{"title":"Paritaprevir ameliorates experimental acute lung injury in vitro and in vivo","authors":"Rui Ren, Xin Wang, Zehui Xu, Wanglin Jiang","doi":"10.1007/s12272-023-01451-4","DOIUrl":null,"url":null,"abstract":"<div><p>Paritaprevir is a potent inhibitor of the NS3/4A protease used to treat chronic hepatitis C virus infection. However, its therapeutic effect on acute lung injury (ALI) remains to be elucidated. In this study, we investigated the effect of paritaprevir on a lipopolysaccharide (LPS)-induced two-hit rat ALI model. The anti-ALI mechanism of paritaprevir was also studied in human pulmonary microvascular endothelial (HM) cells following LPS-induced injury in <i>vitro</i>. Administration of 30 mg/kg paritaprevir for 3 days protected rats from LPS-induced ALI, as reflected by the changes in the lung coefficient (from 0.75 to 0.64) and lung pathology scores (from 5.17 to 5.20). Furthermore, the levels of the protective adhesion protein VE-cadherin and tight junction protein claudin-5 increased, and the cytoplasmic p-FOX-O1 and nuclear β-catenin and FOX-O1 levels decreased. Similar effects were observed in vitro with LPS-treated HM cells, including decreased nuclear β-catenin and FOX-O1 levels and higher VE-cadherin and claudin-5 levels. Moreover, β-catenin inhibition resulted in higher p-FOX-O1 levels in the cytoplasm. These results suggested that paritaprevir could alleviate experimental ALI via the β-catenin/p-Akt/ FOX-O1 signaling pathway.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 6","pages":"564 - 572"},"PeriodicalIF":6.9000,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-023-01451-4.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of Pharmacal Research","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s12272-023-01451-4","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Paritaprevir is a potent inhibitor of the NS3/4A protease used to treat chronic hepatitis C virus infection. However, its therapeutic effect on acute lung injury (ALI) remains to be elucidated. In this study, we investigated the effect of paritaprevir on a lipopolysaccharide (LPS)-induced two-hit rat ALI model. The anti-ALI mechanism of paritaprevir was also studied in human pulmonary microvascular endothelial (HM) cells following LPS-induced injury in vitro. Administration of 30 mg/kg paritaprevir for 3 days protected rats from LPS-induced ALI, as reflected by the changes in the lung coefficient (from 0.75 to 0.64) and lung pathology scores (from 5.17 to 5.20). Furthermore, the levels of the protective adhesion protein VE-cadherin and tight junction protein claudin-5 increased, and the cytoplasmic p-FOX-O1 and nuclear β-catenin and FOX-O1 levels decreased. Similar effects were observed in vitro with LPS-treated HM cells, including decreased nuclear β-catenin and FOX-O1 levels and higher VE-cadherin and claudin-5 levels. Moreover, β-catenin inhibition resulted in higher p-FOX-O1 levels in the cytoplasm. These results suggested that paritaprevir could alleviate experimental ALI via the β-catenin/p-Akt/ FOX-O1 signaling pathway.
期刊介绍:
Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.