{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:00:37Z","timestamp":1791460837232,"version":"4.3.4"},"reference-count":64,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2009,4,28]],"date-time":"2009-04-28T00:00:00Z","timestamp":1240876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2009,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>Background: <\/jats:bold> Hepatic fibrosis is characterized by a progressive accumulation of fibrillar extracellular matrix (ECM) proteins including collagen, which occurs in most types of chronic liver diseases. Transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2)\/Smad3 signalling plays a central role in tissue fibrogenesis, acting as a potent stimulus of ECM accumulation.<\/jats:p><jats:p><jats:bold>Aim: <\/jats:bold> To evaluate the potential protective role of Smad3 deficiency in the pathogenesis of liver fibrosis induced by dimethylnitrosamine (DMN) in Smad3 null mice.<\/jats:p><jats:p><jats:bold>Methods: <\/jats:bold> Chronic hepatitis\u2010associated fibrosis was induced in 13 Smad3 null and 13 wild\u2010type (WT) mice by intraperitoneal DMN administration (10\u2003\u03bcg\/g body weight\/day) for three consecutive days per week for 6 weeks. The liver was excised for macroscopic examination and histological, morphometric and immunohistochemical (IHC) analyses. For IHC, \u03b1\u2010smooth muscle actin (\u03b1\u2010SMA), collagen types I\u2013III, TGF\u2010\u03b21, connective tissue growth factor (CTGF), Smad3, Smad7 and CD3 antibodies were used.<\/jats:p><jats:p><jats:bold>Results: <\/jats:bold> At macroscopic examination, the liver of DMN\u2010treated Smad3 WT appeared harder with a dark brown colouring and necrotic areas compared with that from null mice. Histological and morphometric evaluation revealed a significantly higher degree of hepatic fibrosis and accumulation of connective tissue in the Smad3 WT compared with null mice. IHC evaluation showed a marked increase in \u03b1\u2010SMA, CTGF, collagen I\u2010III, TGF\u2010\u03b2 and Smad3 staining in the liver of Smad3 WT compared with that in null mice, whereas Smad7 was increased only in null mice.<\/jats:p><jats:p><jats:bold>Conclusions: <\/jats:bold> The results indicate that Smad3 loss confers resistance to the development of DMN\u2010induced hepatic fibrosis. The reduced fibrotic response appears to be due to a reduction of fibrogenic myofibroblast activation and ECM production and accumulation. Smad3 could be a novel target for potential treatment of fibrosis complicating chronic hepatitis.<\/jats:p>","DOI":"10.1111\/j.1478-3231.2009.02011.x","type":"journal-article","created":{"date-parts":[[2009,4,28]],"date-time":"2009-04-28T10:17:43Z","timestamp":1240913863000},"page":"997-1009","source":"Crossref","is-referenced-by-count":90,"title":["Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine\u2010induced hepatic fibrosis in mice"],"prefix":"10.1111","volume":"29","author":[{"given":"Giovanni","family":"Latella","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Vetuschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Sferra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Catitti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"D'Angelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Zanninelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen C.","family":"Flanders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Gaudio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,7,2]]},"reference":[{"key":"e_1_2_6_2_2","first-page":"98","article-title":"Mechanisms of disease","volume":"1","author":"Friedman SL.","year":"2004","journal-title":"mechanisms of hepatic fibrosis and therapeutic implications"},{"key":"e_1_2_6_3_2","first-page":"S22","article-title":"Fibrosis in chronic liver diseases","volume":"42","author":"Pinzani M","year":"2005","journal-title":"diagnosis and management"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24282"},{"key":"e_1_2_6_5_2","doi-asserted-by":"crossref","first-page":"C1","DOI":"10.1152\/ajpcell.1999.277.1.C1","article-title":"Myofibroblasts I. Paracrine cells important in health and disease","volume":"277","author":"Powell DW","year":"1999","journal-title":"Am J Physiol Cell Physiol"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2006.tb00292.x"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.2277"},{"key":"e_1_2_6_8_2","first-page":"860","article-title":"Cirrhosis reversal","volume":"40","author":"Desmet VJ","year":"2004","journal-title":"a duel between dogma and myth"},{"key":"e_1_2_6_9_2","first-page":"539","article-title":"Models of liver fibrosis","volume":"117","author":"Iredale JP.","year":"2007","journal-title":"exploring the dynamic nature of inflammation and repair in a solid organ"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.2000.279.2.G245"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.2741\/reeves"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2006.04.014"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2005.088690"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21806"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M700998200"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00432-X"},{"key":"e_1_2_6_17_2","first-page":"1","article-title":"Smad3","volume":"995","author":"Roberts