kallidin and Rhinitis--Allergic--Perennial

To further define the role of neural responses in the hyperreactivity of inflamed human upper airways to bradykinin (BK), we determined if repeated challenges with BK led to tachyphylaxis of neurally mediated responses in subjects with perennial allergic rhinitis. We also tested the hypothesis that enhanced reactivity to kinins in inflamed airways was caused by induction of B1-kinin receptors by comparing the effects of the selective B1-receptor agonist, des-Arg10-lysylbradykinin, and the B2 receptor agonist, BK, in the lower airways of asthmatics and in the upper airways of subjects with perennial allergic rhinitis. Repeated BK challenges led to tachyphylaxis of sneezing and of neurally mediated serous glandular secretion in subjects with perennial allergic rhinitis. Surprisingly, tachyphylaxis of increased local vascular permeability was also observed. By contrast, repeated challenges with BK in normal subjects led to reproducible increases in vascular permeability. Provocation with des-Arg10-lysylbradykinin did not cause bronchoconstriction in asthmatic subjects or increase glandular secretion or vascular permeability in the upper airways of subjects with rhinitis. We conclude that increased reactivity to kinins in inflamed human airways is mediated, at least in part, by neural reflexes, and is not caused by induction of B1-receptors.

Topics: Asthma; Bronchi; Bronchial Provocation Tests; Bronchoconstriction; Capillary Permeability; Cross-Over Studies; Double-Blind Method; Female; Follow-Up Studies; Humans; Inflammation; Kallidin; Kinins; Male; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Reflex; Rhinitis, Allergic, Perennial; Tachyphylaxis

B1 receptors are known to be induced during allergic airway inflammation in animal models. However, little is known regarding in vivo B1 receptor expression in humans. We examined B1 receptor mRNA expression in nasal tissue samples from allergic rhinitis and normal subjects. Allergic rhinitis subjects displayed significantly higher expression of B1 receptor mRNA than did the normal subjects, and nasal allergen challenge increased B1 receptor mRNA expression at 8 to 24 h time points in allergic rhinitis subjects. No significant difference was found in B2 receptor expression. To confirm B2 and B1 receptor functional activity, subjects were challenged with kinin agonists. Nasal challenge with the B1 receptor ligand, Lys-des-Arg-bradykinin (BK), activated extracellular signal-regulated kinase in allergic rhinitis, but not normal, subjects. Nasal challenge with the B2 receptor ligand, BK, activated extracellular signal-regulated kinase in both allergic rhinitis and normal subjects. The consequences of B1 receptor activation were investigated using the human airway epithelial cell lines A549 and BEAS-2B. We demonstrated that Lys-des-Arg-BK activates the transcription factor AP-1. Taken together, these results show that functional B1 receptors are induced in the airway during allergic inflammation and suggest that they participate in the regulation of gene expression.

Topics: Adult; Allergens; Animals; Bradykinin; Case-Control Studies; Enzyme Activation; Epithelial Cells; Humans; In Vitro Techniques; Kallidin; Mitogen-Activated Protein Kinases; Nasal Mucosa; Nasal Provocation Tests; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; RNA, Messenger; Transcription Factor AP-1; Up-Regulation