Abstract
Hepatic ischemia and reperfusion injury (IRI) is an inflammatory condition and a significant cause of morbidity and mortality after surgery. Matrix metalloproteinases (MMPs) have been widely implicated in the pathogenesis of inflammatory diseases. Among the different MMPs, gelatinases (MMP-2 and MMP-9) are within the most prominent MMPs detected during liver IRI. While the role of MMP-9 in liver damage has been fairly documented, direct evidence of the role for MMP-2 activity in hepatic IRI remains to be established. Due to the lack of suitable inhibitors to target individual MMPs in vivo, gene manipulation is as an essential tool to assess MMP direct contribution to liver injury. Hence, we used MMP-2-/- deficient mice and MMP-2+/+ wild-type littermates to examine the function of MMP-2 activity in hepatic IRI. MMP-2 expression was detected along the sinusoids of wild-type livers before and after surgery and in a small population of leukocytes post-IRI. Compared to MMP-2+/+ mice, MMP-2 null (MMP-2-/-) mice showed exacerbated liver damage at 6, 24, and 48 hours post-reperfusion, which was fatal in some cases. MMP-2 deficiency resulted in upregulation of MMP-9 activity, spontaneous leukocyte infiltration in naïve livers, and amplified MMP-9-dependent transmigration of leukocytes in vitro and after hepatic IRI. Moreover, complete loss of MMP-2 activity impaired the degradation of poly (ADP-ribose) polymerase (PARP-1) in extensively damaged livers post-reperfusion. However, the administration of a PARP-1 inhibitor to MMP-2 null mice restored liver preservation to almost comparable levels of MMP-2+/+ mice post-IRI. Deficient PARP-1 degradation in MMP-2-null sinusoidal endothelial cells correlated with their increased cytotoxicity, evaluated by the measurement of LDH efflux in the medium. In conclusion, our results show for the first time that MMP-2 gene deletion exacerbates liver IRI. Moreover, they offer new insights into the MMP-2 modulation of inflammatory responses, which could be relevant for the design of new pharmacological MMP-targeted agents to treat hepatic IRI.
Highlights
Hepatic ischemia and reperfusion injury (IRI) is a pathological condition characterized by an initial hypoxic insult, which is further accentuated by the restoration of blood flow to the compromised organ [1]
In damaged wild-type livers after IRI, while Matrix metalloproteinases (MMPs)-2 expression was scarcely noticed in parts of the vascular bed, it was detected in a small population of infiltrating leukocytes; double staining showed colocalization of MMP-2 and the neutrophil marker Ly6G in the damaged liver tissue (Fig 1D)
The serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (U/L) were significantly increased in MMP-2-/- mice at 6h, 24h and 48h post-IRI (Fig 2D and 2E). These results show that loss of MMP-2 activity exacerbated hepatic IRI
Summary
Hepatic ischemia and reperfusion injury (IRI) is a pathological condition characterized by an initial hypoxic insult, which is further accentuated by the restoration of blood flow to the compromised organ [1]. Hepatic IRI remains a significant challenge in surgical procedures where the blood supply to liver is temporarily interrupted, including in clinical orthotopic liver transplantation (OLT) [2]. IR-induced damage is the result of complex interactions between circulating leukocytes, vascular endothelium, extracellular matrix (ECM), and a wide range of other inflammatory mediators [3,4]. In addition to extracellular matrix (ECM) turnover, MMPs proteolytically activate or degrade a variety of non-matrix subtracts, including cytokines and chemokines, and have regulatory functions in inflammation and immunity [6]. Among the different MMPs, gelatinases (gelatinase A, MMP-2 and gelatinase B, MMP-9) are notably detected in damaged livers postsurgery, including after human liver transplantation [7,8]. MMP-2 is constitutively expressed in naive livers [9,10], whereas MMP-9 is an inducible enzyme produced by infiltrating leukocytes after hepatic IRI [9,11]
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