Inhibition of complement C5 reduces local and remote organ injury after intestinal ischemia/reperfusion in the rat.
OBJECTIVE
Complement activation plays an important role in the local pathogenesis of ischemia/reperfusion (I/R) injury. We investigated the action of anti-C5 monoclonal antibody (mAb) on local and remote organ injuries after intestinal I/R in the rat.


METHODS
Under anesthesia, functional anti-rat C5 mAb (18A), an isotype-matched control anti-C5 mAb (16C), or vehicle (phosphate-buffered saline) was administered 60 minutes before the superior mesenteric artery was occluded for 90 minutes and reperfused for 60 minutes. Tissue injury was assessed by lactate dehydrogenase release, myeloperoxidase activity, and microvessel relaxation. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, and intercellular adhesion molecule (ICAM)-1 expression was assessed by reverse-transcription polymerase chain reaction and immunohistochemistry.


RESULTS
The loss of endothelium-dependent relaxation of microvessels from the superior mesenteric artery after I/R was significantly attenuated by 18A but not by 16C. Intestinal lactate dehydrogenase release after I/R was significantly reversed by 18A treatment. Anti-C5 treatment significantly inhibited the increased myeloperoxidase activity in the lung and intestine after intestinal I/R. Furthermore, increased intestinal TNF-alpha, IL-1alpha, and vascular ICAM-1 expression after I/R were significantly inhibited by anti-C5 mAb.


CONCLUSIONS
Anti-C5 therapy significantly improved intestinal I/R tissue injury as well as lung injury.
Wada
K
K
Center for Experimental Therapeutics & Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Montalto
M C
MC
Stahl
G L
GL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003182:Complement C5 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D015870:Gene Expression / Q000276:immunology; D007167:Immunotherapy; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics; D007422:Intestines / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D007962:Leukocytes / Q000166:cytology / Q000276:immunology; D008297:Male; D008833:Microcirculation / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000911:Antibodies, Monoclonal; D003182:Complement C5; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1