Abstract
In this study, we demonstrated the involvement of matrix metalloproteinases (MMPs) in hepatic ischemia/reperfusion (I/R) injury. Our aim is to evaluate the impact of reperfusion on I/R-related changes in RECK, an MMP modulator, and mitogen-activated protein kinase (MAPKs) pathways (ERK, p38, and JNK). Male Wistar rats were either subjected to 60 min partial-hepatic ischemia or sham-operated. After a 60 min or 120 min reperfusion, liver samples were collected for analysis of MMP-2 and MMP-9 by zymography and RECK, TIMP-1, and TIMP-2 content, MAPKs activation (ERK1/2, JNK1/2, and p38), as well as iNOS and eNOS by Western blot. Serum enzymes AST, ALT, and alkaline-phosphatase were quantified. A transitory decrease in hepatic RECK and TIMPs was associated with a transitory increase in both MMP-2 and MMP-9 activity and a robust activation of ERK1/2, JNK1/2, and p38 were detected at 60 min reperfusion. Hepatic expression of iNOS was maximally upregulated at 120 min reperfusion. An increase in eNOS was detected at 120 min reperfusion. I/R evoked significant hepatic injury in a time-dependent manner. These findings provide new insights into the underlying molecular mechanisms of reperfusion in inducing hepatic injury: a transitory decrease in RECK and TIMPs and increases in both MAPK and MMP activity suggest their role as triggering factors of the organ dysfunction.
Highlights
Hepatic ischemia/reperfusion (I/R) injury may occur in a variety of clinical situations, including transplantation, liver resection, trauma, and vascular surgery
We demonstrated a time-dependent effect of reperfusion injury on the cross-talk mechanisms linking RECK expression to mitogen-activated protein kinase (MAPKs) activity, we cannot rule out the potential impact of the kinetics of the ischemia injury on the activation/expression of the tested signaling cascades
We showed no significant differences in RECK and MAPK content between ischemic livers without reperfusion and either the sham-operated and 120 min reperfusion groups, confirming that activation of the signaling cascades is mainly related to the reperfusion injury in our experimental conditions
Summary
Hepatic ischemia/reperfusion (I/R) injury may occur in a variety of clinical situations, including transplantation, liver resection, trauma, and vascular surgery. The reperfusion after ischemia may trigger I/R injury exacerbating cellular damage. The effects of reperfusion include excessive production of reactive oxygen species, oxidative stress, mitochondrial dysfunction, and systemic inflammatory response. Neutrophils play a critical role during the initial phase of I/R (0–6 h) triggering activation of pro-inflammatory intracellular cascades. One of the best characterized pathways within the context of organ I/R injury is the mitogen-activated protein kinase (MAPKs) family [1]. Among MAPKs, p38, JNK1/2, and ERK 1/2, activated by a variety of cellular stressors including I/R, could potentially serve as potential targets in hepatic I/R injury [2,3]
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