Complement-dependent inflammation and injury in a murine model of brain dead donor hearts.
BACKGROUND
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.


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.
Atkinson
Carl
C
Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
Varela
Juan C
JC
Tomlinson
Stephen
S
D000818:Animals; D001926:Brain Death / Q000276:immunology* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D003167:Complement Activation / Q000276:immunology; D015926:Complement C3a / Q000037:antagonists & inhibitors / Q000276:immunology*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D019194:Ischemic Preconditioning / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D015428:Myocardial Reperfusion Injury / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D014019:Tissue Donors
D015815:Cell Adhesion Molecules; D015926:Complement C3a