Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice

Autores
Motiño García-Miguel, Omar; Frances, Daniel Eleazar Antonio; Casanova, Natalia; Fuertes Agudo, Marina; Cucarella, Carme; Flores, Juana M.; Vallejo Cremades, María Teresa; Olmedilla, Luis; Pérez Peña, José; Bañares, Rafael; Boscá, Lisardo; Casado, Marta; Martin Sanz, Paloma
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Liver ischemia and reperfusion injury (IRI) remains a serious clinical problem affecting liver transplantation outcomes. IRI causes up to 10% of early organ failure and predisposes to chronic rejection. Cyclooxygenase-2 (COX-2) is involved in different liver diseases, but the significance of COX-2 in IRI is a matter of controversy. This study was designed to elucidate the role of COX-2 induction in hepatocytes against liver IRI. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were subjected to IRI. hCOX-2-Tg mice exhibited lower grades of necrosis and inflammation than Wt mice, in part by reduced hepatic recruitment and infiltration of neutrophils, with a concomitant decrease in serum levels of proinflammatory cytokines. Moreover, hCOX-2-Tg mice showed a significant attenuation of the IRI-induced increase in oxidative stress and hepatic apoptosis, an increase in autophagic flux, and a decrease in endoplasmic reticulum stress compared to Wt mice. Interestingly, ischemic preconditioning of Wt mice resembles the beneficial effects observed in hCOX-2-Tg mice against IRI due to a preconditioning-derived increase in endogenous COX-2, which is mainly localized in hepatocytes. Furthermore, measurement of prostaglandin E2 (PGE2) levels in plasma from patients who underwent liver transplantation revealed a significantly positive correlation of PGE2 levels and graft function and an inverse correlation with the time of ischemia. Conclusion: These data support the view of a protective effect of hepatic COX-2 induction and the consequent rise of derived prostaglandins against IRI.
Fil: Motiño García-Miguel, Omar. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; España
Fil: Frances, Daniel Eleazar Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Casanova, Natalia. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; España
Fil: Fuertes Agudo, Marina. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; España
Fil: Cucarella, Carme. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; España
Fil: Flores, Juana M.. Universidad Complutense de Madrid; España
Fil: Vallejo Cremades, María Teresa. Hospital Universitario La Paz. Instituto de Investigación; España
Fil: Olmedilla, Luis. Hospital Gregorio Marañón Instituto de Investigación Sanitaria; España
Fil: Pérez Peña, José. Hospital Gregorio Marañón Instituto de Investigación Sanitaria; España
Fil: Bañares, Rafael. Hospital Gregorio Marañón Instituto de Investigación Sanitaria; España
Fil: Boscá, Lisardo. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; España
Fil: Casado, Marta. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; España
Fil: Martin Sanz, Paloma. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; España
Materia
PGE2
COX-2
HYPOXIA
LIVER
transplantation
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/120520
Acceder
id CONICETDig_95e31e9210f37368a7ef876afc579aae
oai_identifier_str oai:ri.conicet.gov.ar:11336/120520
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in MiceMotiño García-Miguel, OmarFrances, Daniel Eleazar AntonioCasanova, NataliaFuertes Agudo, MarinaCucarella, CarmeFlores, Juana M.Vallejo Cremades, María TeresaOlmedilla, LuisPérez Peña, JoséBañares, RafaelBoscá, LisardoCasado, MartaMartin Sanz, PalomaPGE2COX-2HYPOXIALIVERtransplantationhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Liver ischemia and reperfusion injury (IRI) remains a serious clinical problem affecting liver transplantation outcomes. IRI causes up to 10% of early organ failure and predisposes to chronic rejection. Cyclooxygenase-2 (COX-2) is involved in different liver diseases, but the significance of COX-2 in IRI is a matter of controversy. This study was designed to elucidate the role of COX-2 induction in hepatocytes against liver IRI. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were subjected to IRI. hCOX-2-Tg mice exhibited lower grades of necrosis and inflammation than Wt mice, in part by reduced hepatic recruitment and infiltration of neutrophils, with a concomitant decrease in serum levels of proinflammatory cytokines. Moreover, hCOX-2-Tg mice showed a significant attenuation of the IRI-induced increase in oxidative stress and hepatic apoptosis, an increase in autophagic flux, and a decrease in endoplasmic reticulum stress compared to Wt mice. Interestingly, ischemic preconditioning of Wt mice resembles the beneficial effects observed in hCOX-2-Tg mice against IRI due to a preconditioning-derived increase in endogenous COX-2, which is mainly localized in hepatocytes. Furthermore, measurement of prostaglandin E2 (PGE2) levels in plasma from patients who underwent liver transplantation revealed a significantly positive correlation of PGE2 levels and graft function and an inverse correlation with the time of ischemia. Conclusion: These data support the view of a protective effect of hepatic COX-2 induction and the consequent rise of derived prostaglandins against IRI.Fil: Motiño García-Miguel, Omar. