title: Matrix metalloproteinase-9 in the initial injury after hepatectomy in mice.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Ohashi
authors.forename: Tomohide
authors.initials: T
authors.lastname: Hori
authors.forename: Florence
authors.initials: F
authors.lastname: Chen
authors.forename: Sura
authors.initials: S
authors.lastname: Jermanus
authors.forename: Akimasa
authors.initials: A
authors.lastname: Nakao
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Justin H
authors.initials: JH
authors.lastname: Nguyen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006498:Hepatectomy / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D017093:Liver Failure / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000201:enzymology; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency / Q000235:genetics
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Hepatectomy; Matrix metalloproteinase; Portal hypertension; Shear stress; Sinusoidal injury