Zhang XX, Wang HY, Yang XF, Lin ZQ, Shi N, Chen CJ, Yao LB, Yang XM, Guo J, Xia Q, Xue P. Alleviation of acute pancreatitis-associated lung injury by inhibiting the p38 mitogen-activated protein kinase pathway in pulmonary microvascular endothelial cells. World J Gastroenterol 2021; 27(18): 2141-2159 [PMID: 34025070 DOI: 10.3748/wjg.v27.i18.2141]
Corresponding Author of This Article
Ping Xue, MD, PhD, Professor, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu 610041, Sichuan Province, China. xueping@wchscu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. May 14, 2021; 27(18): 2141-2159 Published online May 14, 2021. doi: 10.3748/wjg.v27.i18.2141
Alleviation of acute pancreatitis-associated lung injury by inhibiting the p38 mitogen-activated protein kinase pathway in pulmonary microvascular endothelial cells
Xiao-Xin Zhang, Hao-Yang Wang, Xue-Fei Yang, Zi-Qi Lin, Na Shi, Chan-Juan Chen, Lin-Bo Yao, Xin-Min Yang, Jia Guo, Qing Xia, Ping Xue, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
Author contributions: Zhang XX, Guo J and Xue P obtained funding and designed the experiments; Zhang XX, Wang HY, Yang XF and Lin ZQ performed the experiments and literature search; Shi N, Chen CJ, Yao LB and Yang XM evaluated histological images and carried out a biochemical analysis; Zhang XX, Xia Q and Xue P wrote and revised the manuscript; All authors have read and approved the final manuscript.
Supported byNational Natural Science Foundation of China, No. 81873107, No. 82004154 and No. 81573766; and Science and Technology Planning Program of Sichuan, No. 2019YFS0259.
Institutional animal care and use committee statement: The study was performed according to the Guidelines of Animal Care and Use Committee of West China Hospital of Sichuan University (protocol number, 2017082A).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The manuscript has been prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ping Xue, MD, PhD, Professor, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu 610041, Sichuan Province, China. xueping@wchscu.cn
Received: December 25, 2020 Peer-review started: December 26, 2020 First decision: January 29, 2021 Revised: February 6, 2021 Accepted: March 29, 2021 Article in press: March 29, 2021 Published online: May 14, 2021 Processing time: 136 Days and 2.9 Hours
ARTICLE HIGHLIGHTS
Research background
Acute lung injury (ALI) is the main reason for the high mortality of patients with severe acute pancreatitis (SAP). Injury and dysfunction of pulmonary microvascular endothelial cells (PMVEC) are considered prerequisites for ALI. The p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway is involved in the development of SAP-related ALI. However, the precise mechanism by which p38 MAPK regulates PMVEC injury in SAP-related ALI is unclear.
Research motivation
To date, no specific pharmacological therapies for SAP associated ALI are available. Elucidating the mechanism of PMVEC injury regulated by p38 MAPK is expected to help identify new treatments for SAP-associated ALI.
Research objectives
To determine the role of p38 MAPK in the tumor necrosis factor-alpha-induced injury of PMVECs in vitro and to explore the effect of SB203580-mediated p38 inhibition on SAP-ALI in vivo.
Research methods
In vitro, PMVECs were transfected with MAPK kinase 6 (Glu) and stimulated with tumor necrosis factor-alpha to detect cell apoptosis and inflammatory cytokine levels. In vivo, SAP-ALI rats were treated with three different doses of SB203580 (2.5, 5.0 or 10.0 mg/kg). Blood, bronchoalveolar lavage fluid and tissue samples were harvested to assess cytokine levels, blood gas analyses, histopathological changes, myeloperoxidase activity, bronchoalveolar protein concentration, Evans blue extravasation, apoptosis and ultrastructural changes of PMVECs. Then, the mechanism underlying the effects of SB203580 was also detected in the lungs.
Research results
In vitro, MAPK kinase (Glu) transfection resulted in higher apoptotic rates and cytokine levels in TNF-α-treated PMVECs. In vivo, SB2035080 attenuated lung histopathological injury, decreased inflammatory activity and preserved pulmonary function. Furthermore, SB203580 significantly reversed the microvascular permeability, the increase in the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells, the increased expression of apoptosis-related proteins and the endothelial microstructure changes. Moreover, SB203580 significantly reduced pulmonary P-p38, NFκB, P-SATA3 and Myd88 levels but increased the IκB and HO-1 levels.
Research conclusions
p38 inhibition may protect against SAP-ALI by alleviating inflammation and the apoptotic death of PMVECs.
Research perspectives
In this study, p38 MAPK overactivation promoted PMVEC injury in vitro, while p38 inhibition protected against SAP-ALI in vivo. These results suggest the potential of applying p38 MAPK inhibitors as treatments for SAP-ALI in the clinical setting.
