Synergism between inflammatory mediators in vivo. Induction of airway hyperresponsiveness to C3a in the guinea pig.
The complement anaphylatoxin C3a causes acute bronchoconstriction after intravenous infusion in guinea pigs. At doses of 6 to 600 micrograms/kg, the peptide causes significant and dose-dependent increases in resistance (RL) and decreases in dynamic compliance (Cdyn). Inhibition of serum carboxypeptidase N, the enzyme thought to be responsible for control of C3a activity in blood, by pretreating animals with DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGPA), resulted in a 4-fold potentiation of the response to 200 micrograms/kg C3a. Responses to lower C3a doses were not significantly affected. Pretreating animals intravenously with histamine prior to administration of C3a resulted in potentiation of C3a-induced bronchoconstriction at all doses tested, decreasing the amount of C3a required to double RL by 15-fold, from 110 to 7 micrograms/kg. The effect appears to be relatively specific for C3a since histamine pretreatment did not alter airway responsiveness to methacholine. Similarly, pretreatment with methacholine at a dose that caused an increase in RL comparable to histamine did not alter subsequent responses to C3a. Administration of capsaicin, under conditions that elicit acute release of endogenous substance P, also resulted in potentiation of C3a responses, to an extent similar to that observed for histamine. These data are consistent with an increase in pulmonary vascular permeability facilitating accessibility of C3a for its receptor to cause bronchoconstriction before it is inactivated by serum carboxypeptidase N. Further, when C3a is generated in the presence of histamine-and/or substance-P-releasing agents, it may be responsible for a greater fraction of altered pulmonary mechanics than has previously been appreciated.
Watson
J W
JW
Department of Medicine, Beth Israel Hospital, Boston, MA 02215.
Drazen
J M
JM
Stimler-Gerard
N P
NP
D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D003176:Complement C3 / Q000502:physiology*; D015926:Complement C3a; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006168:Guinea Pigs; D006632:Histamine / Q000008:administration & dosage; D007275:Injections, Intravenous; D008170:Lung Compliance / Q000187:drug effects*; D008297:Male; D016210:Methacholine Chloride; D008688:Methacholine Compounds / Q000008:administration & dosage; D011014:Pneumonia / Q000139:chemically induced* / Q000503:physiopathology
D003176:Complement C3; D008688:Methacholine Compounds; D016210:Methacholine Chloride; D015926:Complement C3a; D006632:Histamine