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CUTTING EDGE |
*
Institute of Medical Microbiology and
Department of Transplantation Surgery, Medical School, Hannover, Germany;
Fraunhofer Institute of Toxicology and Aerosol Research, Hannover, Germany; and
SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406
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 
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.
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