Complement activation after oxidative stress: role of the lectin complement pathway.
The complement system plays an important role in mediating tissue injury after oxidative stress. The role of mannose-binding lectin (MBL) and the lectin complement pathway (LCP) in mediating complement activation after endothelial oxidative stress was investigated. iC3b deposition on hypoxic (24 hours; 1% O(2))/reoxygenated (3 hours; 21% O(2)) human endothelial cells was attenuated by N-acetyl-D-glucosamine or D-mannose, but not L-mannose, in a dose-dependent manner. Endothelial iC3b deposition after oxidative stress was also attenuated in MBL-deficient serum. Novel, functionally inhibitory, anti-human MBL monoclonal antibodies attenuated MBL-dependent C3 deposition on mannan-coated plates in a dose-dependent manner. Treatment of human serum with anti-MBL monoclonal antibodies inhibited MBL and C3 deposition after endothelial oxidative stress. Consistent with our in vitro findings, C3 and MBL immunostaining throughout the ischemic area at risk increased during rat myocardial reperfusion in vivo. These data suggest that the LCP mediates complement activation after tissue oxidative stress. Inhibition of MBL may represent a novel therapeutic strategy for ischemia/reperfusion injury and other complement-mediated disease states.
Collard
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CD
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Väkevä
A
A
Morrissey
M A
MA
Agah
A
A
Rollins
S A
SA
Reenstra
W R
WR
Buras
J A
JA
Meri
S
S
Stahl
G L
GL
D000117:Acetylglucosamine / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000276:immunology / Q000494:pharmacology / Q000502:physiology; D002460:Cell Line; D037222:Collectins; D003167:Complement Activation / Q000187:drug effects / Q000502:physiology*; D003179:Complement C3b / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D037102:Lectins / Q000502:physiology; D008297:Male; D008358:Mannose / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats; D011917:Rats, Inbred Lew
D002352:Carrier Proteins; D037222:Collectins; D037102:Lectins; D003179:Complement C3b; D008358:Mannose; D000117:Acetylglucosamine