Protection of innate immunity by C5aR antagonist in septic mice.
Innate immune functions are known to be compromised during sepsis, often with lethal consequences. There is also evidence in rats that sepsis is associated with excessive complement activation and generation of the potent anaphylatoxin C5a. In the presence of a cyclic peptide antagonist (C5aRa) to the C5a receptor (C5aR), the binding of murine 125I-C5a to murine neutrophils was reduced, the in vitro chemotactic responses of mouse neutrophils to mouse C5a were markedly diminished, the acquired defect in hydrogen peroxide (H2O2) production of C5a-exposed neutrophils was reversed, and the lung permeability index (extravascular leakage of albumin) in mice after intrapulmonary deposition of IgG immune complexes was markedly diminished. Mice that developed sepsis after cecal ligation/puncture (CLP) and were treated with C5aRa had greatly improved survival rates. These data suggest that C5aRa interferes with neutrophil responses to C5a, preventing C5a-induced compromise of innate immunity during sepsis, with greatly improved survival rates after CLP.
Huber-Lang
Markus S
MS
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA.
Riedeman
Niels C
NC
Sarma
J Vidya
JV
Younkin
Ellen M
EM
McGuire
Stephanie R
SR
Laudes
Ines J
IJ
Lu
Kristina T
KT
Guo
Ren-Feng
RF
Neff
Thomas A
TA
Padgaonkar
Vaishalee A
VA
Lambris
John D
JD
Spruce
L
L
Mastellos
D
D
Zetoune
Firas S
FS
Ward
Peter A
PA
D000818:Animals; D015703:Antigens, CD; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015936:Complement C5a / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007113:Immunity, Innate / Q000187:drug effects*; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D008171:Lung Diseases / Q000276:immunology / Q000517:prevention & control; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D009842:Oligopeptides / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010529:Peritoneal Cavity / Q000166:cytology; D011485:Protein Binding / Q000187:drug effects; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors*; D018805:Sepsis / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D015996:Survival Rate
D015703:Antigens, CD; D009842:Oligopeptides; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D015936:Complement C5a