{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T18:09:42Z","timestamp":1789927782006,"version":"4.0.1"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2010,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,3]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>There is no effective therapy for advanced liver fibrosis. Angiotensin type 1 (AT1) receptor blockers attenuate liver fibrogenesis, yet their efficacy in reversing advanced fibrosis is unknown. We investigated whether the specific delivery of an AT1 receptor blocker to activated hepatic stellate cells (HSCs) reduces established liver fibrosis. We used a platinum-based linker to develop a conjugate of the AT1 receptor blocker losartan and the HSC-selective drug carrier mannose-6-phosphate modified human serum albumin (losartan-M6PHSA). An average of seven losartan molecules were successfully coupled to M6PHSA. Rats with advanced liver fibrosis due to prolonged bile duct ligation or carbon tetrachloride administration were treated with daily doses of saline, losartan-M6PHSA, M6PHSA or oral losartan during 3 days. Computer-based morphometric quantification of inflammatory cells (CD43), myofibroblasts (smooth muscle \u03b1-actin [\u03b1-SMA]) and collagen deposition (Sirius red and hydroxyproline content) were measured. Hepatic expression of procollagen \u03b12(I) and genes involved in fibrogenesis was assessed by quantitative polymerase chain reaction. Losartan-M6PHSA accumulated in the fibrotic livers and colocalized with HSCs, as assessed by immunostaining of anti-HSA and anti\u2013\u03b1-SMA. Losartan-M6PHSA, but not oral losartan, reduced collagen deposition, accumulation of myofibroblasts, inflammation and procollagen \u03b12(I) gene expression. Losartan-M6PHSA did not affect metalloproteinase type 2 and 9 activity and did not cause apoptosis of activated HSCs.<\/jats:bold>\n                      <jats:bold>Conclusion:<\/jats:bold>\n                      <jats:bold>Short-term treatment with HSC-targeted losartan markedly reduces advanced liver fibrosis. This approach may provide a novel means to treat chronic liver diseases. (Hepatology 2010.)<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.23419","type":"journal-article","created":{"date-parts":[[2009,11,9]],"date-time":"2009-11-09T09:32:51Z","timestamp":1257759171000},"page":"942-952","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":81,"title":["Reduction of Advanced Liver Fibrosis by Short-Term Targeted Delivery of An Angiotensin Receptor Blocker to Hepatic Stellate Cells in Rats"],"prefix":"10.1097","volume":"51","author":[{"given":"Montserrat","family":"Moreno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Gonzalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robbert J.","family":"Kok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pau","family":"Sancho-Bru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marike","family":"van Beuge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josine","family":"Swart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jai","family":"Prakash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Temming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantino","family":"Fondevila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Beljaars","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Lacombe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"van der Hoeven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Arroyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaas","family":"Poelstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Brenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pere","family":"Gin\u00e8s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram\u00f3n","family":"Bataller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-25-20241201","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis.","volume":"115","author":"Bataller","year":"2005","journal-title":"J Clin Invest"},{"key":"R2-25-20241201","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1053\/gast.2002.33367","article-title":"Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C.","volume":"122","author":"Arthur","year":"2002","journal-title":"Gastroenterology"},{"key":"R4-25-20241201","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1089\/ars.2005.7.1346","article-title":"Liver fibrogenesis: a new role for the reninangiotensin system.","volume":"7","author":"Bataller","year":"2005","journal-title":"Antioxid Redox Signal"},{"key":"R5-25-20241201","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1053\/gast.2002.36561","article-title":"Upregulation of components of the reninangiotensin system in the bile ductligated rat liver.","volume":"123","author":"Paizis","year":"2002","journal-title":"Gastroenterology"},{"key":"R6-25-20241201","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1172\/JCI18212","article-title":"NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis.","volume":"112","author":"Bataller","year":"2003","journal-title":"J Clin Invest"},{"key":"R7-25-20241201","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1007\/s00535-008-2239-9","article-title":"Angiotensin receptor blockers are superior to angiotensinconverting enzyme inhibitors in the suppression of hepatic fibrosis in a bile ductligated rat model.","volume":"43","author":"Kim","year":"2008","journal-title":"J Gastroenterol"},{"key":"R8-25-20241201","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.jhep.2005.02.034","article-title":"Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice.","volume":"43","author":"Yang","year":"2005","journal-title":"J Hepatol"},{"key":"R9-25-20241201","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1002\/hep.510290526","article-title":"Albumin modified with mannose 6phosphate: A potential carrier for selective delivery of antifibrotic drugs to rat and human hepatic stellate cells.","volume":"29","author":"Beljaars","year":"1999","journal-title":"HEPATOLOGY"},{"key":"R10-25-20241201","first-page":"1429","article-title":"Insulinlike growth factorIImannose 6phosphate receptor is expressed on CCl4exposed rat fatstoring cells and facilitates activation of latent transforming growth factorbeta in cocultures with sinusoidal endothelial cells.","volume":"21","author":"de Bleser","year":"1995","journal-title":"HEPATOLOGY"},{"key":"R11-25-20241201","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.jconrel.2005.12.010","article-title":"Selective targeting of pentoxifylline to hepatic stellate cells using a novel platinumbased linker technology.","volume":"111","author":"Gonzalo","year":"2006","journal-title":"J Control