Original Article
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. May 28, 2013; 19(20): 3027-3042
Published online May 28, 2013. doi: 10.3748/wjg.v19.i20.3027
Matrix metalloproteinase-9 in the initial injury after hepatectomy in mice
Norifumi Ohashi, Tomohide Hori, Florence Chen, Sura Jermanus, Akimasa Nakao, Shinji Uemoto, Justin H Nguyen
Norifumi Ohashi, Akimasa Nakao, Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
Tomohide Hori, Shinji Uemoto, Divisions of Hepato-Pancreato-Biliary, Transplant and Pediatric Surgery, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
Florence Chen, Sura Jermanus, Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
Justin H Nguyen, Division of Transplant Surgery, Department of Transplantation, Mayo Clinic in Florida, Jacksonville, FL 32224, United States
Author contributions: Nguyen JH designed this study; Ohashi N performed the surgery and the assays, wrote the initial draft, and performed statistical analysis; Hori T performed the additional surgeries for the second assays to confirm the initial results; Chen F and Jermanus S helped with the assays; Nguyen JH and Hori T contributed to further drafts; Nakao A, and Uemto S provided important advice for the research; Nguyen JH supervised the research.
Supported by Partially by Grants to Nguyen JH from the Deason Foundation (Sandra and Eugene Davenport, Mayo Clinic CD CRT-II), the AHA (0655589B) and NIH (R01NS051646-01A2); and the Grant to Hori T from the Uehara Memorial Foundation (200940051)
Correspondence to: Tomohide Hori, MD, PhD, Divisions of Hepato-Pancreato-Biliary, Transplant and Pediatric Surgery, Department of Surgery, Kyoto University Graduate School of Medicine, 54 Shogoinkawara-cho, Sakyo-ku, Kyoto 606-8507, Japan. horit@kuhp.kyoto-u.ac.jp
Telephone: +81-75-7513651 Fax: +81-75-7513106
Received: December 17, 2012
Revised: January 7, 2013
Accepted: February 5, 2013
Published online: May 28, 2013
Processing time: 161 Days and 19 Hours
Abstract

AIM: To investigate the role of matrix metalloproteinase (MMP)-9 in the pathogenesis of postoperative liver failure (PLF) after extended hepatectomy (EH).

METHODS: An insufficient volume of the remnant liver (RL) results in higher morbidity and mortality, and a murine model with 80%-hepatectomy was used. All investigations were performed 6 h after EH. Mice were first divided into two groups based on the postoperative course (i.e., the PLF caused or did not), and MMP-9 expression was measured by Western blotting. The source of MMP-9 was then determined by immunohistological stainings. Tissue inhibitor of metalloproteinase (TIMP)-1 is the endogenous inhibitor of MMP-9, and MMP-9 behavior was assessed by the experiments in wild-type, MMP-9(-/-) and TIMP-1(-/-) mice by Western blotting and gelatin zymography. The behavior of neutrophils was also assessed by immunohistological stainings. An anti-MMP-9 monoclonal antibody and a broad-spectrum MMP inhibitor were used to examine the role of MMP-9.

RESULTS: Symptomatic mice showed more severe PLF (histopathological assessments: 2.97 ± 0.92 vs 0.11 ± 0.08, P < 0.05) and a higher expression of MMP-9 (71085 ± 18274 vs 192856 ± 22263, P < 0.01). Nonnative leukocytes appeared to be the main source of MMP-9, because MMP-9 expression corresponding with CD11b positive-cell was observed in the findings of immunohistological stainings. In the histopathological findings, the PLF was improved in MMP-9(-/-) mice (1.65% ± 0.23% vs 0.65% ± 0.19%, P < 0.01) and it was worse in TIMP-1(-/-) mice (1.65% ± 0.23% vs 1.78% ± 0.31%, P < 0.01). Moreover, neutrophil migration was disturbed in MMP-9(-/-) mice in the immunohistological stainings. Two methods of MMP-9 inhibition revealed reduced PLF, and neutrophil migration was strongly disturbed in MMP-9-blocked mice in the histopathological assessments (9.6 ± 1.9 vs 4.2 ± 1.2, P < 0.05, and 9.9 ± 1.5 vs 5.7 ± 1.1, P < 0.05).

CONCLUSION: MMP-9 is important for the process of PLF. The initial injury is associated with MMP-9 derived from neutrophils, and MMP-9 blockade reduces PLF. MMP-9 may be a potential target to prevent PLF after EH and to overcome an insufficient RL.

Keywords: Matrix metalloproteinase; Shear stress; Sinusoidal injury; Hepatectomy; Portal hypertension