Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 7, 2022; 28(9): 918-932
Published online Mar 7, 2022. doi: 10.3748/wjg.v28.i9.918
Cystic fibrosis transmembrane conductance regulator prevents ischemia/reperfusion induced intestinal apoptosis via inhibiting PI3K/AKT/NF-κB pathway
Zhi-Wei Dong, Hui Liu, Fei-Fei Su, Xiao-Zhou Fan, Yong Zhang, Peng Liu
Zhi-Wei Dong, Department of General Surgery, Air Force Medical Center, Beijing 100000, China
Hui Liu, Department of Gastroenterology, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
Fei-Fei Su, Department of Cardiology, Air Force Medical Center, Beijing 100000, China
Xiao-Zhou Fan, Department of Ultrasound, Air Force Medical Center, Beijing 100000, China
Yong Zhang, School of Chemistry and Biological Engineering, University of Science and Technology, Beijing 100000, China
Peng Liu, Research Laboratory of Aero-Medical Support, Air Force Medical Center, Beijing 100000, China
Author contributions: Dong ZW and Liu H contributed equally to this study; Dong ZW, Liu H and Liu P designed the research; Su FF, Fan XZ, and Zhang Y conducted experiments and analyzed the data; Dong ZW and Liu H wrote the manuscript; Liu P revised the manuscript; all authors approved the final version of the article.
Supported by National Natural Science Foundation of China, No. 81800473; and "Young Eagle Project "of Air Force Medical University, No. KT2021DX007.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Air Force Medical Center.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals, No. 2020-43-YJ01.
Conflict-of-interest statement: All other authors have nothing to disclose.
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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Peng Liu, PhD, Research Scientist, Research Laboratory of Aero-Medical Support, Air Force Medical Center, No. 30 Fucheng Road, Haidian District, Beijing 100000, China. liupeng-81@foxmail.com
Received: November 10, 2021
Peer-review started: November 10, 2021
First decision: December 3, 2021
Revised: December 14, 2021
Accepted: January 22, 2022
Article in press: January 22, 2022
Published online: March 7, 2022
Abstract
BACKGROUND

Intestinal ischemia/reperfusion (I/R) injury is a fatal syndrome that occurs under many clinical scenarios. The apoptosis of intestinal cells caused by ischemia can cause cell damage and provoke systemic dysfunction during reperfusion. However, the mechanism of I/R-induced apoptosis remains unclear. Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel. Few researchers have paid attention to its role in intestinal I/R injury, or the relationship between CFTR and intestinal apoptosis induced by hypoxia/reoxygenation (H/R).

AIM

To investigate the effects of CFTR on I/R-induced intestinal apoptosis and its underlying molecular mechanisms.

METHODS

An intestinal I/R injury model was established in mice with superior mesenteric artery occlusion, and Caco2 cells were subjected to H/R for the simulation of I/R in vivo.

RESULTS

The results suggested that CFTR overexpression significantly increased the Caco2 cell viability and decreased cell apoptosis induced by the H/R. Interestingly, we found that the translocation of p65, an NF-κB member, from the cytoplasm to the nucleus after H/R treatment can be reversed by the overexpression of CFTR, the NF-κB P65 would return from the nucleus to the cytoplasm as determined by immunostaining. We also discovered that CFTR inhibited cell apoptosis in the H/R-treated cells, and this effect was significantly curbed by the NF-κB activator BA, AKT inhibitor GSK690693 and the PI3K inhibitor LY294002. Moreover, we demonstrated that CFTR overexpression could reverse the decreased PI3K/AKT expression induced by the I/R treatment in vivo or H/R treatment in vitro.

CONCLUSION

The results of the present study indicate that the overexpression of CFTR protects Caco2 cells from H/R-induced apoptosis; furthermore, it also inhibits H/R-induced apoptosis through the PI3K/AKT/NF-κB signaling pathway in H/R-treated Caco2 cells and intestinal tissues.

Keywords: Apoptosis, Cystic fibrosis transmembrane conductance regulator, Intestinal ischemia-reperfusion injury, PI3K/AKT/NF-κB, Hypoxia/reoxygenation, Caco2 cells

Core Tip: Intestinal ischemia/reperfusion (I/R) injury is a fatal syndrome that occurs under many clinical scenarios. The apoptosis of intestinal cells caused by ischemia can cause cell damage and provoke systemic dysfunction during reperfusion. However, the mechanism of I/R-induced apoptosis remains unclear. In our paper, our data demonstrate that cystic fibrosis transmembrane conductance regulator (CFTR) is downregulated in hypoxia/reoxygenation (H/R)-treated Caco2 cells, and overexpression of CFTR protects Caco2 cells from H/R-induced apoptosis. Additionally, CFTR is involved in inhibiting H/R-induced apoptosis, and it inhibits apoptosis through PI3K/AKT/NF-κB signaling pathway. In all, this work suggests that overexpression of CFTR attenuates H/R-induced apoptosis through PI3K/AKT/NF-κB signaling pathway in H/R-treated Caco2 cells.