In vivo effects of C3a on neutrophils and its contribution to inflammatory lung processes in a guinea-pig model.
C3a, when injected intravenously in guinea-pigs, caused a rapid drop of circulating neutrophils and platelets. The neutropenia was reversible and followed by a neutrophilia, which reached about 200% of baseline values. Upon challenge with octa- and hexapeptide, mimicking the C-terminal sequence of C3a, neutrophils and platelets reacted in the same manner. The hexapeptide-desArg (pentapeptide without the C-terminal arginine of hexapeptide) induced no neutropenia but a significant neutrophilia. Likewise, when injected in animals with a genetic deficiency or dysfunction of the C3a-receptor, the hexapeptide caused no drop of the neutrophils, but a neutrophilia, indicating that both neutrophil reactions are mediated by different mechanisms. With the octapeptide in vivo dose-response studies were performed. Despite maximal doses of octapeptide about 40% of the neutrophils remained in circulation, indicating that some but not all PMNs are susceptible to C3a. By pretreating the animals with an inhibitor of the serum carboxypeptidase N (SCPN-Inh) the C3a-induced neutropenia could be significantly augmented. But intravenous application of the inhibitor itself caused a 20-40% reduction of neutrophils during the first hour after injection, followed by a neutrophilia. In histological studies the timecourse of neutrophil sequestration in the lung was established, showing that the initial high neutrophil content of the lung lasted for at least 1 h and declined thereafter. Structural derangements could not be detected. These observations stress the importance of C3a besides C5a as an important mediator of inflammatory processes in species, where the C3a-receptor is present on inflammatory cells such as granulocytes.
Hoffmann
T
T
Institute of Medical Microbiology, University of Mainz, FRG.
Böttger
E C
EC
Baum
H P
HP
Messner
M
M
Hadding
U
U
Bitter-Suermann
D
D
D015097:3-Mercaptopropionic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000706:Anaphylatoxins / Q000276:immunology; D000818:Animals; D003176:Complement C3 / Q000276:immunology*; D015926:Complement C3a; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D006168:Guinea Pigs; D007249:Inflammation / Q000473:pathology; D007958:Leukocyte Count; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology* / Q000473:pathology; D001121:Lysine Carboxypeptidase / Q000037:antagonists & inhibitors; D009503:Neutropenia / Q000209:etiology; D009504:Neutrophils / Q000276:immunology*; D010976:Platelet Count; D013997:Time Factors
D000706:Anaphylatoxins; D003176:Complement C3; C029729:2-mercaptomethyl-3-guanidinoethylthiopropionic acid; D015926:Complement C3a; D015097:3-Mercaptopropionic Acid; D001121:Lysine Carboxypeptidase