{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:45:12Z","timestamp":1791276312782,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":3956,"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":[[2004,11]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Liver fibrosis is characterized by increased synthesis, and decreased degradation, of extracellular matrix (ECM) within the injured tissue. Decreased ECM degradation results, in part, from increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), which blocks matrix metalloproteinase (MMP) activity. TIMP-1 is also involved in promoting survival of activated hepatic stellate cells (HSCs), a major source of ECM. This study examined the effects of blocking TIMP-1 activity in a clinically relevant model of established liver fibrosis. Rats were treated with carbon tetrachloride (CCl\n                      <jats:sub>4<\/jats:sub>\n                      ), or olive oil control, for 6 weeks; 24 days into the treatment, the rats were administered a neutralizing anti-TIMP-1 antibody derived from a fully human combinatorial antibody library (HuCAL), PBS, or an isotype control antibody. Livers from CCl\n                      <jats:sub>4<\/jats:sub>\n                      -treated rats exhibited substantial damage, including bridging fibrosis, inflammation, and extensive expression of smooth muscle \u03b1-actin (\u03b1-SMA). Compared to controls, rats administered anti-TIMP-1 showed a reduction in collagen accumulation by histological examination and hydroxyproline content. Administration of anti-TIMP-1 resulted in a marked decrease in \u03b1-SMA staining. Zymography analysis showed antibody treatment decreased the activity of MMP-2.\n                      <jats:underline>In conclusion<\/jats:underline>\n                      , administration of a TIMP-1 antibody attenuated CCl\n                      <jats:sub>4<\/jats:sub>\n                      -induced liver fibrosis and decreased HSC activation and MMP-2 activity. (Hepatology 2004.)\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.20425","type":"journal-article","created":{"date-parts":[[2004,9,23]],"date-time":"2004-09-23T09:01:11Z","timestamp":1095930071000},"page":"1106-1115","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":170,"title":["Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats"],"prefix":"10.1097","volume":"40","author":[{"given":"Christopher J.","family":"Parsons","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blair U.","family":"Bradford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clark Q.","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Knorr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Krebs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Kraft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Zahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodo","family":"Brocks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki","family":"Feirt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baisong","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myung-Sam","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roopa","family":"Ramamoorthi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Roldan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggy","family":"Lum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Hirth-Dietrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Tomkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Brenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-12-20241201","doi-asserted-by":"crossref","first-page":"3238","DOI":"10.1016\/S0168-8278(00)80413-4","article-title":"New aspects of hepatic fibrosis.","volume":"32","author":"Brenner","year":"2000","journal-title":"J Hepatol"},{"key":"R2-12-20241201","doi-asserted-by":"crossref","first-page":"52015209","DOI":"10.1128\/MCB.17.9.5201","article-title":"Posttranscriptional regulation of collagen alpha1(I) mRNA in hepatic stellate cells.","volume":"17","author":"Stefanovic","year":"1997","journal-title":"Mol Cell Bio"},{"key":"R3-12-20241201","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1600-0676.1998.tb00120.x","article-title":"Signal transduction in hepatic stellate cells.","volume":"18","author":"Pinzani","year":"1998","journal-title":"Liver"},{"key":"R4-12-20241201","doi-asserted-by":"crossref","first-page":"d808d826","DOI":"10.2741\/reeves","article-title":"Activation of hepatic stellate cells a key issue in liver fibrosis.","volume":"7","author":"Reeves","year":"2002","journal-title":"Front