{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:27:38Z","timestamp":1790270858332,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","license":[{"start":{"date-parts":[[2019,4,22]],"date-time":"2019-04-22T00:00:00Z","timestamp":1555891200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:p>In cirrhosis, liver microvascular dysfunction is a key factor increasing hepatic vascular resistance to portal blood flow, which leads to portal hypertension. De\u2010regulated inflammatory and pro\u2010apoptotic processes due to chronic injury play important roles in the dysfunction of liver sinusoidal cells. The present study aimed at characterizing the effects of the pan\u2010caspase inhibitor emricasan on systemic and hepatic hemodynamics, hepatic cells phenotype, and underlying mechanisms in preclinical models of advanced chronic liver disease. We investigated the effects of 7\u2010day emricasan on hepatic and systemic hemodynamics, liver function, hepatic microcirculatory function, inflammation, fibrosis, hepatic cells phenotype, and paracrine interactions in rats with advanced cirrhosis due to chronic CCl<jats:sub>4<\/jats:sub> administration. The hepato\u2010protective effects of emricasan were additionally investigated in cells isolated from human cirrhotic livers. Cirrhotic rats receiving emricasan showed significantly lower portal pressure than vehicle\u2010treated animals with no changes in portal blood flow, indicating improved vascular resistance. Hemodynamic improvement was associated with significantly better liver function, reduced hepatic inflammation, improved phenotype of hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells and macrophages, and reduced fibrosis. <jats:italic toggle=\"yes\">In vitro<\/jats:italic> experiments demonstrated that emricasan exerted its benefits directly improving hepatocytes\u2019 expression of specific markers and synthetic capacity, and ameliorated nonparenchymal cells through a paracrine mechanism mediated by small extracellular vesicles released by hepatocytes. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: This study demonstrates that emricasan improves liver sinusoidal microvascular dysfunction in cirrhosis, which leads to marked amelioration in fibrosis, portal hypertension and liver function, and therefore encourages its clinical evaluation in the treatment of advanced chronic liver disease.<\/jats:p>","DOI":"10.1002\/hep4.1360","type":"journal-article","created":{"date-parts":[[2019,4,22]],"date-time":"2019-04-22T12:06:02Z","timestamp":1555934762000},"page":"987-1000","source":"Crossref","is-referenced-by-count":55,"title":["Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte\u2010Mediated Paracrine Mechanism"],"prefix":"10.1097","volume":"3","author":[{"given":"Jordi","family":"Gracia\u2010Sancho","sequence":"first","affiliation":[{"name":"Liver Vascular Biology Research Group,Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute,Barcelona,Spain"},{"name":"CIBEREHD,Madrid,Spain"},{"name":"Hepatology, Department of Biomedical Research,Inselspital \u2013 University of Bern,Bern,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol\u00f2","family":"Manicardi","sequence":"additional","affiliation":[{"name":"Liver Vascular Biology Research Group,Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute,Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mart\u00ed","family":"Ortega\u2010Ribera","sequence":"additional","affiliation":[{"name":"Liver Vascular Biology Research Group,Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute,Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Maeso\u2010D\u00edaz","sequence":"additional","affiliation":[{"name":"Liver Vascular Biology Research Group,Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute,Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergi","family":"Guix\u00e9\u2010Muntet","sequence":"additional","affiliation":[{"name":"Liver Vascular Biology Research Group,Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute,Barcelona,Spain"},{"name":"Hepatology, Department of Biomedical Research,Inselspital \u2013 University of Bern,Bern,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anabel","family":"Fern\u00e1ndez\u2010Iglesias","sequence":"additional","affiliation":[{"name":"Liver Vascular Biology Research Group,Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute,Barcelona,Spain"},{"name":"CIBEREHD,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Hide","sequence":"additional","affiliation":[{"name":"Liver Vascular Biology Research Group,Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute,Barcelona,Spain"},{"name":"CIBEREHD,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor","family":"Garc\u00eda\u2010Calder\u00f3","sequence":"additional","affiliation":[{"name":"Liver Vascular Biology Research Group,Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute,Barcelona,Spain"},{"name":"CIBEREHD,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Boyer\u2010D\u00edaz","sequence":"additional","affiliation":[{"name":"Barcelona Liver Bioservices,Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia C.","family":"Contreras","sequence":"additional","affiliation":[{"name":"Conatus Pharmaceuticals,San Diego,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred","family":"Spada","sequence":"additional","affiliation":[{"name":"Conatus Pharmaceuticals,San Diego,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Bosch","sequence":"additional","affiliation":[{"name":"Liver Vascular Biology Research Group,Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute,Barcelona,Spain"},{"name":"CIBEREHD,Madrid,Spain"},{"name":"Hepatology, Department of Biomedical Research,Inselspital \u2013 University of 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