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Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation

INTRODUCTION: Mast cell (MC) degranulation is an important step in the pathogenesis of inflammatory reactions and allergies; however, the mechanism of stabilizing MC membranes to reduce their degranulation is unclear. METHODS: SO(2) content in MC culture supernatant was measured by HPLC-FD. The prot...

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Autores principales: Zhang, Lulu, Jin, Hongfang, Song, Yunjia, Chen, Selena Ying, Wang, Yi, Sun, Yan, Tang, Chaoshu, Du, Junbao, Huang, Yaqian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020161/
https://www.ncbi.nlm.nih.gov/pubmed/33842005
http://dx.doi.org/10.1016/j.jare.2020.08.017
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author Zhang, Lulu
Jin, Hongfang
Song, Yunjia
Chen, Selena Ying
Wang, Yi
Sun, Yan
Tang, Chaoshu
Du, Junbao
Huang, Yaqian
author_facet Zhang, Lulu
Jin, Hongfang
Song, Yunjia
Chen, Selena Ying
Wang, Yi
Sun, Yan
Tang, Chaoshu
Du, Junbao
Huang, Yaqian
author_sort Zhang, Lulu
collection PubMed
description INTRODUCTION: Mast cell (MC) degranulation is an important step in the pathogenesis of inflammatory reactions and allergies; however, the mechanism of stabilizing MC membranes to reduce their degranulation is unclear. METHODS: SO(2) content in MC culture supernatant was measured by HPLC-FD. The protein and mRNA expressions of the key enzymes aspartate aminotransferase 1 (AAT1) and AAT2 and intracellular AAT activity were detected. The cAMP level in MCs was detected by immunofluorescence and ELISA. The release rate of MC degranulation marker β-hexosaminidase was measured. The expression of AAT1 and cAMP, the MC accumulation and degranulation in lung tissues were detected. OBJECTIVES: To exam whether an endogenous sulfur dioxide (SO(2)) pathway exists in MCs and if it serves as a novel endogenous MC stabilizer. RESULTS: We firstly show the existence of the endogenous SO(2)/AAT pathway in MCs. Moreover, when AAT1 was knocked down in MCs, MC degranulation was significantly increased, and could be rescued by a SO(2) donor. Mechanistically, AAT1 knockdown decreased the cyclic adenosine monophosphate (cAMP) content in MCs, while SO(2) prevented this reduction in a dose-independent manner. Pretreatment with the cAMP-synthesizing agonist forskolin or the cAMP degradation inhibitor IBMX significantly blocked the increase in AAT1 knockdown-induced MC degranulation. Furthermore, in hypoxia-stimulated MCs, AAT1 protein expression and SO(2) production were markedly down regulated, and MC degranulation was activated, which were blunted by AAT1 overexpression. The cAMP synthesis inhibitor SQ22536 disrupted the suppressive effect of AAT1 overexpression on hypoxia-induced MC degranulation. In a hypoxic environment, mRNA and protein expression of AAT1 was significantly reduced in lung tissues of rats. Supplementation of SO(2) elevated the cAMP level and reduced perivascular MC accumulation and degranulation in lung tissues of rats exposed to a hypoxic environment in vivo. CONCLUSION: SO(2) serves as an endogenous MC stabilizer via upregulating the cAMP pathway under hypoxic circumstance.
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spelling pubmed-80201612021-04-08 Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation Zhang, Lulu Jin, Hongfang Song, Yunjia Chen, Selena Ying Wang, Yi Sun, Yan Tang, Chaoshu Du, Junbao Huang, Yaqian J Adv Res Basic and Biological Science INTRODUCTION: Mast cell (MC) degranulation is an important step in the pathogenesis of inflammatory reactions and allergies; however, the mechanism of stabilizing MC membranes to reduce their degranulation is unclear. METHODS: SO(2) content in MC culture supernatant was measured by HPLC-FD. The protein and mRNA expressions of the key enzymes aspartate aminotransferase 1 (AAT1) and AAT2 and intracellular AAT activity were detected. The cAMP level in MCs was detected by immunofluorescence and ELISA. The release rate of MC degranulation marker β-hexosaminidase was measured. The expression of AAT1 and cAMP, the MC accumulation and degranulation in lung tissues were detected. OBJECTIVES: To exam whether an endogenous sulfur dioxide (SO(2)) pathway exists in MCs and if it serves as a novel endogenous MC stabilizer. RESULTS: We firstly show the existence of the endogenous SO(2)/AAT pathway in MCs. Moreover, when AAT1 was knocked down in MCs, MC degranulation was significantly increased, and could be rescued by a SO(2) donor. Mechanistically, AAT1 knockdown decreased the cyclic adenosine monophosphate (cAMP) content in MCs, while SO(2) prevented this reduction in a dose-independent manner. Pretreatment with the cAMP-synthesizing agonist forskolin or the cAMP degradation inhibitor IBMX significantly blocked the increase in AAT1 knockdown-induced MC degranulation. Furthermore, in hypoxia-stimulated MCs, AAT1 protein expression and SO(2) production were markedly down regulated, and MC degranulation was activated, which were blunted by AAT1 overexpression. The cAMP synthesis inhibitor SQ22536 disrupted the suppressive effect of AAT1 overexpression on hypoxia-induced MC degranulation. In a hypoxic environment, mRNA and protein expression of AAT1 was significantly reduced in lung tissues of rats. Supplementation of SO(2) elevated the cAMP level and reduced perivascular MC accumulation and degranulation in lung tissues of rats exposed to a hypoxic environment in vivo. CONCLUSION: SO(2) serves as an endogenous MC stabilizer via upregulating the cAMP pathway under hypoxic circumstance. Elsevier 2020-09-08 /pmc/articles/PMC8020161/ /pubmed/33842005 http://dx.doi.org/10.1016/j.jare.2020.08.017 Text en © 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Basic and Biological Science
Zhang, Lulu
Jin, Hongfang
Song, Yunjia
Chen, Selena Ying
Wang, Yi
Sun, Yan
Tang, Chaoshu
Du, Junbao
Huang, Yaqian
Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation
title Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation
title_full Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation
title_fullStr Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation
title_full_unstemmed Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation
title_short Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation
title_sort endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation
topic Basic and Biological Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020161/
https://www.ncbi.nlm.nih.gov/pubmed/33842005
http://dx.doi.org/10.1016/j.jare.2020.08.017
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