Matrix metalloproteinase-9 in the initial injury after hepatectomy in mice

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 broadspectrum 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 block