title: Complement depletion protects lupus-prone mice from ischemia-reperfusion-initiated organ injury.
abstract: Ischemia-reperfusion (IR) injury causes a vigorous immune response that is amplified by complement activation, leading to local and remote tissue damage. Using MRL/lpr mice, which are known to experience accelerated tissue damage after mesenteric IR injury, we sought to evaluate whether complement inhibition mitigates organ damage. We found that complement depletion with cobra venom factor protected mice from local and remote lung tissue damage. Protection from injury was associated with less complement (C3) and membrane attack complex deposition, less neutrophil infiltration, and lower levels of local proinflammatory cytokine production. In addition, complement depletion was able to decrease the level of oxidative stress as measured by glutathione peroxidase 1 mRNA levels and superoxide dismutase activity. Furthermore, blockage of C5a receptor protected MRL/lpr mice from local tissue damage, but not from remote lung tissue damage. In conclusion, although treatments with cobra venom factor and C5a receptor antagonist were able to protect mice from local tissue damage, treatment with C5a receptor antagonist was not able to protect mice from remote lung tissue damage, implying that more factors contribute to the development of remote tissue damage after IR injury. These data also suggest that complement inhibition at earlier, rather than late, stages can have clinical benefit in conditions that are complicated with IR injury.
authors.affiliation: Rheumatology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. aioannou@bidmc.harvard.edu
authors.forename: Antonis
authors.initials: A
authors.lastname: Ioannou
authors.forename: Linda A
authors.initials: LA
authors.lastname: Lieberman
authors.forename: Jurandir J
authors.initials: JJ
authors.lastname: Dalle Lucca
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology; D015936:Complement C5a / Q000037:antagonists & inhibitors; D051056:Complement Inactivating Agents / Q000494:pharmacology; D003165:Complement System Proteins / Q000172:deficiency / Q000502:physiology*; D004546:Elapid Venoms / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D008180:Lupus Erythematosus, Systemic / Q000473:pathology*; D008643:Mesentery / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D020556:Neutrophil Infiltration / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D016612:Paraffin Embedding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000473:pathology*; D013152:Splanchnic Circulation / Q000502:physiology
chemical_list: D001323:Autoantibodies; D051056:Complement Inactivating Agents; D004546:Elapid Venoms; D012333:RNA, Messenger; C016310:cobra venom factor; D015936:Complement C5a; D003165:Complement System Proteins