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; EspañaFil: Frances, Daniel Eleazar Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Casanova, Natalia. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; EspañaFil: Fuertes Agudo, Marina. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; EspañaFil: Cucarella, Carme. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; EspañaFil: Flores, Juana M.. Universidad Complutense de Madrid; EspañaFil: Vallejo Cremades, María Teresa. Hospital Universitario La Paz. Instituto de Investigación; EspañaFil: Olmedilla, Luis. Hospital Gregorio Marañón Instituto de Investigación Sanitaria; EspañaFil: Pérez Peña, José. Hospital Gregorio Marañón Instituto de Investigación Sanitaria; EspañaFil: Bañares, Rafael. Hospital Gregorio Marañón Instituto de Investigación Sanitaria; EspañaFil: Boscá, Lisardo. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; EspañaFil: Casado, Marta. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; EspañaFil: Martin Sanz, Paloma. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; EspañaJohn Wiley & Sons Inc2019-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/120520Motiño García-Miguel, Omar; Frances, Daniel Eleazar Antonio; Casanova, Natalia; Fuertes Agudo, Marina; Cucarella, Carme; et al.; Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice; John Wiley & Sons Inc; Hepatology (Baltimore, Md.); 70; 2; 8-2019; 650-6650270-9139CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://doi.wiley.com/10.1002/hep.30241info:eu-repo/semantics/altIdentifier/doi/10.1002/hep.30241info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:04:58Zoai:ri.conicet.gov.ar:11336/120520instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:04:58.919CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice
title Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice
spellingShingle Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice
Motiño García-Miguel, Omar
PGE2
COX-2
HYPOXIA
LIVER
transplantation
title_short Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice
title_full Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice
title_fullStr Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice
title_full_unstemmed Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice
title_sort Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice
dc.creator.none.fl_str_mv Motiño García-Miguel, Omar
Frances, Daniel Eleazar Antonio
Casanova, Natalia
Fuertes Agudo, Marina
Cucarella, Carme
Flores, Juana M.
Vallejo Cremades, María Teresa
Olmedilla, Luis
Pérez Peña, José
Bañares, Rafael
Boscá, Lisardo
Casado, Marta
Martin Sanz, Paloma
author Motiño García-Miguel, Omar
author_facet Motiño García-Miguel, Omar
Frances, Daniel Eleazar Antonio
Casanova, Natalia
Fuertes Agudo, Marina
Cucarella, Carme
Flores, Juana M.
Vallejo Cremades, María Teresa
Olmedilla, Luis
Pérez Peña, José
Bañares, Rafael
Boscá, Lisardo
Casado, Marta
Martin Sanz, Paloma
author_role author
author2 Frances, Daniel Eleazar Antonio
Casanova, Natalia
Fuertes Agudo, Marina
Cucarella, Carme
Flores, Juana M.
Vallejo Cremades, María Teresa
Olmedilla, Luis
Pérez Peña, José
Bañares, Rafael
Boscá, Lisardo
Casado, Marta
Martin Sanz, Paloma
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PGE2
COX-2
HYPOXIA
LIVER
transplantation
topic PGE2
COX-2
HYPOXIA
LIVER
transplantation
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Liver ischemia and reperfusion injury (IRI) remains a serious clinical problem affecting liver transplantation outcomes. IRI causes up to 10% of early organ failure and predisposes to chronic rejection. Cyclooxygenase-2 (COX-2) is involved in different liver diseases, but the significance of COX-2 in IRI is a matter of controversy. This study was designed to elucidate the role of COX-2 induction in hepatocytes against liver IRI. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were subjected to IRI. hCOX-2-Tg mice exhibited lower grades of necrosis and inflammation than Wt mice, in part by reduced hepatic recruitment and infiltration of neutrophils, with a concomitant decrease in serum levels of proinflammatory cytokines. Moreover, hCOX-2-Tg mice showed a significant attenuation of the IRI-induced increase in oxidative stress and hepatic apoptosis, an increase in autophagic flux, and a decrease in endoplasmic reticulum stress compared to Wt mice. Interestingly, ischemic preconditioning of Wt mice resembles the beneficial effects observed in hCOX-2-Tg mice against IRI due to a preconditioning-derived increase in endogenous COX-2, which is mainly localized in hepatocytes. Furthermore, measurement of prostaglandin E2 (PGE2) levels in plasma from patients who underwent liver transplantation revealed a significantly positive correlation of PGE2 levels and graft function and an inverse correlation with the time of ischemia. Conclusion: These data support the view of a protective effect of hepatic COX-2 induction and the consequent rise of derived prostaglandins against IRI.