Biosci"},{"key":"R5-12-20241201","doi-asserted-by":"crossref","first-page":"373384","DOI":"10.1055\/s-2001-17552","article-title":"Extracellular matrix degradation and the role of hepatic stellate cells.","volume":"21","author":"Benyon","year":"2001","journal-title":"Semin Liver Dis"},{"key":"R6-12-20241201","doi-asserted-by":"crossref","first-page":"58725876","DOI":"10.1074\/jbc.270.11.5872","article-title":"Matrix metalloproteinase-2 is an interstitial collagenase.","volume":"270","author":"Aimes","year":"1995","journal-title":"J Biol Chem"},{"key":"R7-12-20241201","doi-asserted-by":"crossref","first-page":"267283","DOI":"10.1016\/S0167-4838(99)00279-4","article-title":"Tissue inhibitors of metalloproteinases: evolution, structure and function.","volume":"1477","author":"Brew","year":"2000","journal-title":"Biochim Biophys Acta"},{"key":"R8-12-20241201","doi-asserted-by":"crossref","first-page":"479482","DOI":"10.1023\/A:1012493808790","article-title":"Tissue inhibitors of metalloproteinases and programmed cell death: conundrums, controversies and potential implications.","volume":"6","author":"Mannello","year":"2001","journal-title":"Apoptosis"},{"key":"R9-12-20241201","first-page":"176184","article-title":"Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis.","volume":"24","author":"Iredale","year":"1996","journal-title":"HEPATOLOGY"},{"key":"R10-12-20241201","doi-asserted-by":"crossref","first-page":"821831","DOI":"10.1053\/gast.1996.v110.pm8608892","article-title":"Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver.","volume":"110","author":"Benyon","year":"1996","journal-title":"Gastroenterology"},{"key":"R11-12-20241201","doi-asserted-by":"crossref","first-page":"443453","DOI":"10.1007\/s004180000150","article-title":"Expression of matrix metalloproteinases and their inhibitors during hepatic tissue repair in the rat.","volume":"113","author":"Knittel","year":"2000","journal-title":"Histochem Cell Biol"},{"key":"R12-12-20241201","doi-asserted-by":"crossref","first-page":"787795","DOI":"10.1002\/hep.1840210328","article-title":"Increased expression of matrix metalloproteinase-II in experimental liver fibrosis in rats.","volume":"21","author":"Takahara","year":"1995","journal-title":"HEPATOLOGY"},{"key":"R13-12-20241201","doi-asserted-by":"crossref","first-page":"G245G249","DOI":"10.1152\/ajpgi.2000.279.2.G245","article-title":"Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis.","volume":"279","author":"Arthur","year":"2000","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R14-12-20241201","doi-asserted-by":"crossref","first-page":"12481254","DOI":"10.1053\/jhep.2000.20521","article-title":"Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model.","volume":"32","author":"Yoshiji","year":"2000","journal-title":"HEPATOLOGY"},{"key":"R15-12-20241201","doi-asserted-by":"crossref","first-page":"850860","DOI":"10.1053\/jhep.2002.35625","article-title":"Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse.","volume":"36","author":"Yoshiji","year":"2002","journal-title":"HEPATOLOGY"},{"key":"R16-12-20241201","doi-asserted-by":"crossref","first-page":"1106911076","DOI":"10.1074\/jbc.M111490200","article-title":"Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects of matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis.","volume":"277","author":"Murphy","year":"2002","journal-title":"J Biol Chem"},{"key":"R17-12-20241201","doi-asserted-by":"crossref","first-page":"48764882","DOI":"10.1093\/nar\/25.24.4876","article-title":"The ClustalX windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools.","volume":"25","author":"Thompson","year":"1997","journal-title":"Nucl Acids Res"},{"key":"R18-12-20241201","doi-asserted-by":"crossref","first-page":"G200G207","DOI":"10.1152\/ajpgi.2001.281.1.G200","article-title":"Attenuation of CCl4-induced hepatic fibrosis by GdCl3 treatment or dietary glycine.","volume":"281","author":"Rivera","year":"2001","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R19-12-20241201","doi-asserted-by":"crossref","first-page":"89100","DOI":"10.1053\/jhep.2001.25349","article-title":"The role of Smad3 in mediating mouse hepatic stellate cell activation.","volume":"34","author":"Schnabl","year":"2001","journal-title":"HEPATOLOGY"},{"key":"R20-12-20241201","doi-asserted-by":"crossref","first-page":"424429","DOI":"10.1016\/0003-2697(80)90481-9","article-title":"Monitoring of collagen and collagen fragments in chromatography of protein mixtures.","volume":"105","author":"Huszar","year":"1980","journal-title":"Anal Biochem"},{"key":"R21-12-20241201","first-page":"G642G651","article-title":"Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and