Cutting edge:: Guinea pigs with a natural C3a-receptor defect exhibit decreased bronchoconstriction in allergic airway disease:: Evidence for an involvement of the C3a anaphylatoxin in the pathogenesis of asthma

Asthma is a major cause of morbidity worldwide with prevalence and severity still increasing at an alarming pace, Hallmarks of this disease Include early-phase bronchoconstriction with subsequent eosinophil infiltration, symptoms that may be mimicked in vivo by the complement-derived C3a anaphylatoxin, following its interaction with the single copy C3aR, We analyzed the pathophysiological role of the C3a anaphylatoxin In a model of experimental OVA-induced allergic asthma, using an inbred guinea pig strain phenotypically unresponsive to C3a. Molecular analysis of this defect revealed a point mutation within the coding region of the C3aR that creates a stop codon, thereby effectively inactivating gene function, When challenged by OVA inhalation, sensitized animals of this strain exhibited a bronchoconstriction decreased by similar to 30% in comparison to the corresponding wild-type strain. These data suggest an important role of C3a in the pathogenesis of asthma and define a novel target for drug intervention strategies.