AB","year":"2003","journal-title":"a key player in pathogenetic mechanisms dependent on TGF-beta"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M100754200"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63289-0"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00151.2001"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2001.25349"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00779.x"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0959-9673.2004.00377.x"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400035101"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(03)00666-8"},{"key":"e_1_2_6_26_2","first-page":"3908","article-title":"Deficient Smad7 expression","volume":"99","author":"Dong C","year":"2002","journal-title":"a putative molecular defect in scleroderma"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6094"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2007.12.103"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00910.2006"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.5.1280"},{"key":"e_1_2_6_31_2","first-page":"27","article-title":"A simplified method to prepare PCR template DNA for screening of transgenic and knockout mice","volume":"40","author":"Ren Li M","year":"2001","journal-title":"Contemp Top Lab Anim Sci"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v12.i8.1211"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031675"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v10.i7.1037"},{"key":"e_1_2_6_35_2","first-page":"1298","article-title":"Apoptosis in lymphoid and parenchymal cells during sepsis","volume":"25","author":"Hotchkiss RS","year":"1997","journal-title":"findings in normal and T- and B-cell-deficient mice"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840200104"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1177\/33.8.2410480"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1177\/37.3.2465335"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00507.2005"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1478-3231.2005.01192.x"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.30083"},{"key":"e_1_2_6_42_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.9.5859"},{"key":"e_1_2_6_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4804(89)90179-0"},{"key":"e_1_2_6_44_2","first-page":"129","article-title":"Dimethylnitrosamine\u2010induced liver injury in rats","volume":"156","author":"George J","year":"2001","journal-title":"the early deposition of collagen"},{"key":"e_1_2_6_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2006.07.002"},{"key":"e_1_2_6_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2006.02.025"},{"key":"e_1_2_6_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9120(00)00170-3"},{"key":"e_1_2_6_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/0168-8278(89)90160-8"},{"key":"e_1_2_6_49_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e05-02-0149"},{"key":"e_1_2_6_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-4652(2001)9999:9999<00::AID-JCP1059>3.0.CO;2-S"},{"key":"e_1_2_6_51_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.8.5390"},{"key":"e_1_2_6_52_2","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2006.070466"},{"key":"e_1_2_6_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302929"},{"key":"e_1_2_6_54_2","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.894"},{"key":"e_1_2_6_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.03.087"},{"key":"e_1_2_6_56_2","first-page":"878","article-title":"Prevention and treatment of intestinal fibrosis","volume":"38","author":"Latella G","year":"2008","journal-title":"up-regulate smad7 or inhibit smad3 expression"},{"key":"e_1_2_6_57_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.02554"},{"key":"e_1_2_6_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2006.01.001"},{"key":"e_1_2_6_59_2","first-page":"242","article-title":"Hepatic fibrosis 2006","volume":"45","author":"Friedman SL","year":"2007","journal-title":"report of the third AASLD single topic conference"},{"key":"e_1_2_6_60_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207728200"},{"key":"e_1_2_6_61_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.2.770"},{"key":"e_1_2_6_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/31693"},{"key":"e_1_2_6_63_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.7.3667"},{"key":"e_1_2_6_64_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.4.2495"},{"key":"e_1_2_6_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81730-4"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1478-3231.2009.02011.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1478-3231.2009.02011.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T18:38:36Z","timestamp":1697135916000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/j.1478-3231.2009.02011.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,7,2]]},"references-count":64,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2009,8]]}},"alternative-id":["10.1111\/j.1478-3231.2009.02011.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1478-3231.2009.02011.x","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,7,2]]}}}