期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 907, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2021.174282
关键词
PGD(2); Asthma; Bronchoprotection; Mast cell; Eicosanoid; Cyclooxygenase
资金
- Swedish Heart-Lung foundation
- Swedish Research Council Medicine and Health
- Stockholm County Council Research Funds (ALF)
- Swedish Society of Medicine
- Bernard Osher Initiative for Severe Asthma Research
- ChAMP (Centre for Allergy Research Highlights Asthma Markers of Phenotype) consortium - Swedish Foundation for Strategic Research (SSF)
- Karolinska Institutet
- AstraZeneca
- Science for Life Laboratory
- Vardal Foundation
The study revealed the mechanism by which COX inhibition increases antigen-induced responses in airways. Challenge with OVA increased the release of prostaglandins and thromboxanes, and COX inhibition resulted in increased release of mast cell mediators and enhanced bronchoconstriction.
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) D2/E2/F2 alpha/I2 and thromboxanes). This release was eliminated by unselective COX inhibition (indomethacin) whereas selective inhibition of COX-2 (lumiracoxib) did not inhibit release of PGD2 or thromboxanes. Additionally, the increased levels of leukotriene B4 and E4 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 PGD2. Third, a DP1 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 DP1 receptor antagonist (MK-524). In contrast, a DP2 receptor agonist (15(R)-15-methyl PGD2) failed to modulate the OVA-induced constriction. In the guinea pig trachea, endogenous PGD2 is generated via COX-1 and mediates an inhibitory effect of the antigen-induced bronchoconstriction via DP1 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据