Efeito da inibição da clivagem do fator de necrose tumoral (TNF) em modelo de isquemia e reperfusão intestinal

Abstract

TNF-á plays an important role in reperfusion-induced tissue injury andlethality. Here, we assessed the effect of PKF242-484 and PKF241-466, two dual inhibitors of TNF-á converting enzyme (TACE) and matrixmetalloproteinases (MMPs). We examine the role of these enzymesmodulating TNF-á levels in tissue and serum after ischemia and reperfusion of the superior mesenteric artery in mice using lethality and the extent of tissue injury. Reperfused animals that received PKF242-484 or PKF241-466 treatment had a dose dependent reduction of TNF-á concentrations in serum. In agreement with this last result, both drugs were able to delay and partially inhibit lethality induced by ischemia and reperfusion. Maximal inhibition occurred at 10 mg/kg. TACE and MMPs inhibitors reduced reperfusion associated local and remote tissue injury, as assessed by changes in vascular permeability, neutrophil recruitment and haemorrhage. In addition, PKF242-484 or PKF241-466 markedly reduced the production of TNF-á, KC and MCP-1 in intestine and lungs of animals which underwent reperfusion. In contrast, nor PKF242-484 or PKF241-466 affected the elevations of serum and tissue levels of anti-inflammatory cytokine IL-10. To test the relevance of MMP in these results we used a specific inhibitor of MMP which possesses no effect on TACE, FN-439. The treatment with 10 mg/kg of FN-439 decreased MMPss activities assessed by zimography but showed no effects on lethality nor could reduce production of soluble TNF-á . No changes in other measured inflammatory parameters were observed. PKF242-484 and PKF241-466, a novel dual TACE and MMPs inhibitors, were effective in improving reperfusion-associated tissue injury and systemic inflammation. Combined TACE and MMPs inhibitors may be effective co-adjuvants in treatments of injuries that follow reperfusion of an ischemic vascular territory. Treatment with specific inhibitors of MMP in this model showed no advantages. Inhibition of TACEs ability in shed TNF-á seems to be the main mechanism involved in this beneficial response.