Prostaglandin D 2 inhibits mediator release and antigen induced bronchoconstriction in the Guinea pig trachea by activation of DP 1 receptors

• Published in: European journal of pharmacology 2021-09, Vol.907, p.174282
• Main Authors: Säfholm, Jesper, Abma, Willem, Liu, Jielu, Balgoma, David, Fauland, Alexander, Kolmert, Johan, Wheelock, Craig E, Adner, Mikael, Dahlén, Sven-Erik
• Format: Article
• Language: English
• Subjects: Animals; Antigens - immunology; Bronchoconstriction - drug effects; Cyclooxygenase Inhibitors - pharmacology; Guinea Pigs; Hydantoins; Male; Ovalbumin - immunology; Prostaglandin D2 - metabolism; Prostaglandin D2 - pharmacology; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; Receptors, Prostaglandin - antagonists & inhibitors; Receptors, Prostaglandin - metabolism; Trachea - drug effects; Trachea - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174282

The mechanism by which cyclooxygenase (COX) inhibition increases antigen-induced responses in airways remains unknown. Male albino guinea pigs were sensitized to ovalbumin (OVA). Intact rings of the trachea were isolated and mounted in organ baths for either force measurements or lipid mediator release analysis by UPLC-MS/MS or EIA following relevant pharmacological interventions. First, challenge with OVA increased the release of all primary prostanoids (prostaglandin (PG) D /E /F /I and thromboxanes). This release was eliminated by unselective COX inhibition (indomethacin) whereas selective inhibition of COX-2 (lumiracoxib) did not inhibit release of PGD or thromboxanes. Additionally, the increased levels of leukotriene B and E after OVA were further amplified by unselective COX inhibition. Second, unselective inhibition of COX and selective inhibition of the prostaglandin D synthase (2-Phenyl-Pyrimidine-5-Carboxylic Acid (2,3-dihydro-indol-1-yl)-amide) amplified the antigen-induced bronchoconstriction which was reversed by exogenous PGD . Third, a DP receptor agonist (BW 245c) concentration-dependently reduced the antigen-induced constriction as well as reducing released histamine and cysteinyl-leukotrienes, a response inhibited by the DP receptor antagonist (MK-524). In contrast, a DP receptor agonist (15(R)-15-methyl PGD ) failed to modulate the OVA-induced constriction. In the guinea pig trachea, endogenous PGD is generated via COX-1 and mediates an inhibitory effect of the antigen-induced bronchoconstriction via DP receptors inhibiting mast cell release of bronchoconstrictive mediators. Removal of this protective function by COX-inhibition results in increased release of mast cell mediators and enhanced bronchoconstriction.