to resolve inflammation. In this study, we investigated mechanisms underlying the effect of RvD1 in modulating proresolving COX-2 expression. In a self-limited ARDS model, an LPS challenge induced the biphasic activation of COX-2, and RvD1 promoted COX-2 expression during the resolution phase. However, it was significantly blocked by treatment of a NF-κB inhibitor. In pulmonary fibroblasts, NF-κB p50/p50 was shown to be responsible for the proresolving activity of COX-2. Additionally, RvD1 potently promoted p50 homodimer nuclear translocation and robustly triggered DNA-binding activity, upregulating COX-2 expression via lipoxin A receptor/formyl peptide receptor 2. Finally, the absence of p50 in knockout mice prevented RvD1 from promoting COX-2 and PGD expression and resulted in excessive pulmonary inflammation. In conclusion, RvD1 expedites the resolution of inflammation through activation of lipoxin A receptor/formyl peptide receptor 2 receptor and NF-κB p50/p50-COX-2 signaling pathways, indicating that RvD1 might have therapeutic potential in the management of ARDS.
急性呼吸窘迫综合征（ARDS）是一种以炎症失控为特征的严重疾病。炎症的消退是一个由内源性介质严格调控的过程，如消退素D1（RvD1）。据报道，环氧合酶-2（COX-2）在炎症起始阶段与前列腺素E（PGE）一起促进炎症，同时在炎症后期，前列腺素D（PGD）发挥作用促使炎症消退时，COX-2也参与其中。我们之前的研究表明，RvD1可增强COX-2和PGD的表达以促进炎症消退。在本研究中，我们探究了RvD1调节促消退性COX-2表达作用的潜在机制。在一个自限性ARDS模型中，脂多糖（LPS）刺激诱导了COX-2的双相激活，而RvD1在炎症消退阶段促进COX-2表达。然而，用核因子κB（NF-κB）抑制剂处理后，这种促进作用被显著阻断。在肺成纤维细胞中，NF-κB p50/p50被证明负责COX-2的促消退活性。此外，RvD1有力地促进了p50同型二聚体的核转位，并强烈触发DNA结合活性，通过脂氧素A受体/甲酰肽受体2上调COX-2表达。最后，基因敲除小鼠中p50的缺失阻止了RvD1促进COX-2和PGD表达，并导致肺部炎症过度。总之，RvD1通过激活脂氧素A受体/甲酰肽受体2和NF-κB p50/p50-COX-2信号通路加速炎症消退，表明RvD1在ARDS的治疗中可能具有潜在的治疗价值。
