The major mast cell prostanoid PGD 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 affects release of other prostanoids in human mast cells.
To determine the biochemical consequences of inhibition of the hematopoietic prostaglandin D synthase (hPGDS) PGD in human mast cells.
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.
All mast cells almost exclusively released PGD 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 , PGE was detected and release of TXA increased. Conversely, when the thromboxane synthase was inhibited, levels of PGD increased. Adding exogenous PGH confirmed predominant conversion to PGD under control conditions, and increased levels of TXB and PGE when hPGDS was inhibited. However, PGE was formed by non-enzymatic degradation.
Inhibition of hPGDS effectively blocks mast cell dependent PGD formation. The inhibition was associated with redirected use of the intermediate PGH and shunting into biosynthesis of TXA . However, the levels of TXA did not reach those of PGD in naïve cells. It remains to determine if this diversion occurs in vivo and has clinical relevance.

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