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Complement-dependent inflammation and injury in a murine model of brain dead donor hearts
Carl Atkinson1, Juan C Varela, Stephen Tomlinson
1Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
Insights
Brain death (BD) in organ donors causes heart injury. Complement component C3 plays a key role in this inflammation and damage, suggesting complement inhibition could protect donor hearts.
Area of Science:
- Immunology
- Cardiovascular Research
- Transplantation Science
Background:
- Brain death (BD) in organ donors leads to physiological changes that increase heart susceptibility to ischemia/reperfusion injury.
- These changes negatively impact long-term allograft survival in heart transplantation.
Purpose of the Study:
- To develop a novel mouse model of brain death (BD).
- To investigate the role of the complement system in BD-induced myocardial inflammation and injury.
Main Methods:
- BD was induced in mice using a cranial balloon catheter.
- Serum complement component (C)3a levels and cardiac C3 deposition were analyzed.
- Myocardial injury, leukocyte infiltration, and inflammatory marker expression were assessed in wild-type and C3-deficient mice.
Main Results:
- BD significantly increased C3a and cardiac C3 deposition in wild-type mice.
- C3-deficient mice showed significantly reduced cardiac troponin levels and histological injury compared to wild-type.
- C3 deficiency led to reduced leukocyte infiltration and inflammatory marker expression in the heart.
Conclusions:
- Complement activation, specifically involving C3, is crucial in BD-induced myocardial inflammation and injury.
- Targeting complement inhibition in the donor, in addition to the recipient, may offer protective benefits for the transplanted heart graft.
Rationale:
Donor brain death (BD) is an unavoidable occurrence in heart transplantation and results in profound physiological derangements that render the heart more susceptible to ischemia/reperfusion injury in the recipient and likely has negative long-term consequences to allograft survival.
Objective:
We developed a novel mouse model of BD and investigated the role of complement in BD-induced myocardial inflammation and injury.
Methods And Results:
BD was induced by inflation of a balloon catheter in the cranial cavity. BD in wild-type mice resulted in a significant increase in serum concentrations of the complement activation product complement component (C)3a, and immunohistochemical analysis of heart sections demonstrated C3 deposition on the vascular endothelium and surrounding myocytes. Following induction of BD in complement (C3)-deficient mice, cardiac troponin levels, and histological evidence of injury were significantly reduced compared to wild-type mice. C3 deficiency was also associated with reduced myocardial leukocyte infiltration and reduced or absent expression of P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor-alpha, and interleukin-1beta.
Conclusions:
These data indicate an important role for complement in BD-induced inflammation and injury and suggest that a complement inhibitory strategy applied to the donor (in addition to the recipient) may provide graft protection.