Li Congcong, Bo Liyan, Li Pengcheng, Lu Xi, Li Wangping, Pan Lei, Sun Yani, Mu Deguang, Liu Wei, Jin Faguang
Department of Respiration, Tangdu Hospital, Fourth Military Medical University, 710038, PR China.
Department of Respiration, Tangdu Hospital, Fourth Military Medical University, 710038, PR China.
Pulm Pharmacol Ther. 2017 Aug;45:69-79. doi: 10.1016/j.pupt.2017.05.002. Epub 2017 May 5.
Losartan is a selective antagonist of AngⅠ type (AT1) receptor of Angiotensin Ⅱ (Ang Ⅱ), which is widely used as a clinical medicine for the hypertension. Recent studies have shown that losartan was shown to protect from acute lung injury (ALI). However, the underlying mechanism remains unclear. The aim of this research was to clarify whether Ang Ⅱ participated in the inflammatory response of ALI induced by seawater inhalation, and whether losartan had the protective effects on ALI by blocking the combination of Ang Ⅱ and AT1 receptor. In the current study, the severity of lung injury and the inflammatory reactions during seawater drowning induced ALI were assessed. Besides, we also detected the activation of relative pathways such as NF-κB, JAK2/STATs and apoptosis. The results showed that seawater inhalation could up-regulate the expression of Ang Ⅱ and AT1. While pretreatment of losartan (especially 15 mg/kg and 30 mg/kg) alleviated lung injury by inhibiting Ang-Ⅱ and AT1 receptor combination and in turn decreased the expression of p-NF-κB and activation of JAK2/STATs pathway. We also confirmed that losartan could reduce the apoptotic ratio of cells in the lung by modulating the phosphorylation of JNK and leak of cytochrome C to cytosol. Taken together, these findings demonstrate that losartan might have a therapeutic potential as an anti-inflammatory agent for treating SWI-ALI.
氯沙坦是血管紧张素Ⅱ（AngⅡ）的AngⅠ型（AT1）受体的选择性拮抗剂，被广泛用作治疗高血压的临床药物。最近的研究表明，氯沙坦可预防急性肺损伤（ALI）。然而，其潜在机制仍不清楚。本研究的目的是阐明AngⅡ是否参与海水吸入诱导的ALI的炎症反应，以及氯沙坦是否通过阻断AngⅡ与AT1受体的结合而对ALI具有保护作用。在本研究中，评估了海水溺水诱导的ALI期间的肺损伤严重程度和炎症反应。此外，我们还检测了相关通路如NF-κB、JAK2/STATs的激活情况以及细胞凋亡。结果表明，海水吸入可上调AngⅡ和AT1的表达。而氯沙坦预处理（尤其是15mg/kg和30mg/kg）通过抑制AngⅡ与AT1受体结合减轻肺损伤，进而降低p-NF-κB的表达和JAK2/STATs通路的激活。我们还证实，氯沙坦可通过调节JNK的磷酸化和细胞色素C向胞质溶胶的泄漏来降低肺细胞的凋亡率。综上所述，这些发现表明氯沙坦作为一种抗炎药物可能具有治疗海水吸入性急性肺损伤（SWI-ALI）的潜力。
