Cutting Edge:Guinea Pigs with a Natural C3a-Receptor Defect Exhibit Decreased Bronchoconstruiction in Allergic Airway Disease:Evidence for an Involvement of the C3a Anaphylatoxin in the Pathogenesis of Asthma

摘要

Asthma is a major cause of morbidity worldwide with prevalence and severity stillincreasing 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 anaphyatoxin,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 train exhibited a rbronchoconstriction decreased by approx 30% ncomparison to the corresponding wild-type strain.These data sugest an important role of C3a in the pathogenesis of asthma and define a novel target for drug intervention strategies.