Study of the expression and regulation of the autocrine loop components of the cyclooxygenase pathway and their implication in aspirin exacerbated respiratory disease

Aspirin exacerbated respiratory disease (AERD) is a clinical syndrome characterized by the combination of nasal polyps (NPs), chronic hypertrophic eosinophilic sinusitis, asthma and severity to any medication that inhibits cyclooxygenase (COX)-1 enzymes, namely aspirin and other non-steroidal anti-i...

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Autor: Machado de Carvalho, Liliana Sofia
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/396213
Acceso en línea:http://hdl.handle.net/10803/396213
Access Level:acceso abierto
Palabra clave:Malalties de l'aparell respiratori
Enfermedades del aparato respiratorio
Respiratory diseases
Antiinflamatoris no esteroïdals
Antiinflamatorios no esteroides
Nonsteroidal anti-inflammatory agents
Ciències de la Salut
616.2
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oai_identifier_str oai:www.tdx.cat:10803/396213
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Study of the expression and regulation of the autocrine loop components of the cyclooxygenase pathway and their implication in aspirin exacerbated respiratory disease
title Study of the expression and regulation of the autocrine loop components of the cyclooxygenase pathway and their implication in aspirin exacerbated respiratory disease
spellingShingle Study of the expression and regulation of the autocrine loop components of the cyclooxygenase pathway and their implication in aspirin exacerbated respiratory disease
Machado de Carvalho, Liliana Sofia
Malalties de l'aparell respiratori
Enfermedades del aparato respiratorio
Respiratory diseases
Antiinflamatoris no esteroïdals
Antiinflamatorios no esteroides
Nonsteroidal anti-inflammatory agents
Ciències de la Salut
616.2
title_short Study of the expression and regulation of the autocrine loop components of the cyclooxygenase pathway and their implication in aspirin exacerbated respiratory disease
title_full Study of the expression and regulation of the autocrine loop components of the cyclooxygenase pathway and their implication in aspirin exacerbated respiratory disease
title_fullStr Study of the expression and regulation of the autocrine loop components of the cyclooxygenase pathway and their implication in aspirin exacerbated respiratory disease
title_full_unstemmed Study of the expression and regulation of the autocrine loop components of the cyclooxygenase pathway and their implication in aspirin exacerbated respiratory disease
title_sort Study of the expression and regulation of the autocrine loop components of the cyclooxygenase pathway and their implication in aspirin exacerbated respiratory disease
dc.creator.none.fl_str_mv Machado de Carvalho, Liliana Sofia
author Machado de Carvalho, Liliana Sofia
author_facet Machado de Carvalho, Liliana Sofia
author_role author
dc.contributor.none.fl_str_mv Picado Vallés, César
Roca i Ferrer, Jordi
Universitat de Barcelona. Facultat de Medicina
dc.subject.none.fl_str_mv Malalties de l'aparell respiratori
Enfermedades del aparato respiratorio
Respiratory diseases
Antiinflamatoris no esteroïdals
Antiinflamatorios no esteroides
Nonsteroidal anti-inflammatory agents
Ciències de la Salut
616.2
topic Malalties de l'aparell respiratori
Enfermedades del aparato respiratorio
Respiratory diseases
Antiinflamatoris no esteroïdals
Antiinflamatorios no esteroides
Nonsteroidal anti-inflammatory agents
Ciències de la Salut
616.2
description Aspirin exacerbated respiratory disease (AERD) is a clinical syndrome characterized by the combination of nasal polyps (NPs), chronic hypertrophic eosinophilic sinusitis, asthma and severity to any medication that inhibits cyclooxygenase (COX)-1 enzymes, namely aspirin and other non-steroidal anti-inflammatory drugs. AERD is characterized by intense inflammation of the respiratory mucosa, with large number of activated tissue eosinophils, mast cells, monocytes, and neutrophils. The persistent inflammation likely contributes to the recurrent development of severe nasal polyposis. The pathogenesis of AERD is not fully understood and many questions remain unsolved. However, several studies have reported that the pathogenic mechanisms of this condition may be due, at