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 approximately 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.
Bautsch
W
W
Institute of Medical Microbiology, Medical School, Hannover, Germany. Bautsch.Wilfried@MH-Hannover.de
Hoymann
H G
HG
Zhang
Q
Q
Meier-Wiedenbach
I
I
Raschke
U
U
Ames
R S
RS
Sohns
B
B
Flemme
N
N
Meyer zu Vilsendorf
A
A
Grove
M
M
Klos
A
A
Köhl
J
J
D000280:Administration, Inhalation; D000403:Airway Resistance / Q000235:genetics / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D016084:Bronchoconstriction / Q000276:immunology*; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D015926:Complement C3a / Q000378:metabolism / Q000502:physiology*; D004804:Eosinophils / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D005819:Genetic Markers / Q000276:immunology; D006168:Guinea Pigs; D006801:Humans; D007274:Injections, Intraperitoneal; D008565:Membrane Proteins; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D017354:Point Mutation / Q000276:immunology; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D013045:Species Specificity; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D005819:Genetic Markers; D008565:Membrane Proteins; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a; D010047:Ovalbumin