The inhibition of Macrophage Migration Inhibitory Factor by ISO-1 attenuates trauma-induced multi organ dysfunction in rats

BackgroundMulti organ dysfunction syndrome caused by systemic inflammation after trauma is responsible for a high number of deaths worldwide. The cytokine Migration Inhibitory Factor (MIF) is recognized as a modulator of inflammatory response, however, its role in trauma is unknown. The aim of this study was to investigate (a) the levels of MIF in serum of trauma patients and of rats after hemorrhagic shock, (b) the potential of the MIF tautomerase activity inhibitor ISO-1 to reduce multi organ dysfunction syndrome in an acute and chronic hemorrhagic shock rat model and (c) whether treatment with ISO-1 attenuates NF-κB and NLRP3 activation in hemorrhagic shock.MethodsThe serum MIF-levels in trauma patients and rats with hemorrhagic shock were measured by Enzyme-Linked Immunosorbent Assays. Acute and chronic hemorrhagic shock rat models were performed to determine the influence of ISO-1 on multi organ dysfunction syndrome. The activation of NF-κB and NLRP3 pathways were analyzed by western blot.ResultsWe demonstrated that (a) MIF levels are increased in serum of trauma patients on arrival in the emergency room and in serum of rats after hemorrhagic shock, (b) hemorrhagic shock caused organ damage and low blood pressure (after resuscitation) in rats, while (c) treatment of hemorrhagic shock rats with ISO-1 attenuated organ injury and dysfunction in acute and chronic hemorrhagic shock rat models and (d) decreased the activation of NF-κB and NLRP3 pathways.ConclusionOur results point to a role of MIF in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that MIF tautomerase activity inhibitors may have potential in the therapy of the multi organ dysfunction syndrome after trauma and/or hemorrhage.