The shortage of donor organs has led to an increased use of suboptimal steatotic livers in transplantation; however, fatty livers present high risks of dysfunction based on their elevated susceptibility to ischemia/reperfusion injury (IRI). Leukocytes are critical mediators of liver IRI and matrix metalloproteinase-9 (MMP-9) has a key role in facilitating their transmigration across vascular barriers. Here, we test the significance of MMP-9 selective inhibition in marginal steatotic liver IRI. Methods: MMP-9KO mice and matched wild-type (WT) littermates were fed with a 60% high-fat diet. Mice with about 50% macrovascular steatosis (MaS) were submitted to partial warm ischemia for 60 min, followed by reperfusion. Results: MMP-9 expression/activation was negative in MaS-MMP-9KO livers and readily detected in MaS-WT livers post-IRI. Histological damage was selectively sheltered in MaS-MMP-9KO livers, which showed decreased periportal congestion and necrosis compared to respective MaS-WT controls post-IRI (n=6/group). Hepatic function was significantly improved in MaS-MMP-9KO mice, as evidenced by decreased AST levels (IU/L) at 6h (2,638±1,115 vs. 8,750±2,528, p<0.05) and 24h (2,825±2,125 vs. 11,461±4,293, p<0.05) post-IRI. Additionally, MPO activity (U/g) (3.03±1.2 vs. 8.12±1.38, p<0.002) and infiltration of Ly6G (6h:29.3±11.1 vs.65.7±18.3;24h: 94.2±67.0 vs.247.5±34.6; p<0.02;) and Mac-1 (6h:32.4±14.6 vs. 60.9±11.0; 24h:78.7±51.6 vs. 234.9±22.7;p<0.002) leukocytes were diminished in MaS-MMP-9KO livers post-IRI. MaS-MMP-9KO livers were characterized by decreased pro-inflammatory TNF-Α (p<0.05) and IL-6 (p<0.05) expression, compared to MaS-WT controls. Impaired regeneration is another important aspect attributed to steatotic livers. Indeed, PCNA (49.7±19.5 vs. 15.2±8.6;p<0.01) and Mitotic (67.9±9.1 vs.16.8±5.9;p<0.01) indexes (%) were significantly increased in MaS-MMP-9KO livers at 24h post-IRI, providing evidence that hepatocyte progression into S phase and mitosis was enhanced in the absence of MMP-9. Conclusion: Our data evidence a critical function for MMP-9 in the pathogenesis of steatotic hepatic IRI. MMP-9 deficiency profoundly attenuated steatotic liver damage and enhanced steatotic hepatic regeneration post-IRI. Overall, these novel results offer a rationale for identification of improved therapeutic approaches against steatotic liver IRI that allow the successful utilization of marginal grafts in transplantation.

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