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Selective inhibitio...
Selective inhibition of prostaglandin D-2 biosynthesis in human mast cells to overcome need for multiple receptor antagonists : Biochemical consequences
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- Johnsson, Anna-Karin (författare)
- Karolinska Institutet,Karolinska Inst, Inst Environm Med, Stockholm, Sweden.;Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden.
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- Choi, Jeong-Hee (författare)
- Karolinska Inst, Inst Environm Med, Stockholm, Sweden.;Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden.;Hallym Univ, Dept Pulmonol & Allergy, Dongtan Sacred Heart Hosp, Hwaseong, South Korea.;Hallym Univ, Coll Med, Allergy & Clin Immunol Res Ctr, Chunchon, South Korea.
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- Ronnberg, Elin (författare)
- Karolinska Institutet,Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden.;Karolinska Inst, Dept Med, Immunol & Allergy Div, Solna, Sweden.;Karolinska Univ Hosp, Solna, Sweden.
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- Fuchs, David (författare)
- Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden.
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- Kolmert, Johan (författare)
- Karolinska Institutet,Karolinska Inst, Inst Environm Med, Stockholm, Sweden.;Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden.
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- Hamberg, Mats (författare)
- Karolinska Institutet,Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden.
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- Dahlen, Barbro (författare)
- Karolinska Institutet,Karolinska Univ Hosp, Dept Med, Clin Asthma & Allergy Res Lab, Huddinge, Sweden.
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- Wheelock, Craig E. (författare)
- Karolinska Institutet,Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden.
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- Dahlen, Sven-Erik (författare)
- Karolinska Institutet,Karolinska Inst, Inst Environm Med, Stockholm, Sweden.;Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden.
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- Nilsson, Gunnar (författare)
- Karolinska Institutet,Uppsala universitet,Hematologi,Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden.;Karolinska Inst, Dept Med, Immunol & Allergy Div, Solna, Sweden.;Karolinska Univ Hosp, Solna, Sweden.
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Karolinska Institutet Karolinska Inst, Inst Environm Med, Stockholm, Sweden;Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden. (creator_code:org_t)
- 2021-02-12
- 2021
- Engelska.
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Ingår i: Clinical and Experimental Allergy. - : John Wiley & Sons. - 0954-7894 .- 1365-2222. ; 51:4, s. 594-603
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Nyckelord
- asthma
- basic mechanisms
- IgE
- mast cells
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- ref (ämneskategori)
- art (ämneskategori)
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Johnsson, Anna-K ...
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Choi, Jeong-Hee
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Ronnberg, Elin
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Fuchs, David
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Kolmert, Johan
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Hamberg, Mats
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visa fler...
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Dahlen, Barbro
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Wheelock, Craig ...
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Dahlen, Sven-Eri ...
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Nilsson, Gunnar
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