title: Two different mechanisms for modulation of bronchoconstriction in guinea-pigs by cyclooxygenase metabolites.
abstract: Leukotriene D(4) (LTD(4))-induced bronchoconstriction in guinea-pig airways has a cyclooxygenase (COX)-dependent component. The main objective of this study was to establish if prostaglandin (PG) D(2)-induced bronchoconstriction also was modulated by COX products. The effects of non-selective and selective COX-1 and COX-2 inhibitors on bronchoconstriction induced by LTD(4) and PGD(2) were investigated in the perfused and ventilated guinea-pig lung (IPL). Both LTD(4)-induced bronchoconstriction and thromboxane (TX) A(2) release was suppressed by COX inhibitors or by TX synthesis inhibition. The release of additional COX products following CysLT(1) receptor activation by LTD(4) was established by measurements of immunoreactive 6-keto PGF(1alpha) (a stable metabolite of PGI(2)) and PGE(2). In contrast, TP receptor-mediated bronchoconstriction by PGD(2) was somewhat enhanced by COX inhibitors, and there was no measurable release of COX products after TP receptor activation with U-46619. PGE(2) was bronchoprotective in IPL as it inhibited the histamine-induced bronchoconstriction. In the isolated guinea-pig trachea, neither PGD(2) nor U-46619 actively released PGE(2), but continuous production of PGE(2) and PGI(2) was established, and the response to PGD(2) was enhanced also in the trachea by COX inhibition. The study documented that bronchoconstriction induced by LTD(4) and PGD(2) in IPL was modulated differently by COX products. Whereas bronchoconstriction induced by LTD(4) was amplified predominantly by secondarily released TXA(2), that induced by PGD(2) was attenuated by bronchoprotective PGE(2) and PGI(2), presumably tonically produced in the airways.
authors.affiliation: The National Institute of Environmental Medicine, Division of Physiology and Centre for Allergy Research, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Ewa
authors.initials: E
authors.lastname: Selg
authors.forename: Margareta
authors.initials: M
authors.lastname: Andersson
authors.forename: Lena
authors.initials: L
authors.lastname: Låstbom
authors.forename: Ake
authors.initials: A
authors.lastname: Ryrfeldt
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Dahlén
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D011464:Epoprostenol / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D017998:Leukotriene D4 / Q000494:pharmacology; D008168:Lung / Q000187:drug effects; D008297:Male; D015230:Prostaglandin D2 / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
chemical_list: D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D016861:Cyclooxygenase Inhibitors; D015121:6-Ketoprostaglandin F1 alpha; D017998:Leukotriene D4; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D015230:Prostaglandin D2