least in part, to a marked imbalance in eicosanoid metabolism, possibly increasing and perpetuating the process of inflammation. A central feature of AERD is its association with a profound overproduction and overresponsiveness to cysteinyl leukotrienes (cys-LTs) occurring concomitantly with a marked underproduction and underresponsiveness to prostaglandin (PG) E2, which result in a disproportion between pro-inflammatory and anti-inflammatory mediators. The downregulation of PG pathways impedes its mediators to participate in the attenuation of pro-inflammatory responses. Recent studies have demonstrated that the pattern of cytokine expression could differentiate patients with AERD and patients with asthma or eosinophilic sinusitis who tolerate aspirin. We hypothesized that the characteristics of the inflammatory airway milieu (cytokine profile) in AERD is responsible for the deficient expression of EP2 , modifying its capacity to respond to PGE2, resulting in an altered regulation of the autocrine positive loop of the COX pathway that contributes to the exacerbated inflammation and remodeling processes usually present in AERD. In summary, this study provides evidence supporting the hypothesis that the inflammatory environment in the airways of patients with AERD induces alterations in the expression of EP2. This anomaly alters the induction of interleukin-1 receptor type I (IL-1RI), the main factor receptor responsible for the activation of COX-2 by interleukin (IL)-1β, which, in turn, results in a low production of PGE2 which, associated with the low expression of the EP2 receptor, alters the autocrine feedback loop that regulates the COX pathway. The EP2 receptor plays a central role in the alteration of PGE2 synthesis, since its reestablishment can recover the normal function of the autocrine loop and thereby normalizing the expression and function of all the components that constitute it (IL-1RI, COX-2, microsomal PGE synthase-1 (mPGES-1) and PGE2). The decrease in the synthesis of PGE2 may contribute to the perpetuation of the eosinophilic inflammation and remodeling processes in the airways of patients who suffer from AERD.
publishDate 2015
dc.date.none.fl_str_mv 2015
2016
2016
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/396213
url http://hdl.handle.net/10803/396213
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.format.none.fl_str_mv 240 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869421681013948416
spelling Study of the expression and regulation of the autocrine loop components of the cyclooxygenase pathway and their implication in aspirin exacerbated respiratory diseaseMachado de Carvalho, Liliana SofiaMalalties de l'aparell respiratoriEnfermedades del aparato respiratorioRespiratory diseasesAntiinflamatoris no esteroïdalsAntiinflamatorios no esteroidesNonsteroidal anti-inflammatory agentsCiències de la Salut616.2Aspirin exacerbated respiratory disease (AERD) is a clinical syndrome characterized by the combination of nasal polyps (NPs), chronic hypertrophic eosinophilic sinusitis, asthma and severity to any medication that inhibits cyclooxygenase (COX)-1 enzymes, namely aspirin and other non-steroidal anti-inflammatory drugs. AERD is characterized by intense inflammation of the respiratory mucosa, with large number of activated tissue eosinophils, mast cells, monocytes, and neutrophils. The persistent inflammation likely contributes to the recurrent development of severe nasal polyposis. The pathogenesis of AERD is not fully understood and many questions remain unsolved. However, several studies have reported that the pathogenic mechanisms of this condition may be due, at least in part, to a marked imbalance in eicosanoid metabolism, possibly increasing and perpetuating the process of inflammation. A central feature of AERD is its association with a profound overproduction and overresponsiveness to cysteinyl leukotrienes (cys-LTs) occurring concomitantly with a marked underproduction and underresponsiveness to prostaglandin (PG) E2, which result in a disproportion between pro-inflammatory and anti-inflammatory mediators. The downregulation of PG pathways impedes its mediators to participate in the attenuation of pro-inflammatory responses. Recent studies have demonstrated that the pattern of cytokine expression could