Journal
CLINICAL AND EXPERIMENTAL ALLERGY
Volume 51, Issue 4, Pages 594-603Publisher
WILEY
DOI: 10.1111/cea.13831
Keywords
asthma; basic mechanisms; IgE; mast cells
Categories
Funding
- Swedish Research Council
- Swedish Heart-Lung Foundation
- Swedish Cancer Society
- Ellen, Walter and Lennart Hesselman's Foundation
- Tore Nilsons Foundation
- Lars Hiertas Memory Fund
- Tornspiran Foundation
- Konsul Th C Berghs Foundation
- O.E. and Edla Johanssons Foundation
- Stockholm County Council Research Funds, ALF
- Swedish Foundation for Strategic Research
- Karolinska Institutet
- ChAMP (Centre for Allergy Research Highlights Asthma Markers of Phenotype) consortium
- AstraZeneca
- Science for Life Laboratory Joint Research Collaboration
- Cayman Biomedical Research Institute
- CaBRI
- ERS/Marie-Curie joint research fellowship
- Swedish Society for Medical Research
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Inhibition of hPGDS effectively blocks mast cell-dependent PGD(2) formation, leading to redirected use of the intermediate PGH(2) and shunting into biosynthesis of TXA(2). However, the levels of TXA(2) did not reach those of PGD(2) in naive cells. It remains to be determined if this diversion occurs in vivo and has clinical relevance.
Background The major mast cell prostanoid PGD(2) is targeted for therapy of asthma and other diseases, because the biological actions include bronchoconstriction, vasodilation and regulation of immune cells mediated by three different receptors. It is not known if the alternative to selectively inhibit the biosynthesis of PGD(2) affects release of other prostanoids in human mast cells. Objectives To determine the biochemical consequences of inhibition of the hematopoietic prostaglandin D synthase (hPGDS) PGD(2) in human mast cells. Methods Four human mast cell models, LAD2, cord blood derived mast cells (CBMC), peripheral blood derived mast cells (PBMC) and human lung mast cells (HLMC), were activated by anti-IgE or ionophore A23187. Prostanoids were measured by UPLC-MS/MS. Results All mast cells almost exclusively released PGD(2) when activated by anti-IgE or A23187. The biosynthesis was in all four cell types entirely initiated by COX-1. When pharmacologic inhibition of hPGDS abolished formation of PGD(2), PGE(2) was detected and release of TXA(2) increased. Conversely, when the thromboxane synthase was inhibited, levels of PGD(2) increased. Adding exogenous PGH(2) confirmed predominant conversion to PGD(2) under control conditions, and increased levels of TXB2 and PGE(2) when hPGDS was inhibited. However, PGE(2) was formed by non-enzymatic degradation. Conclusions Inhibition of hPGDS effectively blocks mast cell dependent PGD(2) formation. The inhibition was associated with redirected use of the intermediate PGH(2) and shunting into biosynthesis of TXA(2). However, the levels of TXA(2) did not reach those of PGD(2) in naive cells. It remains to determine if this diversion occurs in vivo and has clinical relevance.
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