Carl Atkinson1, Juan C Varela, Stephen Tomlinson. 1. Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
Abstract
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.
RATIONALE: Donorbrain 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)-deficientmice, 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.
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