pro-inflammatory events in the liver.","volume":"28","author":"Bataller","year":"2003","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R22-12-20241201","doi-asserted-by":"crossref","first-page":"5786","DOI":"10.1006\/jmbi.1999.3444","article-title":"Functional synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides.","volume":"296","author":"Knappik","year":"2000","journal-title":"J Mol Biol"},{"key":"R23-12-20241201","doi-asserted-by":"crossref","first-page":"3819438205","DOI":"10.1074\/jbc.M303164200","article-title":"Human Combinatorial Fab Library Yielding Specific and Functional Antibodies against the Human Fibroblast Growth Factor Receptor 3.","volume":"278","author":"Rauchenberger","year":"2003","journal-title":"J Biol Chem"},{"key":"R24-12-20241201","doi-asserted-by":"crossref","first-page":"164169","DOI":"10.1006\/jsre.1998.5424","article-title":"Phenobarbital in comparison with carbon tetrachloride and phenobarbital-induced cirrhosis in rat liver regeneration.","volume":"81","author":"Hashimoto","year":"1999","journal-title":"J Surg Res"},{"key":"R25-12-20241201","doi-asserted-by":"crossref","first-page":"242248","DOI":"10.1002\/hep.1840120210","article-title":"Adenosine partially prevents cirrhosis induced by carbon tetrachloride in rats.","volume":"12","author":"Hernandez-Munoz","year":"1990","journal-title":"HEPATOLOGY"},{"key":"R26-12-20241201","first-page":"131146","article-title":"Fat-storing cells and myofibroblasts are involved in the initial phase of carbon tetrachloride-induced hepatic fibrosis in BNBiRij rat.","volume":"75","author":"Seifert","year":"1994","journal-title":"Int J Exp Pathol"},{"key":"R28-12-20241201","doi-asserted-by":"crossref","first-page":"493503","DOI":"10.1053\/jhep.2003.50127","article-title":"Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal.","volume":"37","author":"Bataller","year":"2003","journal-title":"HEPATOLOGY"},{"key":"R29-12-20241201","doi-asserted-by":"crossref","first-page":"427436","DOI":"10.1055\/s-2001-17557","article-title":"Hepatic stellate cell behavior during resolution of liver injury.","volume":"21","author":"Iredale","year":"2001","journal-title":"Semin Liver Dis"},{"key":"R30-12-20241201","doi-asserted-by":"crossref","first-page":"11891199","DOI":"10.1002\/hep.510230538","article-title":"DAmbrosio L, Curto P, Casini A, Mancini R, Jezequel AM, et al. Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis.","volume":"23","author":"Baroni","year":"1996","journal-title":"HEPATOLOGY"},{"key":"R31-12-20241201","doi-asserted-by":"crossref","first-page":"13031313","DOI":"10.1053\/gast.2002.33023","article-title":"Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C.","volume":"122","author":"Poynard","year":"2002","journal-title":"Gastroenterology"},{"key":"R32-12-20241201","first-page":"545549","article-title":"Hepatocyte growth factor promotes liver regeneration and protein synthesis after hepatectomy in cirrhotic rats.","volume":"48","author":"Ogura","year":"2001","journal-title":"Hepatogastroenterology"},{"key":"R33-12-20241201","doi-asserted-by":"crossref","first-page":"247255","DOI":"10.1053\/jhep.2000.9109","article-title":"Inhibition of transforming growth factor beta prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats.","volume":"32","author":"Nakamura","year":"2000","journal-title":"HEPATOLOGY"},{"key":"R34-12-20241201","doi-asserted-by":"crossref","first-page":"474481","DOI":"10.1016\/S0168-8278(01)00169-6","article-title":"Inhibitory effect of Y-27632, a ROCK inhibitor, on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells.","volume":"35","author":"Murata","year":"2001","journal-title":"J Hepatol"},{"key":"R35-12-20241201","doi-asserted-by":"crossref","first-page":"348356","DOI":"10.1159\/000069792","article-title":"Angiotensin-I-converting enzyme inhibitors may be an alternative anti-angiogenic 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"},{"key":"R36-12-20241201","doi-asserted-by":"crossref","first-page":"445458","DOI":"10.1053\/gast.2003.50063","article-title":"Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat.","volume":"124","author":"Iimuro","year":"2003","journal-title":"Gastroenterology"},{"key":"R37-12-20241201","doi-asserted-by":"crossref","first-page":"316319","DOI":"10.3748\/wjg.v9.i2.316","article-title":"Inhibition on the production of collagen type I, III of activated hepatic stellate cells by antisense TIMP-1 recombinant plasmid.","volume":"9","author":"Liu","year":"2003","journal-title":"World J Gastroenterol"},{"key":"R38-12-20241201","doi-asserted-by":"crossref","first-page":"905912","DOI":"10.1095\/biolreprod63.3.905","article-title":"Disruption