Release"},{"key":"R12-25-20241201","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.jhep.2005.04.014","article-title":"Studies on the targeted delivery of the antifibrogenic compound mycophenolic acid to the hepatic stellate cell.","volume":"43","author":"Greupink","year":"2005","journal-title":"J Hepatol"},{"key":"R13-25-20241201","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1002\/cmdc.200600201","article-title":"Rational design of RGDalbumin conjugates for targeted delivery of the VEGFR kinase inhibitor PTK787 to angiogenic endothelium.","volume":"1","author":"Temming","year":"2006","journal-title":"ChemMedChem"},{"key":"R14-25-20241201","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1021\/bc0600158","article-title":"Delivery of the p38 MAPkinase inhibitor SB202190 to angiogenic endothelial cells: development of novel RGDequipped and PEGylated drugalbumin conjugates using platinum(II)based drug linker technology.","volume":"17","author":"Temming","year":"2006","journal-title":"Bioconjug Chem"},{"key":"R15-25-20241201","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1124\/jpet.106.106054","article-title":"Intracellular delivery of the p38 mitogenactivated protein kinase inhibitor SB202190 4(4fluorophenyl)2(4hydroxyphenyl)5(4pyridyl)1Himidazole in renal tubular cells: a novel strategy to treat renal fibrosis.","volume":"319","author":"Prakash","year":"2006","journal-title":"J Pharmacol Exp Ther"},{"key":"R16-25-20241201","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1034\/j.1600-0676.2001.210504.x","article-title":"Characteristics of the hepatic stellate cellselective carrier mannose 6phosphate modified albumin (M6P(28)HSA).","volume":"21","author":"Beljaars","year":"2001","journal-title":"Liver"},{"key":"R17-25-20241201","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1002\/hep.20665","article-title":"Systemic infusion of angiotensin II exacerbates liver fibrosis in bile ductligated rats.","volume":"41","author":"Bataller","year":"2005","journal-title":"HEPATOLOGY"},{"key":"R18-25-20241201","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1016\/S0002-9440(10)64331-3","article-title":"Nitric oxide synthase 3dependent vascular remodeling and circulatory dysfunction in cirrhosis.","volume":"162","author":"FernandezVaro","year":"2003","journal-title":"Am J Pathol"},{"key":"R19-25-20241201","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/S0168-8278(98)80153-0","article-title":"Targeting of sugarand chargemodified albumins to fibrotic rat livers: the accessibility of hepatic cells after chronic bile duct ligation.","volume":"29","author":"Beljaars","year":"1998","journal-title":"J Hepatol"},{"key":"R20-25-20241201","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/S0168-8278(02)00307-0","article-title":"Hemodynamic and antifibrotic effects of losartan in rats with liver fibrosis andor portal hypertension.","volume":"37","author":"Croquet","year":"2002","journal-title":"J Hepatol"},{"key":"R21-25-20241201","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1023\/B:DDAS.0000043369.88701.5b","article-title":"Effect of losartan, an angiotensin II antagonist, on hepatic fibrosis induced by CCl4 in rats.","volume":"49","author":"Wei","year":"2004","journal-title":"Dig Dis Sci"},{"key":"R22-25-20241201","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1159\/000060162","article-title":"Angiotensin II, TGFbeta and renal fibrosis.","volume":"135","author":"Gaedeke","year":"2001","journal-title":"Contrib Nephrol"},{"key":"R24-25-20241201","doi-asserted-by":"crossref","first-page":"3611","DOI":"10.1073\/pnas.0737293100","article-title":"New clues for platinum antitumor chemistry: kinetically controlled metal binding to DNA.","volume":"100","author":"Reedijk","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R25-25-20241201","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1124\/jpet.106.114496","article-title":"Local inhibition of liver fibrosis by specific delivery of a plateletderived growth factor kinase inhibitor to hepatic stellate cells.","volume":"321","author":"Gonzalo","year":"2007","journal-title":"J Pharmacol Exp Ther"},{"key":"R26-25-20241201","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1023\/B:DDAS.0000043369.88701.5b","article-title":"Effect of losartan, an angiotensin II antagonist, on hepatic fibrosis induced by CCl4 in rats.","volume":"49","author":"Wei","year":"2004","journal-title":"Dig Dis Sci"},{"key":"R27-25-20241201","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/S0168-8278(02)00307-0","article-title":"Hemodynamic and antifibrotic effects of losartan in rats with liver fibrosis andor portal hypertension.","volume":"37","author":"Croquet","year":"2002","journal-title":"J Hepatol"},{"key":"R28-25-20241201","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/S0016-5085(00)70368-4","article-title":"Angiotensin II induces contraction and proliferation of human hepatic stellate cells.","volume":"118","author":"Bataller","year":"2000","journal-title":"Gastroenterology"},{"key":"R29-25-20241201","doi-asserted-by":"crossref","first-page":"d1899","DOI":"10.2741\/A887","article-title":"Chemokines in liver inflammation and fibrosis.","volume":"7","author":"Marra","year":"2002","journal-title":"Front Biosci"},{"key":"R30-25-20241201","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1053\/gast.2001.25480","article-title":"Angiotensinconverting enzyme inhibition attenuates the progression of rat hepatic fibrosis.","volume":"121","author":"Jonsson","year":"2001","journal-title":"Gastroenterology"},{"key":"R31-25-20241201","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1159\/000069792","article-title":"AngiotensinIconverting enzyme inhibitors may be an alternative antiangiogenic strategy in the treatment of liver fibrosis and hepatocellular carcinoma. Possible role of vascular endothelial growth factor.","volume":"23","author":"Yoshiji","year":"2002","journal-title":"Tumour Biol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.23419","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201003000-00025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T08:32:09Z","timestamp":1733041929000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201003000-00025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,3]]},"references-count":29,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2010]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.23419","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.2478961.2118059","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.2478961.793499781","asserted-by":"object"}]},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2010,3]]}}}