Copyright
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Recombinant angiopoietin-like protein 4 attenuates intestinal barrier structure and function injury after ischemia/reperfusion
Zi-Yi Wang, Jian-Yu Lin, Yang-Rong Feng, De-Shun Liu, Xu-Zi Zhao, Tong Li, Si-Yuan Li, Jing-Chao Sun, Shu-Feng Li, Wen-Yan Jia, Hui-Rong Jing
Zi-Yi Wang, Emergent Intensive Care Unit, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
Jian-Yu Lin, Department of Gastrointestinal Surgery, Weihai Central Hospital, Weihai 264200, Shandong Province, China
Yang-Rong Feng, Graduate College, Shandong First Medical University, Jinan 271000, Shandong Province, China
De-Shun Liu, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, Liaoning Province, China
Xu-Zi Zhao, Department of Pharmacology, Dalian Medical University, Dalian 116044, Liaoning Province, China
Tong Li, Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100000, China
Si-Yuan Li, Jing-Chao Sun, Shu-Feng Li, Hui-Rong Jing, Department of General Surgery, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, Shandong Province, China
Wen-Yan Jia, Physiological Examination Center, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
Author contributions: Wang ZY, Jing HR and Lin JY designed the study; Jing HR and Wang ZY supervised the study; Liu DS, Zhao XZ and Sun JC collected and analyzed the data; Li SY and Feng YR performed the R Script; Lin JY and Li SF and Jia WY prepared the figures and drafted the manuscript; Jing HR and Li Tong revised the manuscript for important intellectual content; Jing HR and Jia WY contributed equally as co-corresponding authors; all authors read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81600446; the Science and Technology of Traditional Chinese Medicine Foundation in Qingdao, No. 2021-zyyz03; and the Science and technology development of Medicine and health Foundation in Shandong Province, China, No. 202004010508.
Institutional animal care and use committee statement: The study was reviewed and approved by the Dalian Medical University Institutional Review Board (Approval No. L20190232).
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was 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: Hui-Rong Jing, MD, PhD, Associate Professor, Surgeon, Department of General Surgery, Qingdao Municipal Hospital, Qingdao University, No. 5 Donghai Middle Road, Southern District, Qingdao 266071, Shandong Province, China. jhrdlmu_edu@126.com
Received: April 24, 2021
Peer-review started: April 24, 2021
First decision: June 3, 2021
Revised: June 17, 2021
Accepted: July 30, 2021
Article in press: July 30, 2021
Published online: August 28, 2021
BACKGROUND
Intestinal barrier breakdown, a frequent complication of intestinal ischemia-reperfusion (I/R) including dysfunction and the structure changes of the intestine, is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality. To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration. Recombinant human angiopoietin-like protein 4 (rhANGPTL4) is reported to protect the blood-brain barrier when administered exogenously, and endogenous ANGPTL4 deficiency deteriorates radiation-induced intestinal injury.
AIM
To identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R.
METHODS
Intestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion. Intestinal epithelial (Caco-2) cells and human umbilical vein endothelial cells were challenged by hypoxia/ reoxygenation to mimic I/R in vitro.
RESULTS
Indicators including fluorescein isothiocyanate-conjugated dextran (4 kilodaltons; FD-4) clearance, ratio of phosphorylated myosin light chain/total myosin light chain, myosin light chain kinase and loss of zonula occludens-1, claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation. rhANGPTL4 treatment significantly reversed these indicators, which were associated with inhibiting the inflammatory and oxidative cascade, excessive activation of cellular autophagy and apoptosis and improvement of survival rate. Similar results were observed in vitro when cells were challenged by hypoxia/reoxygenation, whereas rhANGPTL4 reversed the indicators close to normal level in Caco-2 cells and human umbilical vein endothelial cells significantly.
CONCLUSION
rhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival via maintenance of intestinal barrier structure and functions.
Core Tip: Improving therapy on intestinal barrier dysfunction induced by ischemia/ reperfusion is still challenging. Most recently, studies indicated that patients who suffered from coronavirus disease 2019 are associated with intestinal hypoperfusion. We investigated the effect of recombinant human angiopoietin-like protein 4 on intestinal barrier structure and function deterioration using intestinal ischemia/ reperfusion models in rats as well as hypoxia/reoxygenation models in cells. Intestinal barrier indicators associated with the inflammatory and oxidative cascade, excessive activation of cellular autophagy and apoptosis were compared. Our results indicated that recombinant human angiopoietin-like protein 4 behaved as a promising therapeutic agent for intestinal ischemia/reperfusion-induced intestine injury.