of the tissue inhibitor of metalloproteinase-1 gene results in altered reproductive cyclicity and uterine morphology in reproductive-age female mice.","volume":"63","author":"Nothnick","year":"2000","journal-title":"Biol Reprod"},{"key":"R39-12-20241201","doi-asserted-by":"crossref","first-page":"H364H371","DOI":"10.1152\/ajpheart.00511.2002","article-title":"Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice.","volume":"284","author":"Creemers","year":"2003","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"R40-12-20241201","doi-asserted-by":"crossref","first-page":"6069","DOI":"10.1046\/j.1523-1755.2002.00403.x","article-title":"Inhibition of apoptosis in rat mesangial cells by tissue inhibitor of metalloproteinase-1.","volume":"62","author":"Lin","year":"2002","journal-title":"Kidney Int"},{"key":"R41-12-20241201","doi-asserted-by":"crossref","first-page":"376381","DOI":"10.1093\/molehr\/5.4.376","article-title":"Secretion of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases into the uterine compartments during early pregnancy.","volume":"5","author":"Riley","year":"1999","journal-title":"Mol Hum Reprod"},{"issue":"Pt 9","key":"R42-12-20241201","first-page":"11471153","article-title":"Cell cycle-associated accumulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) in the nuclei of human gingival fibroblasts.","volume":"111","author":"Zhao","year":"1998","journal-title":"J Cell Sci"},{"key":"R43-12-20241201","doi-asserted-by":"crossref","first-page":"4860","DOI":"10.1016\/S0168-8278(99)80007-5","article-title":"Expression patterns of matrix metalloproteineases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGF-beta1.","volume":"30","author":"Knittel","year":"1999","journal-title":"J Hepatol"},{"key":"R44-12-20241201","doi-asserted-by":"crossref","first-page":"282287","DOI":"10.1172\/JCI115850","article-title":"Human hepatic lipocytes synthesize tissue inhibitor of metalloproteinases-1: Implications for regulation of matrix degradation in liver.","volume":"90","author":"Iredale","year":"1992","journal-title":"J Clin Invest"},{"key":"R45-12-20241201","doi-asserted-by":"crossref","first-page":"22512263","DOI":"10.1016\/j.lfs.2003.09.059","article-title":"Herbal medicine Sho-saiko-to (TJ-9) increases expression matrix metalloproteinases (MMPs) with reduced expression of tissue inhibitor of metalloproteinases (TIMPs) in rat stellate cell.","volume":"74","author":"Sakaida","year":"2004","journal-title":"Life Sciences"},{"key":"R46-12-20241201","doi-asserted-by":"crossref","first-page":"187195","DOI":"10.1016\/j.bbrc.2004.01.038","article-title":"Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet.","volume":"315","author":"Kawaguchi","year":"2004","journal-title":"Biochem and Biophys Res Commun"},{"key":"R47-12-20241201","doi-asserted-by":"crossref","first-page":"465473","DOI":"10.1016\/S0168-8278(01)00177-5","article-title":"Dynamic change of cells expressing MMP-2 mRNA and MT1-MMP mRNA in the recovery from liver fibrosis in the rat.","volume":"35","author":"Watanabe","year":"2001","journal-title":"J Hepatol"},{"key":"R48-12-20241201","doi-asserted-by":"crossref","first-page":"325331","DOI":"10.1053\/jhep.2002.31166","article-title":"Inhibition of rat liver fibrogenesis through noradrenergic antagonism.","volume":"35","author":"Dubuisson","year":"2002","journal-title":"HEPATOLOGY"},{"key":"R49-12-20241201","doi-asserted-by":"crossref","first-page":"677687","DOI":"10.1053\/jhep.2001.27949","article-title":"Adenosine reverses a preestablished CCl4-induced micronodular cirrhosis through enhancing collagenalytic activity and stimulating hepatocyte cell proliferation in rats.","volume":"34","author":"Hernandez-Munoz","year":"2001","journal-title":"HEPATOLOGY"},{"key":"R50-12-20241201","doi-asserted-by":"crossref","first-page":"538549","DOI":"10.1172\/JCI1018","article-title":"Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.","volume":"102","author":"Iredale","year":"1998","journal-title":"J Clin Invest"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.20425","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200411000-00012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T06:31:39Z","timestamp":1733034699000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200411000-00012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,11]]},"references-count":49,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2004]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.20425","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2004,11]]}}}