Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway.
Trypsin and mast cell tryptase can signal to epithelial cells, myocytes, and nerve fibers of the respiratory tract by cleaving proteinase-activated receptor 2 (PAR2). Since tryptase inhibitors are under development to treat asthma, a precise understanding of the contribution of PAR2 to airway inflammation is required. We examined the role of PAR2 in allergic inflammation of the airway by comparing OVA-sensitized and -challenged mice lacking or overexpressing PAR2. In wild-type mice, immunoreactive PAR2 was detected in airway epithelial cells and myocytes, and intranasal administration of a PAR2 agonist stimulated macrophage infiltration into bronchoalveolar lavage fluid. OVA challenge of immunized wild-type mice stimulated infiltration of leukocytes into bronchoalveolar lavage and induced airway hyperreactivity to inhaled methacholine. Compared with wild-type animals, eosinophil infiltration was inhibited by 73% in mice lacking PAR2 and increased by 88% in mice overexpressing PAR2. Similarly, compared with wild-type animals, airway hyperreactivity to inhaled methacholine (40 micro g/ml) was diminished 38% in mice lacking PAR2 and increased by 52% in mice overexpressing PAR2. PAR2 deletion also reduced IgE levels to OVA sensitization by 4-fold compared with those of wild-type animals. Thus, PAR2 contributes to the development of immunity and to allergic inflammation of the airway. Our results support the proposal that tryptase inhibitors and PAR2 antagonists may be useful therapies for inflammatory airway disease.
Schmidlin
Fabien
F
Department of Surgery and Physiology, University of California, San Francisco 94143, USA.
Amadesi
Silvia
S
Dabbagh
Karim
K
Lewis
David E
DE
Knott
Patrick
P
Bunnett
Nigel W
NW
Gater
Paul R
PR
Geppetti
Pierangelo
P
Bertrand
Claude
C
Stevens
Mary E
ME
D000485:Allergens / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D003433:Crosses, Genetic; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D000485:Allergens; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; D007073:Immunoglobulin E; D010047:Ovalbumin