In vitro sensitization of human bronchus by beta2-adrenergic agonists.
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 x 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-kappaB 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 B(2) receptor antagonist), SB-203580 (an inhibitor of the 38-kDa mitogen-activated protein kinase, p38(MAPK)), or calphostin C (a protein kinase C blocker). Our results suggest that chronic exposure to fenoterol induces proinflammatory effects mediated by nuclear factor-kappaB and pathways involving leukotrienes, prostanoids, bradykinin, tachykinins, protein kinase C, and p38(MAPK), leading to the regulation of smooth muscle contraction to ET-1 and ACh.
Faisy
Christophe
C
Unité Propre de Recherche de l'Enseignement Supérior Equipe d'Accueil 220, Faculté de Médecine Paris-Ouest, 75006 Paris, France.
Naline
Emmanuel
E
Diehl
Jean-Luc
JL
Emonds-Alt
Xavier
X
Chinet
Thierry
T
Advenier
Charles
C
D000109:Acetylcholine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D005576:Colforsin / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D005280:Fenoterol / Q000494:pharmacology; D000068759:Formoterol Fumarate; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D019332:Endothelin-1; D004983:Ethanolamines; D018343:Receptors, Adrenergic, beta-2; D005576:Colforsin; D005280:Fenoterol; D000109:Acetylcholine; D000420:Albuterol; D000068759:Formoterol Fumarate