{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T18:11:52Z","timestamp":1780078312851,"version":"3.54.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2002,1,1]],"date-time":"2002-01-01T00:00:00Z","timestamp":1009843200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2003,12,30]],"date-time":"2003-12-30T00:00:00Z","timestamp":1072742400000},"content-version":"vor","delay-in-days":728,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Grant-in-Aid for scientific research from the Ministry of Education, Science, and Culture of Japan"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,1]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>During chronic liver injury, transforming growth factor \u03b2 (TGF-\u03b2) plays a prominent role in stimulating liver fibrogenesis by myofibroblast-like cells derived from hepatic stellate cells (HSCs). On the other hand, Smad 7 was recently shown to antagonize the TGF-\u03b2-induced activation of signal-transducing Smads (2 and 3). In this study, we investigated the regulatory mechanisms of the TGF-\u03b2 signals in rat HSCs during acute liver injury and myofibroblasts (MFBs) during chronic liver injury, focusing on the roles of Smad 2 and antagonistic Smad 7. In acute liver injury, HSC-derived TGF-\u03b2 increased plasminogen activator inhibitor type 1 (PAI-1) and \u03b12(I) procollagen (COL1A2) transcripts. Smad 2 in HSCs during liver injury and primary cultured HSCs were activated by an autocrine mechanism, because high levels of Smad 2 phosphorylation and induction of PAI-1 transcript by TGF-\u03b2 were observed in HSCs. Thereafter, Smad 7 induced by TGF-\u03b2 negatively regulated the Smad 2 action. These results indicated that endogenous TGF\u03b2-mediated Smad 7 in HSCs terminated the fibrotic signals mediated by signal-transducing Smads, and might be involved in the transient response to autocrine TGF-\u03b2 signal after acute liver injury. By contrast, Smad 7 was not induced by the autocrine TGF-\u03b2 signal, and constitutive Smad 2 activation was observed in MFBs throughout chronic liver injury, although Smad 7 could inhibit the TGF-\u03b2 signal requiring Smad 2 phosphorylation by activated TGF-\u03b2 receptor in cultured MFBs. This constitutive phosphorylation of Smad 2 by endogenous TGF-\u03b2 under a low level of Smad 7 could be involved in the progression of liver fibrosis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1053\/jhep.2002.30083","type":"journal-article","created":{"date-parts":[[2002,8,25]],"date-time":"2002-08-25T03:46:10Z","timestamp":1030247170000},"page":"49-61","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":151,"title":["Differential regulation of TGF-\u03b2 signal in hepatic stellate cells between acute and chronic rat liver injury"],"prefix":"10.1097","volume":"35","author":[{"given":"Yoshiya","family":"Tahashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Matsuzaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Date","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsunori","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fukiko","family":"Furukawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Sugano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Matsushita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Himeno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Inagaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoichi","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"10.1053\/jhep.2002.30083-BIB1|cit1","first-page":"419","volume-title":"Handbook of experimental pharmacology","author":"Roberts","year":"1990"},{"key":"10.1053\/jhep.2002.30083-BIB2|cit2","first-page":"2842","article-title":"Transforming growth factor production by chemically transformed cells","volume":"41","author":"Moses","year":"1981","journal-title":"Cancer Res"},{"key":"10.1053\/jhep.2002.30083-BIB3|cit3","doi-asserted-by":"crossref","first-page":"5339","DOI":"10.1073\/pnas.78.9.5339","article-title":"New class of transforming growth factors potentiated by epidermal growth factor: Isolation from non-neoplastic tissues","volume":"78","author":"Roberts","year":"1981","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1053\/jhep.2002.30083-BIB4|cit4","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1146\/annurev.biochem.67.1.753","article-title":"TGF-\u03b2 signal transduction","volume":"67","author":"Massagu\u00e8","year":"1998","journal-title":"Annu Rev Biochem"},{"key":"10.1053\/jhep.2002.30083-BIB5|cit5","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0092-8674(00)81556-1","article-title":"Regulation of Smad activity","volume":"100","author":"Wrana","year":"2000","journal-title":"Cell"},{"key":"10.1053\/jhep.2002.30083-BIB6|cit6","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/S0092-8674(00)80303-7","article-title":"The MAD-related protein Smad7 associates with the TGF\u03b2 receptor and functions as an antagonist of TGF\u03b2 signaling","volume":"89","author":"Hayashi","year":"1997","journal-title":"Cell"},{"key":"10.1053\/jhep.2002.30083-BIB7|cit7","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/39369","article-title":"Identification of Smad7, a TGF\u03b2-inducible antagonist of TGF-\u03b2 signaling","volume":"389","author":"Nakao","year":"1997","journal-title":"Nature"},{"key":"10.1053\/jhep.2002.30083-BIB8|cit8","doi-asserted-by":"crossref","first-page":"33412","DOI":"10.1074\/jbc.274.47.33412","article-title":"Regulation of Smad7 promoter by direct association with Smad3 and Smad4","volume":"274","author":"Nagarajan","year":"1999","journal-title":"J Biol Chem"},{"key":"10.1053\/jhep.2002.30083-BIB9|cit9","doi-asserted-by":"crossref","first-page":"11320","DOI":"10.1074\/jbc.275.15.11320","article-title":"Smad3 and Smad4 mediate transcriptional activation of the human Smad7 promoter by transforming growth factor \u03b2","volume":"275","author":"von Gersdorff","year":"2000","journal-title":"J Biol Chem"},{"key":"10.1053\/jhep.2002.30083-BIB10|cit10","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1056\/NEJM199306243282508","article-title":"The cellular basis of hepatic fibrosis. 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