Sivelestat sodium attenuates acute lung injury by inhibiting JNK/NF-κB and activating Nrf2/HO-1 signaling pathways

Hong Zhang; Jun  Zeng; Jiankang  Li; Huankai Gong; Meiling Chen; Quan Li; Shengxing  Liu; Shanjun  Luo; Huanxiang Dong; Yingke Xu; Huanling Duan; Ling Haung; Chuanzhu Lv

doi:10.17305/bb.2022.8549

Authors

Hong Zhang Emergency and Trauma College, Hainan Medical University, Haikou, Hainan, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan, China https://orcid.org/0000-0001-7235-9758
Jun Zeng Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
Jiankang Li Emergency and Trauma College, Hainan Medical University, Haikou, Hainan, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan, China
Huankai Gong Emergency and Trauma College, Hainan Medical University, Haikou, Hainan, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan, China
Meiling Chen Emergency and Trauma College, Hainan Medical University, Haikou, Hainan, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan, China
Quan Li Department of Emergency, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Shengxing Liu Department of Orthopedics, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
Shanjun Luo Intensive Care Unit, Chenzhou Third People's Hospital, Chenzhou, Hunan, China
Huanxiang Dong Emergency and Trauma College, Hainan Medical University, Haikou, Hainan, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan, China
Yingke Xu Emergency and Trauma College, Hainan Medical University, Haikou, Hainan, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan, China
Huanling Duan Emergency and Trauma College, Hainan Medical University, Haikou, Hainan, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan, China
Ling Haung Hainan Pharmacopoeia Review Center of Hainan Provincial Drug Administration, Haikou, Hainan, China; State Key Laboratory of Trauma, Burns and Combined Injury, Department of Wound Infection and Drug, Daping Hospital, Army Medical University, Chongqing, China; Research Center for Drug Safety Evaluation of Hainan Province, Hainan Medical University, Haikou, Hainan, China
Chuanzhu Lv Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan, China; Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Research Unit of Island Emergency Medicine, Chinese Academy of Medical Sciences (No. 2019RU013), Hainan Medical University, Haikou, Hainan, China

DOI:

https://doi.org/10.17305/bb.2022.8549

Keywords:

Sivelestat sodium, acute lung injury, inflammation, oxidative stress, JNK/NF-κB, Nrf2/HO-1

Abstract

Sivelestat sodium (SIV), a neutrophil elastase inhibitor, is mainly used for the clinical treatment of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI). However, studies investigating the effects of SIV treatment of ALI are limited. Therefore, this study investigated the potential molecular mechanism of the protective effects of SIV against ALI. Human pulmonary microvascular endothelial cells (HPMECs) were stimulated with tumor necrosis factor α (TNF-α), and male Sprague-Dawley rats were intratracheally injected with Klebsiella pneumoniae (KP) and treated with SIV, ML385, and anisomycin (ANI) to mimic the pathogenetic process of ALI in vitro and in vivo, respectively. The levels of inflammatory cytokines and indicators of oxidative stress were assessed in vitro and in vivo. The wet/dry (W/D) ratio of lung tissues, histopathological changes, inflammatory cells levels in bronchoalveolar lavage fluid (BALF), and survival rates of rats were analyzed. The JNK/NF-κB (p65) and Nrf2/HO-1 levels in the HPMECs and lung tissues were analyzed by western blot and immunofluorescence analyses. Administration of SIV reduced the inflammatory factors levels, intracellular reactive oxygen species (ROS) production, and malondialdehyde (MDA) levels and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissues. Meanwhile, SIV alleviated pathological injuries, decreased the W/D ratio, and inflammatory cell infiltration in lung tissue. In addition, SIV also inhibited the activation of JNK/NF-κB signaling pathway, promoted nuclear translocation of Nrf2, and upregulated the expression of heme oxygenase 1 (HO-1). However, ANI or ML385 significantly reversed these changes. SIV effectively attenuated the inflammatory response and oxidative stress. Its potential molecular mechanism was related to the JNK/NF-κB activation and Nrf2/HO-1 signaling pathway inhibition. This further deepened the understanding of the protective effects of SIV against ALI.