Han QJ, Mu YL, Zhao HJ, Zhao RR, Guo QJ, Su YH, Zhang J. Fasudil prevents liver fibrosis via activating natural killer cells and suppressing hepatic stellate cells. World J Gastroenterol 2021; 27(24): 3581-3594 [PMID: 34239271 DOI: 10.3748/wjg.v27.i24.3581]
Corresponding Author of This Article
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
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/
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 byThe 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
ARTICLE HIGHLIGHTS
Research background
Rho kinase inhibition reportedly improves liver fibrosis. Fasudil, as a RhoA kinase inhibitor, is used to improve brain microcirculation and promote nerve regeneration clinically. The viability of Fasudil in liver fibrosis is still unknown.
Research motivation
Repositioning existing drugs e.g., Fasudil might be an effective strategy for obtaining therapeutics against liver fibrosis.
Research objectives
To evaluate the anti-fibrotic effects of Fasudil in vitro and in a mouse model of thioacetamide (TAA)-induced liver fibrosis.
Research methods
The anti-fibrotic effect of Fasudil was investigated in a TAA-induced mouse model. At 1 wk after induction with TAA, Fasudil was intraperitoneally injected once a day for 3 wk, hepatic pathological changes, liver fibrosis and immune cell activation were determined using hematoxylin and eosin staining, sirius red staining, western blotting and quantitative polymerase chain reaction and fluorescence-activated cell sorting. Furthermore, the effect of Fasudil on hepatic stellate cell (HSC) and natural killer (NK) cells was assayed in vitro.
Research results
Treatment with Fasudil alleviated hepatic pathological changes and reversed hepatic fibrosis in the TAA-chronic models with decreased deposition of collagen fibers, reduced expression of HSC activation marker (alpha smooth muscle actin), and reduced secretion of transforming growth factor beta 1 (TGF-β1), matrix metalloproteinase 2 (MMP-2), and MMP-9. Fasudil treatment increased NK cell activation and cytotoxicity by activating the extracellular signal-related kinase and nuclear factor kappa B signaling pathways. Fasudil directly promoted the apoptosis and inhibited the proliferation of HSC by decreasing α-SMA and TGF-β1.
Research conclusions
Fasudil inhibited liver fibrosis by activating NK cells and blocking HSC activation.
Research perspectives
Fasudil treatment prevents liver fibrosis via activating NK cells but suppressing HSCs. As a drug used clinically, these results provide a feasible solution for the clinical treatment of liver fibrosis.
