The inhibition of MIF by ISO-1 attenuates trauma-induced multiple organ failure in rats
Objective: The aim of this study was to investigate (a) the levels of Macrophage Migration Inhibitory Factor (MIF) in serum of trauma patients and of rats after hemorrhagic shock (HS), (b) the potential of the MIF tautomerase activity inhibitor ISO-1 to reduce shock-induced multiple organ failure (MOF) in an acute HS rat model and (c) whether treatment with ISO-1 attenuates NF-κB and NLRP3 activation in HS.
Background: MOF caused by systemic inflammation after trauma is responsible for a high number of deaths worldwide. The cytokine MIF is recognized as a modulator of inflammatory response, however, its role in trauma is unknown.
Methods: The serum MIF-levels in trauma patients and rats with HS were measured by ELISA. An acute HS rat model was performed to determine the influence of ISO-1 on MOF. The activation of NF-κB and NLRP3 pathways were analyzed by western blot.
Results: We demonstrated that (a) MIF levels are increased in serum of trauma patients on arrival in the emergency room and in serum of rats after HS, (b) HS caused organ damage and low blood pressure (after resuscitation) in rats, while (c) treatment of HS-rats with ISO-1 attenuated organ injury and dysfunction in an acute HS rat model and (d) decreased the activation of NF-κB and NLRP3 pathways.
Conclusion: Our 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 MOF after trauma and/or hemorrhage.