Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 28, 2021; 27(24): 3581-3594
Published online Jun 28, 2021. doi: 10.3748/wjg.v27.i24.3581
Fasudil prevents liver fibrosis via activating natural killer cells and suppressing hepatic stellate cells
Qiu-Ju Han, Yong-Liang Mu, Hua-Jun Zhao, Rong-Rong Zhao, Quan-Juan Guo, Yu-Hang Su, Jian Zhang
Qiu-Ju Han, Yong-Liang Mu, Hua-Jun Zhao, Rong-Rong Zhao, Quan-Juan Guo, Jian Zhang, Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
Yu-Hang Su, Department of Emergency Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
Author contributions: Han QJ and Mu YL performed the majority of experiments and wrote the manuscript, and they contributed equally; Su YH and Zhang J designed the study and corrected the manuscript, and they both are corresponding authors; Zhao HJ is involved in analytical tools; Zhao RR and Guo QJ participated to the interpretation of data; All authors read and approved the final version of the manuscript.
Supported by The National Natural Science Foundation of China, No. 81972694 and No. 81972686.
Institutional animal care and use committee statement: The procedures were approved by the Research Ethics Committee of Shandong University (License No. LL-201602065).
Conflict-of-interest statement: None declared.
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: Jian Zhang, PhD, Dean, Professor, Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhua West Road, Jinan 250012, Shandong Province, China. zhangj65@sdu.edu.cn
Received: January 15, 2021
Peer-review started: January 15, 2021
First decision: March 29, 2021
Revised: April 9, 2021
Accepted: May 27, 2021
Article in press: May 27, 2021
Published online: June 28, 2021
Processing time: 161 Days and 1.2 Hours
Abstract
BACKGROUND

Fasudil, as a Ras homology family member A (RhoA) kinase inhibitor, is used to improve brain microcirculation and promote nerve regeneration clinically. Increasing evidence shows that Rho-kinase inhibition could improve liver fibrosis.

AIM

To evaluate the anti-fibrotic effects of Fasudil in a mouse model of liver fibrosis induced by thioacetamide (TAA).

METHODS

C57BL/6 mice were administered TAA once every 3 d for 12 times. At 1 wk after induction with TAA, Fasudil was intraperitoneally injected once a day for 3 wk, followed by hematoxylin and eosin staining, sirius red staining, western blotting, and quantitative polymerase chain reaction (qPCR), and immune cell activation was assayed by fluorescence-activated cell sorting. Furthermore, the effects of Fasudil on hepatic stellate cells and natural killer (NK) cells were assayed in vitro.

RESULTS

First, we found that TAA-induced liver injury was protected, and the positive area of sirius red staining and type I collagen deposition were significantly decreased by Fasudil treatment. Furthermore, western blot and qPCR assays showed that the levels of alpha smooth muscle actin (α-SMA), matrix metalloproteinase 2 (MMP-2), MMP-9, and transforming growth factor beta 1 (TGF-β1) were inhibited by Fasudil. Moreover, flow cytometry analysis revealed that NK cells were activated by Fasudil treatment in vivo and in vitro. Furthermore, Fasudil directly promoted the apoptosis and inhibited the proliferation of hepatic stellate cells by decreasing α-SMA and TGF-β1.

CONCLUSION

Fasudil inhibits liver fibrosis by activating NK cells and blocking hepatic stellate cell activation, thereby providing a feasible solution for the clinical treatment of liver fibrosis.

Keywords: Liver fibrosis; Natural killer cells; Fasudil; Hepatic stellate cells

Core Tip: Liver fibrosis is caused by inflammation and characterized by accumulation of the extracellular matrix; there is no clinically safe and efficient drug to treat this condition. Fasudil treatment inhibited liver injury and liver fibrosis in vivo, and prevented liver fibrosis via activating natural killer cells but suppressing hepatic stellate cells in a thioacetamide-induced model. As a drug used clinically, these results provide a feasible solution for the clinical treatment of liver fibrosis.