Contribution of anaphylatoxin C5a to late airway responses after repeated exposure of antigen to allergic rats

We attempted to elucidate the contribution of complement to allergic asthma . Rat sensitized to OVA received repeated intratracheal exposures to OVA fo r up to 3 consecutive days, and pulmonary resistance was then estimated for up to 6 h after the last exposure. Whereas the immediate airway response ( IAR) in terms of R-L tended to decrease in proportion to the number of OVA exposures, late airway response (LAR) became prominent only after three. Al though premedication with two kinds of complement inhibitors, soluble compl ement receptor type 1 (sCR1) or nafamostat mesylate, resulted in inhibition of the IAR after either a single or a double exposure, the LAR was inhibit ed after the triple. Premedication with a C5a receptor antagonist (C5aRA) b efore every exposure to OVA also inhibited the LAR after three. Repeated OV A exposure resulted in eosinophil and neutrophil infiltration into the bron chial submucosa which was suppressed by premedication with sCR1 or C5aRA. U p-regulation of C5aR mRNA was shown in lungs after triple OVA exposure, but almost no up-regulation of C3aR. Pretreatment with sCR1 or C5aRA suppresse d the up-regulation of C5aR expression as well as cytokine messages in the lungs. The suppression of LAR by pretreatment with sCR1 was reversed by int ratracheal instillation of rat C5a desArg the action of which was inhibited by C5aRA. In contrast, rat C3a desArg or cytokine-induced neutrophil chemo attractant-1 induced cellular infiltration into the bronchial submucosa by costimulation with OVA, but these had no influence on the LAR. These differ ences might be explained by the fact that costimulation with OVA and C5a sy nergistically potentiated IAR, whereas that with OVA and either C3a or cyto kine-induced neutrophil chemoattractant-1 did not. C5a generated by Ag-Ab c omplexes helps in the production of cytokines and contributes to the LAR af ter repeated exposure to Ag.