Fil: Motiño García-Miguel, Omar. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; España
Fil: Frances, Daniel Eleazar Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Casanova, Natalia. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; España
Fil: Fuertes Agudo, Marina. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; España
Fil: Cucarella, Carme. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; España
Fil: Flores, Juana M.. Universidad Complutense de Madrid; España
Fil: Vallejo Cremades, María Teresa. Hospital Universitario La Paz. Instituto de Investigación; España
Fil: Olmedilla, Luis. Hospital Gregorio Marañón Instituto de Investigación Sanitaria; España
Fil: Pérez Peña, José. Hospital Gregorio Marañón Instituto de Investigación Sanitaria; España
Fil: Bañares, Rafael. Hospital Gregorio Marañón Instituto de Investigación Sanitaria; España
Fil: Boscá, Lisardo. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; España
Fil: Casado, Marta. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; España
Fil: Martin Sanz, Paloma. Consejo Superior de Investigaciones Científicas; España. Instituto de Biomedicina de Valencia; España
description Liver ischemia and reperfusion injury (IRI) remains a serious clinical problem affecting liver transplantation outcomes. IRI causes up to 10% of early organ failure and predisposes to chronic rejection. Cyclooxygenase-2 (COX-2) is involved in different liver diseases, but the significance of COX-2 in IRI is a matter of controversy. This study was designed to elucidate the role of COX-2 induction in hepatocytes against liver IRI. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were subjected to IRI. hCOX-2-Tg mice exhibited lower grades of necrosis and inflammation than Wt mice, in part by reduced hepatic recruitment and infiltration of neutrophils, with a concomitant decrease in serum levels of proinflammatory cytokines. Moreover, hCOX-2-Tg mice showed a significant attenuation of the IRI-induced increase in oxidative stress and hepatic apoptosis, an increase in autophagic flux, and a decrease in endoplasmic reticulum stress compared to Wt mice. Interestingly, ischemic preconditioning of Wt mice resembles the beneficial effects observed in hCOX-2-Tg mice against IRI due to a preconditioning-derived increase in endogenous COX-2, which is mainly localized in hepatocytes. Furthermore, measurement of prostaglandin E2 (PGE2) levels in plasma from patients who underwent liver transplantation revealed a significantly positive correlation of PGE2 levels and graft function and an inverse correlation with the time of ischemia. Conclusion: These data support the view of a protective effect of hepatic COX-2 induction and the consequent rise of derived prostaglandins against IRI.
publishDate 2019
dc.date.none.fl_str_mv 2019-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/120520
Motiño García-Miguel, Omar; Frances, Daniel Eleazar Antonio; Casanova, Natalia; Fuertes Agudo, Marina; Cucarella, Carme; et al.; Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice; John Wiley & Sons Inc; Hepatology (Baltimore, Md.); 70; 2; 8-2019; 650-665
0270-9139
CONICET Digital
CONICET
url http://hdl.handle.net/11336/120520
identifier_str_mv Motiño García-Miguel, Omar; Frances, Daniel Eleazar Antonio; Casanova, Natalia; Fuertes Agudo, Marina; Cucarella, Carme; et al.; Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia–Reperfusion Injury in Mice; John Wiley & Sons Inc; Hepatology (Baltimore, Md.); 70; 2; 8-2019; 650-665
0270-9139
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://doi.wiley.com/10.1002/hep.30241
info:eu-repo/semantics/altIdentifier/doi/10.1002/hep.30241
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv John Wiley & Sons Inc
publisher.none.fl_str_mv John Wiley & Sons Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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