MG53 mitigates warm ischemic lung injury in a murine model of transplantation

Abstract

ObjectivesLung transplant warm ischemia–reperfusion injury (IRI) results in cellular injury, inflammation, and poor graft function. Mitsugumin 53 (MG53) is an endogenous protein with cell membrane repair properties and the ability to modulate the inflammasome. We hypothesize that the absence of circulating MG53 protein in the recipient increases IRI, and higher levels of circulating MG53 protein mitigate IRI associated with lung transplantation. MethodsTo demonstrate protection, wild-type (wt) lung donor allografts were transplanted into a wt background, a MG53 knockout (mg53−/−), or a constitutively overexpressed MG53 (tissue plasminogen activator-MG53) recipient mouse after 1 hour of warm ischemic injury. Mice survived for 5 days after transplantation. Bronchioalveolar lavage, serum, and tissue were collected at sacrifice. Bronchioalveolar lavage, serum, and tissue markers of apoptosis and a biometric profile of lung health were analyzed. Resultsmg53−/− mice had significantly greater levels of markers of overall cell lysis and endothelial cell injury. Overexpression of MG53 resulted in a signature similar to that of wt controls. At the time of explant, tissue plasminogen activator-MG53 recipient tissue expressed significantly greater levels of MG53, measured by immunohistochemistry, compared with mg53−/−, demonstrating uptake of endogenous overexpressed MG53 into donor tissue. ConclusionsIn a warm IRI model of lung transplantation, the absence of MG53 resulted in increased cell injury and inflammation. Endogenous overexpression of MG53 in the recipient results in protection in the wt donor. Together, these data suggest that MG53 is a potential therapeutic agent for use in lung transplantation to mitigate IRI.