Matrix Metalloproteinases (MMPs) are a family of proteinases with key roles in tissue homeostasis, inflammation and repair. We have recently shown that MMP-9 and MMP-2, the two members of the gelatinase subgroup of MMPs, are pivotal in liver ischemia reperfusion injury (IRI). While MMP-9 inhibition has a protective role, loss of MMP-2 leads to increased MMP-9 activity and exacerbated liver injury. This study was designed to assess the extent to which MMP-9 inhibition confers protection against MMP-2 mAb-induced liver damage during liver IRI. Methods and Results: MMP-9KO, MMP-2KO, and wild-type (WT) C57Bl6 mice were either treated with anti-MMP-2 neutralizing monoclonal antibodies (MMP-2 mAb; 3mg/Kg, i.v.) or isotype-matched IgG and subject to 90 min partial liver ischemia followed by 6h reperfusion. MMP-9-/- mice treated with MMP-2 mAb were characterized by lower AST levels (~2-fold decrease; p<0.05) and improved liver histological preservation post-IRI when compared to WT mice treated with MMP-2 mAb. However, MMP-9 null mice treated with MMP-2 mAb showed higher AST levels (~1.5-fold increase p<0.05) and more liver histological damage after IRI than MMP-9 null mice treated with IgG. Administration of MMP-2 mAb to MMP-2KO mice had no effect in these mice, as their high AST levels and extensive hepatocellular necrosis were comparable to MMP-2KO mice treated with IgG. Compared to WT mice depleted of MMP-2, in which MMP-9 activity was exacerbated post-reperfusion, MMP-9KO mice depleted of MMP-2 had reduced inflammatory leukocyte infiltration (CD11b⁺:39±9 vs. 55±6, p<0.05; Ly-6G⁺:41±10 vs. 59±9, p<0.05) and proinflammatory cytokine expression (p<0.05), supporting that loss of MMP-2 activity in hepatic IRI exacerbates disease, in part, through a MMP-9-dependent mechanism. On the other hand, anti-MMP-2 mAb administration to MMP-9KO mice markedly reduced the strong sinusoidal PECAM-1 expression and tomato lectin staining in IgG treated MMP-9KO livers post-IRI, suggesting a protective role for MMP-2 in the sinusoidal endothelium, which is independent of MMP-9. In conclusion: Our novel findings support a dual protective role for MMP-2 expression in hepatic IRI. We show that while MMP-2 specific inhibition worsens hepatic IRI by enhancing MMP-9 mediated leukocyte infiltration, it has also a significant MMP-9-independent role in the development of sinusoidal endothelial cell damage during hepatic IRI.

CITATION INFORMATION: Duarte S, Matian P, Kato H, Busuttil R, Coito A. Matrix Metalloproteinase-2 (MMP-2) Activity Protects Against Hepatic Ischemia Reperfusion Injury Through MMP-9-Dependent and MMP-9-Independent Mechanisms. Am J Transplant. 2016;16 (suppl 3).

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