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Inhibition of 15-prostaglandin dehydrogenase attenuates acetaminophen-induced liver injury via suppression of apoptosis in liver endothelial cells.
Shimada, Hiroaki; Yokotobi, Akito; Yamamoto, Nonoka; Takada, Mao; Kawase, Atsushi; Nakanishi, Takeo; Iwaki, Masahiro.
Afiliación
  • Shimada H; Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan. Electronic address: shimada@phar.kindai.ac.jp.
  • Yokotobi A; Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan.
  • Yamamoto N; Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan.
  • Takada M; Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan.
  • Kawase A; Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan.
  • Nakanishi T; Department of Pharmacy, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki 370-0033, Japan.
  • Iwaki M; Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan.
Prostaglandins Leukot Essent Fatty Acids ; 202: 102640, 2024 Mar.
Article en En | MEDLINE | ID: mdl-39217773
ABSTRACT
Hepatic microvascular disruption caused by injury to liver sinusoidal endothelial cells (LSECs) is an aggravating factor for drug-induced liver injury (DILI). It is suggested that prostaglandin E2 (PGE2) may be able to attenuate LSEC injury. However, it is also known that 15-keto PGE2, a metabolite of PGE2 produced by 15-prostaglandin dehydrogenase (15-PGDH) that is not a ligand of PGE2 receptors, suppresses inflammatory acute liver injury as a ligand of peroxisome proliferator-activated receptor γ. In this study, we aimed to understand whether 15-PGDH activity is essential for preventing DILI by suppressing hepatic microvascular disruption in a mouse model of acetaminophen (APAP)-induced liver injury. To inhibit 15-PGDH activity prior to APAP-induced LSEC injury, we administered the 15-PGDH inhibitor, SW033291, 1 h before and 3 h after APAP treatment. We observed that LSEC injury preceded hepatocellular injury in APAP administered mice. Hepatic endogenous PGE2 levels did not increase up till the initiation of LSEC injury but rather increased after hepatocellular injury. Moreover, hepatic 15-PGDH activity was downregulated in APAP-induced liver injury. The inhibition of 15-PGDH attenuated LSEC injury and subsequently hepatic injury by inhibiting apoptosis in APAP administered mice. Our in vitro studies also suggested that PGE2 inhibited APAP-induced apoptosis via the EP4/PI3K pathway in endothelial cells. Therefore, a decrease in 15-PGDH activity would be beneficial for preventing APAP-induced liver injury by attenuating LSEC injury.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dinoprostona / Hidroxiprostaglandina Deshidrogenasas / Apoptosis / Células Endoteliales / Enfermedad Hepática Inducida por Sustancias y Drogas / Hígado / Acetaminofén Límite: Animals Idioma: En Revista: Prostaglandins Leukot Essent Fatty Acids Asunto de la revista: ENDOCRINOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dinoprostona / Hidroxiprostaglandina Deshidrogenasas / Apoptosis / Células Endoteliales / Enfermedad Hepática Inducida por Sustancias y Drogas / Hígado / Acetaminofén Límite: Animals Idioma: En Revista: Prostaglandins Leukot Essent Fatty Acids Asunto de la revista: ENDOCRINOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido