Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation

Background: The emerging role of sphingosine-1-phosphate (S1P) in regulating smooth muscle functions has led to the exploration of the possibility that this sphingolipid could represent a potential therapeutic target in asthma and other lung diseases. Several studies in animal surrogates have sugges...

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Autores: Maguire, Thomas J A, Yung, Stephanie, Ortiz-Zapater, Elena, Kayode, O Stephanie, Till, Stephen, Corrigan, Chris, Siew, Leonard Q C, Knock, Gregory A, Woszczek, Grzegorz
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:INCLIVA
Repositorio:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p17713
Acceso en línea:https://incliva.portalinvestigacion.com/publicaciones/17713
Access Level:acceso abierto
Palabra clave:Asthma
airway contraction
sphingolipids
airway smooth muscle
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spelling Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferationMaguire, Thomas J AYung, StephanieOrtiz-Zapater, ElenaKayode, O StephanieTill, StephenCorrigan, ChrisSiew, Leonard Q CKnock, Gregory AWoszczek, GrzegorzAsthmaairway contractionsphingolipidsairway smooth muscleBackground: The emerging role of sphingosine-1-phosphate (S1P) in regulating smooth muscle functions has led to the exploration of the possibility that this sphingolipid could represent a potential therapeutic target in asthma and other lung diseases. Several studies in animal surrogates have suggested a role for S1P-mediated signaling in the regulation of airway smooth muscle (ASM) contraction, airway hyperresponsiveness, and airway remodeling, but evidence from human studies is lacking.Objective: We sought to compare the responsiveness of the airways to S1P in healthy and asthmatic individuals in vivo, in isolated human airways ex vivo, and in murine airways dissected from healthy and house dust mite (HDM)-sensitized animals. Methods: Airway responsiveness was measured by spirometry during inhalation challenges and by wire myography in airways isolated from human and mouse lungs. Thymidine incorporation and calcium mobilization assays were used to study human ASM cell responses.Results: S1P did not induce contraction of airways isolated from healthy and HDM-exposed mice, nor in human airways. Similarly, there was no airway constriction observed in healthy and asthmatic subjects in response to increasing concentrations of inhaled S1P. However, a 30-minute exposure to S1P induced a significant concentration-dependent enhancement of airway reactivity to methacholine and to histamine in murine and human airways, respectively. HDM-sensitized mice demonstrated a significant increase in methacholine responsiveness, which was not further enhanced by S1P treatment. S1P also concentration-dependently enhanced proliferation of human ASM cells, an effect mediated through S1P receptor type 2, as shown by selective antagonism and S1P receptor type 2 small-interfering RNA knockdown.Conclusions: Our data suggest that S1P released locally into the airways may be involved in the regulation of ASM hyperresponsiveness and hyperplasia, defining a novel target for future therapies. (J Allergy Clin Immunol 2023;152:1131-40.)MOSBY-ELSEVIER2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://incliva.portalinvestigacion.com/publicaciones/17713JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGYISSN: 00916749ISSNe: 10976825reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVAinstname:INCLIVAInglésinfo:eu-repo/semantics/openAccessoai:incliva.fundanetsuite.com:p177132026-06-07T16:35:31Z
dc.title.none.fl_str_mv Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation
title Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation
spellingShingle Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation
Maguire, Thomas J A
Asthma
airway contraction
sphingolipids
airway smooth muscle
title_short Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation
title_full Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation
title_fullStr Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation
title_full_unstemmed Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation
title_sort Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation
dc.creator.none.fl_str_mv Maguire, Thomas J A
Yung, Stephanie
Ortiz-Zapater, Elena
Kayode, O Stephanie
Till, Stephen
Corrigan, Chris
Siew, Leonard Q C
Knock, Gregory A
Woszczek, Grzegorz
author Maguire, Thomas J A
author_facet Maguire, Thomas J A
Yung, Stephanie
Ortiz-Zapater, Elena
Kayode, O Stephanie
Till, Stephen
Corrigan, Chris
Siew, Leonard Q C
Knock, Gregory A
Woszczek, Grzegorz
author_role author
author2 Yung, Stephanie
Ortiz-Zapater, Elena
Kayode, O Stephanie
Till, Stephen
Corrigan, Chris
Siew, Leonard Q C
Knock, Gregory A
Woszczek, Grzegorz
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Asthma
airway contraction
sphingolipids
airway smooth muscle
topic Asthma
airway contraction
sphingolipids
airway smooth muscle
description Background: The emerging role of sphingosine-1-phosphate (S1P) in regulating smooth muscle functions has led to the exploration of the possibility that this sphingolipid could represent a potential therapeutic target in asthma and other lung diseases. Several studies in animal surrogates have suggested a role for S1P-mediated signaling in the regulation of airway smooth muscle (ASM) contraction, airway hyperresponsiveness, and airway remodeling, but evidence from human studies is lacking.Objective: We sought to compare the responsiveness of the airways to S1P in healthy and asthmatic individuals in vivo, in isolated human airways ex vivo, and in murine airways dissected from healthy and house dust mite (HDM)-sensitized animals. Methods: Airway responsiveness was measured by spirometry during inhalation challenges and by wire myography in airways isolated from human and mouse lungs. Thymidine incorporation and calcium mobilization assays were used to study human ASM cell responses.Results: S1P did not induce contraction of airways isolated from healthy and HDM-exposed mice, nor in human airways. Similarly, there was no airway constriction observed in healthy and asthmatic subjects in response to increasing concentrations of inhaled S1P. However, a 30-minute exposure to S1P induced a significant concentration-dependent enhancement of airway reactivity to methacholine and to histamine in murine and human airways, respectively. HDM-sensitized mice demonstrated a significant increase in methacholine responsiveness, which was not further enhanced by S1P treatment. S1P also concentration-dependently enhanced proliferation of human ASM cells, an effect mediated through S1P receptor type 2, as shown by selective antagonism and S1P receptor type 2 small-interfering RNA knockdown.Conclusions: Our data suggest that S1P released locally into the airways may be involved in the regulation of ASM hyperresponsiveness and hyperplasia, defining a novel target for future therapies. (J Allergy Clin Immunol 2023;152:1131-40.)
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://incliva.portalinvestigacion.com/publicaciones/17713
url https://incliva.portalinvestigacion.com/publicaciones/17713
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MOSBY-ELSEVIER
publisher.none.fl_str_mv MOSBY-ELSEVIER
dc.source.none.fl_str_mv JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
ISSN: 00916749
ISSNe: 10976825
reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
instname:INCLIVA
instname_str INCLIVA
reponame_str r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
collection r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
repository.name.fl_str_mv
repository.mail.fl_str_mv
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