Original Article
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. May 21, 2012; 18(19): 2320-2333
Published online May 21, 2012. doi: 10.3748/wjg.v18.i19.2320
Matrix metalloproteinase-9 contributes to parenchymal hemorrhage and necrosis in the remnant liver after extended hepatectomy in mice
Norifumi Ohashi, Tomohide Hori, Florence Chen, Sura Jermanus, Christopher B Eckman, 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, Christopher B Eckman, Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
Justin H Nguyen, Division of Transplant Surgery, Department of Transplantation, Mayo Clinic, Jacksonville, FL 32224, United States
Author contributions: Nguyen JH and Eckman CB designed the study; Ohashi N performed the surgery, the assays and the statistical analysis, and wrote the initial draft; Hori T performed the additional surgery 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 Uemoto S provided important advice for the research; Nguyen JH supervised the research.
Supported by Grants to Nguyen JH from the Deason Foundation, Sandra and Eugene Davenport, Mayo Clinic CD CRT-II, and from the National Institutes of Health, No. R01NS051646-01A2; a grant to Hori T from the Uehara Memorial Foundation, No. 200940051, Tokyo 171-0033, Japan
Correspondence to: Tomohide Hori, PhD, MD, 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: August 26, 2011
Revised: October 27, 2011
Accepted: February 27, 2012
Published online: May 21, 2012
Abstract

AIM: To investigate the effect of matrix metalloproteinase-9 (MMP-9) on the remnant liver after massive hepatectomy in the mouse.

METHODS: Age-matched, C57BL/6 wild-type (WT), MMP-9(-/-), and tissue inhibitors of metalloproteinases (TIMP)-1(-/-) mice were used. The mice received 80%-partial hepatectomy (PH). Samples were obtained at 6 h after 80%-PH, and we used histology, immunohistochemical staining, western blotting analysis and zymography to investigate the effect of PH on MMP-9. The role of MMP-9 after PH was investigated using a monoclonal antibody and MMP inhibitor.

RESULTS: We examined the remnant liver 6 h after 80%-PH and found that MMP-9 deficiency attenuated the formation of hemorrhage and necrosis. There were significantly fewer and smaller hemorrhagic and necrotic lesions in MMP-9(-/-) remnant livers compared with WT and TIMP-1(-/-) livers (P < 0.01), with no difference between WT and TIMP-1(-/-) mice. Serum alanine aminotransaminase levels were significantly lower in MMP-9(-/-) mice compared with those in TIMP-1(-/-) mice (WT: 476 ± 83 IU/L, MMP-9(-/-): 392 ± 30 IU/L, TIMP-1(-/-): 673 ± 73 IU/L, P < 0.01). Western blotting and gelatin zymography demonstrated a lack of MMP-9 expression and activity in MMP-9(-/-) mice, which was in contrast to WT and TIMP-1(-/-) mice. No change in MMP-2 expression was observed in any of the study groups. Similar to MMP-9(-/-) mice, when WT mice were treated with MMP-9 monoclonal antibody or the synthetic inhibitor GM6001, hemorrhagic and necrotic lesions were significantly smaller and fewer than in control mice (P < 0.05). These results suggest that MMP-9 plays an important role in the development of parenchymal hemorrhage and necrosis in the small remnant liver.

CONCLUSION: Successful MMP-9 inhibition attenuates the formation of hemorrhage and necrosis and might be a potential therapy to ameliorate liver injury after massive hepatectomy.

Keywords: Matrix metalloproteinase, Liver remnant, Hepatectomy, Liver failure, Necrosis