{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:55:24Z","timestamp":1776819324677,"version":"3.51.2"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T00:00:00Z","timestamp":1561420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T00:00:00Z","timestamp":1561420800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:p>Alcoholic liver disease (ALD) is a major cause of liver\u2010related mortality. There is still no US Food and Drug Administration\u2013approved therapy for ALD, and therefore, identifying therapeutic targets is needed. Our previous work demonstrated that ethanol exposure leads to up\u2010regulation of cAMP\u2010degrading phosphodiesterase 4 (PDE4) expression, which compromises normal cAMP signaling in monocytes\/macrophages and hepatocytes. This effect of ethanol on cAMP signaling contributes to dysregulated inflammatory response and altered lipid metabolism. It is unknown whether chronic alcohol consumption in humans alters hepatic PDE4 expression and cAMP signaling and whether inadequate cAMP signaling plays a pathogenic role in alcohol\u2010induced liver injury. Our present work shows that expression of the PDE4 subfamily of enzymes is significantly up\u2010regulated and cAMP levels are markedly decreased in hepatic tissues of patients with severe ALD. We also demonstrate the anti\u2010inflammatory efficacy of roflumilast, a clinically available PDE4 inhibitor, on endotoxin\u2010inducible proinflammatory cytokine production <jats:italic toggle=\"yes\">ex vivo<\/jats:italic> in whole blood of patients with alcoholic hepatitis. Moreover, we demonstrate that ethanol\u2010mediated changes in hepatic PDE4 and cAMP levels play a causal role in liver injury in <jats:italic toggle=\"yes\">in vivo<\/jats:italic> and <jats:italic toggle=\"yes\">in vitro<\/jats:italic> models of ALD. This study employs a drug delivery system that specifically delivers the PDE4 inhibitor rolipram to the liver to avoid central nervous system side effects associated with this drug. Our results show that PDE4 inhibition significantly attenuates ethanol\u2010induced hepatic steatosis and injury through multiple mechanisms, including reduced oxidative and endoplasmic reticulum stress both <jats:italic toggle=\"yes\">in vivo<\/jats:italic> and <jats:italic toggle=\"yes\">in vitro<\/jats:italic>. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Increased PDE4 plays a pathogenic role in the development of ALD; hence, directed interventions aimed at inhibiting PDE4 might be an effective treatment for ALD.<\/jats:p>","DOI":"10.1002\/hep.30761","type":"journal-article","created":{"date-parts":[[2019,5,13]],"date-time":"2019-05-13T14:05:35Z","timestamp":1557756335000},"page":"1958-1971","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":51,"title":["Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to 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