Inhibition of 15-prostaglandin dehydrogenase attenuates acetaminophen-induced liver injury via suppression of apoptosis in liver endothelial cells

IF 3
Hiroaki Shimada , Akito Yokotobi , Nonoka Yamamoto , Mao Takada , Atsushi Kawase , Takeo Nakanishi , Masahiro Iwaki
{"title":"Inhibition of 15-prostaglandin dehydrogenase attenuates acetaminophen-induced liver injury via suppression of apoptosis in liver endothelial cells","authors":"Hiroaki Shimada ,&nbsp;Akito Yokotobi ,&nbsp;Nonoka Yamamoto ,&nbsp;Mao Takada ,&nbsp;Atsushi Kawase ,&nbsp;Takeo Nakanishi ,&nbsp;Masahiro Iwaki","doi":"10.1016/j.plefa.2024.102640","DOIUrl":null,"url":null,"abstract":"<div><p>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 E<sub>2</sub> (PGE<sub>2</sub>) may be able to attenuate LSEC injury. However, it is also known that 15-keto PGE<sub>2</sub>, a metabolite of PGE<sub>2</sub> produced by 15-prostaglandin dehydrogenase (15-PGDH) that is not a ligand of PGE<sub>2</sub> 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 PGE<sub>2</sub> 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 <em>in vitro</em> studies also suggested that PGE<sub>2</sub> 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.</p></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"202 ","pages":"Article 102640"},"PeriodicalIF":3.0000,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Prostaglandins, leukotrienes, and essential fatty acids","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0952327824000346","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

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.

Abstract Image

抑制 15-前列腺素脱氢酶可通过抑制肝内皮细胞凋亡减轻对乙酰氨基酚诱发的肝损伤
肝窦内皮细胞(LSECs)损伤导致的肝微血管破坏是药物性肝损伤(DILI)的一个加重因素。有研究表明,前列腺素 E2 (PGE2) 可减轻 LSEC 的损伤。然而,人们也知道,15-酮 PGE2 是由 15-前列腺素脱氢酶(15-PGDH)产生的 PGE2 的代谢产物,它不是 PGE2 受体的配体,但作为过氧化物酶体增殖激活受体 γ 的配体,它能抑制炎症性急性肝损伤。在本研究中,我们旨在了解在对乙酰氨基酚(APAP)诱导的肝损伤小鼠模型中,15-PGDH 的活性是否是通过抑制肝微血管破坏来预防 DILI 的必要条件。为了在 APAP 诱导的 LSEC 损伤之前抑制 15-PGDH 的活性,我们在 APAP 治疗前 1 小时和治疗后 3 小时分别施用了 15-PGDH 抑制剂 SW033291。我们观察到,在施用 APAP 的小鼠中,LSEC 损伤先于肝细胞损伤。肝脏内源性 PGE2 水平在 LSEC 损伤开始前并没有增加,而是在肝细胞损伤后增加。此外,在 APAP 诱导的肝损伤中,肝脏 15-PGDH 活性下调。抑制 15-PGDH 可减轻 LSEC 损伤,并通过抑制 APAP 小鼠的细胞凋亡减轻肝损伤。我们的体外研究还表明,PGE2 可通过 EP4/PI3K 通路抑制 APAP 诱导的内皮细胞凋亡。因此,降低 15-PGDH 的活性有利于通过减轻 LSEC 损伤来预防 APAP 引起的肝损伤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Prostaglandins, leukotrienes, and essential fatty acids
Prostaglandins, leukotrienes, and essential fatty acids Clinical Biochemistry, Endocrinology, Diabetes and Metabolism
CiteScore
5.30
自引率
0.00%
发文量
0
审稿时长
64 days
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信