Masuo H, Shimizu A, Motoyama H, Kubota K, Notake T, Yoshizawa T, Hosoda K, Yasukawa K, Kobayashi A, Soejima Y. Impact of endothelial nitric oxide synthase activation on accelerated liver regeneration in a rat ALPPS model. World J Gastroenterol 2023; 29(5): 867-878 [PMID: 36816620 DOI: 10.3748/wjg.v29.i5.867]
Corresponding Author of This Article
Akira Shimizu, MD, PhD, Associate Professor, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto 390-8621, Japan. ashimizu@shinshu-u.ac.jp
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/
Hitoshi Masuo, Akira Shimizu, Hiroaki Motoyama, Koji Kubota, Tsuyoshi Notake, Takahiro Yoshizawa, Kiyotaka Hosoda, Koya Yasukawa, Akira Kobayashi, Yuji Soejima, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
Author contributions: Masuo H, Motoyama H, Yoshizawa T, Hosoda K, and Yasukawa K contributed to the acquisition and analysis of experimental data and drafting of the manuscript; Shimizu A, Kubota K, Notake T, Kobayashi A, and Soejima Y contributed to the conception and design of the study and made critical revisions related to the important intellectual content of the manuscript; and all authors have provided final approval for the version of the manuscript for submission.
Supported bythe JSPS KAKENHI, JP17K10664.
Institutional animal care and use committee statement: Based on national and institutional regulations and guidelines, all procedures for animal experiments were reviewed by the Committee for Animal Experiments and approved by the President of Shinshu University (Approval numbers 270018 and 019067).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Corresponding author: Akira Shimizu, MD, PhD, Associate Professor, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto 390-8621, Japan. ashimizu@shinshu-u.ac.jp
Received: October 29, 2022 Peer-review started: October 29, 2022 First decision: November 30, 2022 Revised: December 7, 2022 Accepted: January 11, 2023 Article in press: January 11, 2023 Published online: February 7, 2023 Processing time: 94 Days and 5.4 Hours
Abstract
BACKGROUND
Although the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces more rapid liver regeneration than portal vein embolization, the mechanism remains unclear.
AIM
To assess the influence of inflammatory cytokines and endothelial nitric oxide synthase (eNOS) activation on liver regeneration in ALPPS.
METHODS
The future liver remnant/body weight (FLR/BW) ratio, hepatocyte proliferation, inflammatory cytokine expression, and activation of the Akt-eNOS pathway were evaluated in rat ALPPS and portal vein ligation (PVL) models. Hepatocyte proliferation was assessed based on Ki-67 expression, which was confirmed using immunohistochemistry. The serum concentrations of inflammatory cytokines were measured using enzyme linked immune-solvent assays. The Akt-eNOS pathway was assessed using western blotting. To explore the role of inflammatory cytokines and NO, Kupffer cell inhibitor gadolinium chloride (GdCl3), NOS inhibitor N-nitro-arginine methyl ester (L-NAME), and NO enhancer molsidomine were administered intraperitoneally.
RESULTS
The ALPPS group showed significant FLR regeneration (FLR/BW: 1.60% ± 0.08%, P < 0.05) compared with that observed in the PVL group (1.33% ± 0.11%) 48 h after surgery. In the ALPPS group, serum interleukin-6 expression was suppressed using GdCl3 to the same extent as that in the PVL group. However, the FLR/BW ratio and Ki-67 labeling index were significantly higher in the ALPPS group administered GdCl3 (1.72% ± 0.19%, P < 0.05; 22.25% ± 1.30%, P < 0.05) than in the PVL group (1.33% ± 0.11% and 12.78% ± 1.55%, respectively). Phospho-Akt Ser473 and phospho-eNOS Ser1177 levels were enhanced in the ALPPS group compared with those in the PVL group. There was no difference between the ALPPS group treated with L-NAME and the PVL group in the FLR/BW ratio and Ki-67 labeling index. In the PVL group treated with molsidomine, the FLR/BW ratio and Ki-67 labeling index increased to the same level as in the ALPPS group.
CONCLUSION
Early induction of inflammatory cytokines may not be pivotal for accelerated FLR regeneration after ALPPS, whereas Akt-eNOS pathway activation may contribute to accelerated regeneration of the FLR.
Core Tip: In extended hepatectomy for hepatobiliary tumors, adequate future liver remnant (FLR) is essential to prevent postoperative liver failure. Portal vein embolization (PVE) and associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) are performed to increase the FLR. Although ALPPS induces more rapid liver regeneration than PVE, the mechanism remains unclear. In this study, we compared ALPPS with portal vein ligation (PVL) in a rat model and found that activation of the Akt-endothelial nitric oxide synthase pathway promotes liver regeneration. The combination of PVL and nitric oxide-producing agents may induce liver regeneration comparable to ALPPS in a non-invasive manner.
