Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.).
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
J Pharmacol Exp Ther. 2021 Nov;379(2):156-165. doi: 10.1124/jpet.121.000712. Epub 2021 Aug 31.
Acute respiratory distress syndrome (ARDS), a common and fatal clinical condition, is characterized by the destruction of epithelium and augmented permeability of the alveolar-capillary barrier. Resolvin conjugates in tissue regeneration 1 (RCTR1) is an endogenous lipid mediator derived from docosahexaenoic acid , exerting proresolution effects in the process of inflammation. In our research, we evaluated the role of RCTR1 in alveolar fluid clearance (AFC) in lipopolysaccharide-induced ARDS/acute lung injury (ALI) rat model. Rats were injected with RCTR1 (5 μg/kg) via caudal veins 8 hours after lipopolysaccharide (LPS) (14 mg/kg) treatment, and then AFC was estimated after 1 hour of ventilation. Primary type II alveolar epithelial cells were incubated with LPS (1 ug/ml) with or without RCTR1 (10 nM) for 8 hours. Our results showed that RCTR1 significantly enhanced the survival rate, promoted the AFC, and alleviated LPS-induced ARDS/ALI in vivo. Furthermore, RCTR1 remarkably elevated the protein expression of sodium channels and Na, K-ATPase and the activity of Na, K-ATPase in vivo and in vitro. Additionally, RCTR1 also decreased neural precursor cell expressed developmentally downregulated 4-2 (Nedd4-2) level via upregulating Ser-phosphorylated-Akt expression. Besides this, inhibitors of receptor for lipoxin A4 (ALX), cAMP, and phosphatidylinositol 3-kinase (PI3K) (BOC-2, KH-7, and LY294002) notably inhibited the effects of RCTR1 on AFC. In summary, RCTR1 enhances the protein levels of sodium channels and Na, K-ATPase and the Na, K-ATPase activity to improve AFC in ALI through ALX/cAMP/PI3K/Nedd4-2 pathway, suggesting that RCTR1 may become a therapeutic drug for ARDS/ALI. SIGNIFICANCE STATEMENT: RCTR1, an endogenous lipid mediator, enhanced the rate of AFC to accelerate the resolution of inflammation in the LPS-induced murine lung injury model. RCTR1 upregulates the expression of epithelial sodium channels (ENaCs) and Na, K-ATPase in vivo and in vitro to accelerate the AFC. The efficacy of RCTR1 on the ENaC and Na, K-ATPase level was in an ALX/cAMP/PI3K/Nedd4-2-dependent manner.
急性呼吸窘迫综合征（ARDS）是一种常见且致命的临床病症，其特征为上皮细胞破坏和肺泡毛细血管屏障通透性增加。组织再生 1 型(resolvin conjugates in tissue regeneration 1，RCTR1)是一种内源性脂质介质，来源于二十二碳六烯酸，在炎症过程中发挥促解决作用。在我们的研究中，我们评估了 RCTR1 在脂多糖诱导的 ARDS/急性肺损伤（ALI）大鼠模型中对肺泡液清除（alveolar fluid clearance，AFC）的作用。大鼠在脂多糖（LPS）（14mg/kg）处理后 8 小时经尾静脉注射 RCTR1（5μg/kg），然后通气 1 小时后评估 AFC。将原代 II 型肺泡上皮细胞与 LPS（1μg/ml）孵育，同时加入或不加入 RCTR1（10nM）孵育 8 小时。我们的结果表明，RCTR1 显著提高了 LPS 诱导的 ARDS/ALI 大鼠的生存率，促进了 AFC，并在体内和体外均显著提高了 AFC。此外，RCTR1 还显著提高了体内和体外钠通道和 Na+，K+-ATP 酶的蛋白表达和 Na+，K+-ATP 酶的活性。此外，RCTR1 还通过上调丝氨酸磷酸化 Akt 的表达来降低神经前体细胞表达发育下调 4-2（neural precursor cell expressed developmentally downregulated 4-2，Nedd4-2）水平。除此之外，脂氧素 A4（lipoxin A4，ALX）、环磷酸腺苷（cyclic adenosine monophosphate，cAMP）和磷脂酰肌醇 3-激酶（phosphatidylinositol 3-kinase，PI3K）受体抑制剂（BOC-2、KH-7 和 LY294002）显著抑制了 RCTR1 对 AFC 的作用。总之，RCTR1 通过 ALX/cAMP/PI3K/Nedd4-2 通路增强钠通道和 Na+，K+-ATP 酶的蛋白水平，提高 ALI 中的 Na+，K+-ATP 酶活性，从而改善 AFC，提示 RCTR1 可能成为 ARDS/ALI 的治疗药物。意义：内源性脂质介质 RCTR1 通过上调上皮钠通道（epithelial sodium channels，ENaC）和 Na+，K+-ATP 酶的表达和活性，加速 LPS 诱导的小鼠肺损伤模型中的炎症消退，从而增强 AFC。RCTR1 对 ENaC 和 Na+，K+-ATP 酶水平的作用依赖于 ALX/cAMP/PI3K/Nedd4-2 途径。
