In vitro sensitization of human bronchus by β2-adrenergic agonists

Abstract

Incubation of human distal bronchi from 48 patients for 15 h with 10−7 M fenoterol induced sensitization characterized by an increase in maximal contraction to endothelin-1 (ET-1) and acetylcholine (ACh). Incubation of human bronchi with 10−6, 3 × 10−6, and 10−5 M forskolin (an adenyl cyclase activator) reproduced sensitization to ET-1 and ACh. The sensitizing effect of fenoterol was inhibited by coincubation with gliotoxine (a nuclear factor-κB inhibitor), dexamethasone, indomethacin (a cyclooxygenase inhibitor), GR-32191 (a TP prostanoid receptor antagonist), MK-476 (a cysteinyl leukotriene type 1 receptor antagonist), SR-140333 + SR-48968 + SR-142801 (neurokinin types 1, 2, and 3 tachykinin receptor antagonists) with or without HOE-140 (a bradykinin B2receptor antagonist), SB-203580 (an inhibitor of the 38-kDa mitogen-activated protein kinase, p38MAPK), or calphostin C (a protein kinase C blocker). Our results suggest that chronic exposure to fenoterol induces proinflammatory effects mediated by nuclear factor-κB and pathways involving leukotrienes, prostanoids, bradykinin, tachykinins, protein kinase C, and p38MAPK, leading to the regulation of smooth muscle contraction to ET-1 and ACh.