Capsaicin Attenuates LPS-Induced Acute Lung Injury by Inhibiting Inflammation and Autophagy Through Regulation of the TRPV1/AKT Pathway

Qin Hu,1,2 Haoran Liu,1,2 Ruiyu Wang,3 Li Yao,3 Shikun Chen,4 Yang Wang,3 Chuanzhu Lv2,3,5 1Emergency and Trauma College, Hainan Medical University, Haikou, People’s Republic of China; 2Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, People’s Republic of China; 3Emergency Medicine Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 4Department of Anesthesiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 5Research Unit of Island Emergency Medicine, Chinese Academy of Medical Sciences (No. 2019RU013), Hainan Medical University, Haikou, People’s Republic of ChinaCorrespondence: Yang Wang, Emergency Medicine Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China, Tel +86-15086867864, Email young0416@163.com Chuanzhu Lv, Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Research Unit of Island Emergency Medicine, Chinese Academy of Medical Sciences (No. 2019RU013), Hainan Medical University, Haikou, People’s Republic of China, Tel +86- 19113953671, Email lvchuanzhu677@126.comPurpose: Acute lung injury (ALI) is a severe pulmonary disease characterized by damage to the alveoli and pulmonary blood vessels, leading to severe impairment of lung function. Studies on the effect of capsaicin (8-methyl-N-geranyl-6-nonamide, CAP) on lipopolysaccharide (LPS)-induced ALI in bronchial epithelial cells transformed with Ad12-SV40 2B (BEAS-2B) are still limited. This study aimed to investigate the effect and specific mechanism by which CAP improves LPS-induced ALI.Methods: The present study investigated the effect of CAP and the potential underlying mechanisms in LPS-induced ALI in vitro and vivo via RNA sequencing, Western blotting (WB), quantitative real-time reverse transcription PCR (qRT‒PCR), enzyme-linked immunosorbent assay (ELISA), and transmission electron microscopy (TEM). The TRPV1 inhibitor AMG9810 and the AKT agonist SC79 were used to confirm the protective effect of the TRPV1/AKT axis against ALI. The autophagy agonist rapamycin (Rapa) and the autophagy inhibitors 3-methyladenine (3-MA) and bafilomycin A1 (Baf-A1) were used to clarify the characteristics of LPS-induced autophagy.Results: Our findings demonstrated that CAP effectively suppressed inflammation and autophagy in LPS-induced ALI, both in vivo and in vitro. This mechanism involves regulation by the TRPV1/AKT signaling pathway. By activating TRPV1, CAP reduces the expression of P-AKT, thereby exerting its anti-inflammatory and inhibitory effects on pro-death autophagy. Furthermore, prior administration of CAP provided substantial protection to mice against ALI induced by LPS, reduced the lung wet/dry ratio, decreased proinflammatory cytokine expression, and downregulated LC3 expression.Conclusion: Taken together, our results indicate that CAP protects against LPS-induced ALI by inhibiting inflammatory responses and autophagic death through the TRPV1/AKT signaling pathway, presenting a novel strategy for ALI therapy.Keywords: capsaicin, acute lung injury, Inflammation, autophagy, TRPV1, AKT