title: A role for complement in the enhanced susceptibility of steatotic livers to ischemia and reperfusion injury.
abstract: Hepatic steatosis typically renders the donor organ unusable, as donor organs with >30% steatosis are more likely to develop graft failure. The mechanisms leading to failure are not well defined, but steatosis enhances hepatic susceptibility to ischemia reperfusion injury (IRI). We investigated the role of complement in hepatic IRI in lean and steatotic (diet-induced) mice. Steatotic mice were significantly more susceptible to total warm hepatic IRI than lean mice as determined by serum alanine aminotransferase, histopathologically assessed damage, and 24-h survival. C3 deficiency protected both lean and steatotic mice from IRI, as determined by all measured outcomes. Furthermore, treatment of wild-type mice with the complement inhibitor CR2-Crry provided protection equivalent to that seen in C3-deficient mice. Importantly, although steatotic livers were much more susceptible to IRI than lean livers, by most measures there was no statistical difference between the level of IRI to steatotic or lean livers when complement was inhibited. To investigate the clinical relevance of these findings in the context of transplantation, we treated recipients of lean or steatotic liver grafts with saline or CR2-Crry. There was a marked reduction in graft inflammation and injury and significantly improved 7-day survival in CR2-Crry-treated recipients of either lean or steatotic grafts. These data indicate that complement plays a key role in the enhanced susceptibility of steatotic livers to IRI and suggest that complement inhibition represents a potential strategy to reduce the donor shortage by allowing the more routine use of marginal steatotic donor livers.
authors.affiliation: Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina 29245, USA.
authors.forename: Songqing
authors.initials: S
authors.lastname: He
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Zachary
authors.initials: Z
authors.lastname: Evans
authors.forename: Justin D
authors.initials: JD
authors.lastname: Ellett
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.forename: Andrew
authors.initials: A
authors.lastname: Elvington
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Chavin
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D004041:Dietary Fats / Q000008:administration & dosage; D004198:Disease Susceptibility / Q000276:immunology; D005234:Fatty Liver / Q000276:immunology* / Q000601:surgery; D006084:Graft Rejection / Q000276:immunology; D008099:Liver / Q000098:blood supply* / Q000276:immunology*; D016031:Liver Transplantation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015427:Reperfusion Injury / Q000276:immunology* / Q000517:prevention & control / Q000601:surgery
chemical_list: C527099:CR2-Crry fusion protein, mouse; D003176:Complement C3; D004041:Dietary Fats; D011993:Recombinant Fusion Proteins