Role of matrix metalloproteinase-8 as a mediator of injury in intestinal ischemia and reperfusion

Abstract

Acute mesenteric ischemia is associated with highmorbidity and mortality. In recent studies, we found that the intestine is an important source of matrix metalloproteinase (MMP)8 during intestinal injury. We hypothesized that genetic ablation or pharmacological inhibition of MMP8 would reduce intestinal injury in mice subjected to intestinal ischemia'reperfusion (I/R) injury.Male mice aged 8'12 wk were subjected to intestinal I/R injury by transient occlusion of the superior mesenteric artery for 30 min. MMP8 was inhibited by genetic and pharmacological approaches. In vivo study endpoints included several functional, histological, and biochemical assays. Intestinal sectionswere assessed for barrier function and expression of tight junction proteins. I/Rinjury led to increased intestinal and systemic expression of MMP8. This increase was associated with increased intestinal neutrophil infiltration, epithelial injury, and permeability. I/R injury was associated with increased systemic inflammationandweight loss.Theseparameterswereamelioratedby inhibitingMMP8. I/Rinjury causeda lossof the tight junction protein claudin-3, which was ameliorated by genetic ablation of MMP8.MMP8 plays an important role in intestinal I/Rinjury throughmechanisms involving increased inflammation and loss of claudin-3. Inhibition ofMMP8is a potential therapeutic strategy in this setting.-Daly,M. C.,Atkinson, S. J.,Varisco,B.M., Klingbeil L., Hake, P., Lahni,P.,Piraino, G.,Wu,D.,Hogan, S. P.,Zingarelli,B.,Wong,H.R.Role ofmatrixmetalloproteinase-8 as a mediator of injury in intestinal ischemia and reperfusion.