differentiate patients with AERD and patients with asthma or eosinophilic sinusitis who tolerate aspirin. We hypothesized that the characteristics of the inflammatory airway milieu (cytokine profile) in AERD is responsible for the deficient expression of EP2 , modifying its capacity to respond to PGE2, resulting in an altered regulation of the autocrine positive loop of the COX pathway that contributes to the exacerbated inflammation and remodeling processes usually present in AERD. In summary, this study provides evidence supporting the hypothesis that the inflammatory environment in the airways of patients with AERD induces alterations in the expression of EP2. This anomaly alters the induction of interleukin-1 receptor type I (IL-1RI), the main factor receptor responsible for the activation of COX-2 by interleukin (IL)-1β, which, in turn, results in a low production of PGE2 which, associated with the low expression of the EP2 receptor, alters the autocrine feedback loop that regulates the COX pathway. The EP2 receptor plays a central role in the alteration of PGE2 synthesis, since its reestablishment can recover the normal function of the autocrine loop and thereby normalizing the expression and function of all the components that constitute it (IL-1RI, COX-2, microsomal PGE synthase-1 (mPGES-1) and PGE2). The decrease in the synthesis of PGE2 may contribute to the perpetuation of the eosinophilic inflammation and remodeling processes in the airways of patients who suffer from AERD.La enfermedad respiratoria exacerbada por antiinflamatorios no esteroides (EREA) se caracteriza por la presencia de asma bronquial, rinosinusitis crónica con pólipos nasales e hipersensibilidad a la aspirina y otros antiinflamatorios no esteroides. La inflamación de las vías aéreas en los pacientes con EREA se ha relacionada con diversas alteraciones en el metabolismo del ácido araquidónico (AA) las cuales podrían contribuir al incremento y perpetuación de los procesos inflamatorios. Además, estudios recientes también han demostrado que el perfil de citocinas (sobreexpresión de interferón (IFN)-γ e interleucina (IL)-4) en las vías aéreas, podría tener un papel relevante en la regulación del metabolismo del AA en la EREA. La hipótesis general del estudio establece que las características del entorno inflamatorio de las vías aéreas (perfil de citocinas) en la EREA es responsable de la expresión deficiente del receptor EP2, modificando su capacidad de responder a la PGE2, lo que provoca una alteración en la regulación del bucle de retroalimentación positivo autocrina de la vía de la COX, lo cual contribuye a la inflamación descontrolada y a los procesos de remodelado de las vías aéreas normalmente presentes en la EREA. En suma, este estudio aporta evidencias que soportan la hipótesis de que el entorno inflamatorio en las vías aéreas de los pacientes con enfermedad respiratoria exacerbada por antiinflamatorios no esteroides induce la alteración en la expresión del receptor EP2 de la PGE2. Esta anomalía altera la inducción del receptor tipo I de la interleucina-1 (IL-1RI), principal responsable de la activación de la COX-2 por la citocina IL-1β, lo que, a su vez, da como resultado una baja producción de PGE2 que asociada a la baja expresión de su receptor EP2 altera el bucle de retroalimentación autocrina que regula la vía de la COX. El receptor EP2 juega un papel central en la alteración de la síntesis de la prostaglandina E2 ya que su reparación permite recuperar el funcionamiento normal del bucle autocrino y con ello la normalización en la expresión y funcionamiento de todos los componentes del mismo (IL-1RI, COX-2, PGE sintasa microsomal-1 (mPGES-1) y PGE2). La disminución en la síntesis de PGE2 contribuye a perpetuar la inflamación eosinofílica y el proceso de remodelado de las vías aéreas de los pacientes con enfermedad respiratoria exacerbada por antiinflamatorios no esteroides.Universitat de BarcelonaPicado Vallés, CésarRoca i Ferrer, JordiUniversitat de Barcelona. Facultat de Medicina201620162015info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion240 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/396213TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/3962132026-06-14T12:46:07Z
score 15,300719

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