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Updated: Jul 11, 2025
A Rat Lung Transplantation Model of Warm Ischemia/Reperfusion Injury: Optimizations to Improve Outcomes
Published on: October 28, 2021
MG53 mitigates warm ischemic lung injury in a murine model of transplantation
Doug A Gouchoe1, Tai Yi2, Jung-Lye Kim3
1COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; 88th Surgical Operations Squadron, Wright-Patterson Medical Center, Wright-Patterson AFB, Ohio.
Objectives:
Lung 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.
Methods:
To 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.
Results:
mg53-/- 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.
Conclusions:
In 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.
Insights
The absence of Mitsugumin 53 (MG53) protein worsens lung transplant injury, while its overexpression protects the lung graft. MG53 shows potential as a therapeutic agent to reduce lung transplant warm ischemia-reperfusion injury (IRI).
Area of Science:
- Transplantation immunology
- Cellular biology
- Biochemistry
Background:
- Lung transplant warm ischemia-reperfusion injury (IRI) leads to cellular damage, inflammation, and impaired graft function.
- Mitsugumin 53 (MG53) is an endogenous protein known for its cell membrane repair capabilities and inflammasome modulation.
- The role of MG53 in mitigating lung transplant IRI is not fully understood.
Purpose of the Study:
- To investigate the impact of recipient MG53 levels on lung transplant IRI.
- To determine if MG53 deficiency exacerbates IRI and if MG53 overexpression provides protection.
Main Methods:
- Wild-type lung allografts were transplanted into MG53 knockout, MG53 overexpressing, and wild-type recipient mice after 1 hour of warm ischemic injury.
- Mice were observed for 5 days post-transplantation.
- Analysis included bronchioalveolar lavage, serum, and tissue markers of apoptosis and lung health.
Main Results:
- MG53 knockout recipients exhibited significantly higher levels of cell lysis and endothelial cell injury.
- MG53 overexpression in recipients led to outcomes comparable to wild-type controls.
- Immunohistochemistry confirmed uptake of overexpressed MG53 into donor lung tissue in recipient mice.
Conclusions:
- Absence of MG53 in recipients increases cell injury and inflammation in a lung transplant warm IRI model.
- Endogenous MG53 overexpression in the recipient protects the wild-type donor lung.
- MG53 emerges as a potential therapeutic target for mitigating lung transplant IRI.
