Adeno-associated virus mediated interferon-gamma inhibits the progression of hepatic fibrosis in vitro and in vivo

To investigate the effects of adeno-associated virus (AAV) mediated expression of human interferon-gamma for gene therapy in experimental hepatic fibrosis in vitro and in vivo. We constructed the recombinant AAV encoding human INF-gamma (rAAV- INF-gamma) and took the primary rat hepatic stellate cel...

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Published in:World journal of gastroenterology : WJG 2005-07, Vol.11 (26), p.4045-4051
Main Authors: Chen, Miao, Wang, Guang-Ji, Diao, Yong, Xu, Rui-An, Xie, Hai-Tang, Li, Xin-Yan, Sun, Jian-Guo
Format: Article
Language:English
Subjects:
Animals
Basic Research
Carbon Tetrachloride Poisoning - prevention & control
Cells, Cultured
Collagenases - genetics
Dependovirus - genetics
Dependovirus - immunology
Disease Models, Animal
Disease Progression
Humans
Interferon-gamma - pharmacology
Liver - cytology
Liver - drug effects
Liver - immunology
Liver Cirrhosis, Experimental - prevention & control
Liver Function Tests
Matrix Metalloproteinase 13
Rats
Recombinant Proteins
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
Tissue Inhibitor of Metalloproteinase-1 - genetics
Transforming Growth Factor beta - genetics
Virion - immunology
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container_title World journal of gastroenterology : WJG
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creator Chen, Miao
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Xu, Rui-An
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Sun, Jian-Guo
description To investigate the effects of adeno-associated virus (AAV) mediated expression of human interferon-gamma for gene therapy in experimental hepatic fibrosis in vitro and in vivo. We constructed the recombinant AAV encoding human INF-gamma (rAAV- INF-gamma) and took the primary rat hepatic stellate cells and carbon tetrachloride induced rats as the experimental hepatic fibrosis model in vitro and in vivo. Immunocytochemistry analysis was used to reveal the expression of alpha-SMA, the marker protein expressed in hepatic stellate cells. The mRNA expression of TGF-beta, TIMP-1, and MMP-13 were analyzed by RT-PCR method. In vivo study, the hydroxyproline content in liver and serum AST, ALT were also detected. In vitro study, AAV vector could mediated efficient expression of human INF-gamma, which inhibit the activation of hepatic stellate cells, decrease the expression of alpha-SMA and mRNA of TIMP-1, TGF-beta, with the MMP-13 unchanged. In vivo study, the histological examination revealed that rAAV- INF-gamma could inhibit the progression of the hepatic fibrosis. In the rAAV-INF-gamma induced group, the hydroxyproline content and serum AST, ALT level were decreased to 177+/-28 microg/g wet liver, 668.5+/-140.0, 458.4+/-123.5 U/L, compare with the fibrosis control group 236+/-31 microg/g wet liver, 1 019.1+/-276.3, 770.5+/-154.3 U/L, respectively (P
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We constructed the recombinant AAV encoding human INF-gamma (rAAV- INF-gamma) and took the primary rat hepatic stellate cells and carbon tetrachloride induced rats as the experimental hepatic fibrosis model in vitro and in vivo. Immunocytochemistry analysis was used to reveal the expression of alpha-SMA, the marker protein expressed in hepatic stellate cells. The mRNA expression of TGF-beta, TIMP-1, and MMP-13 were analyzed by RT-PCR method. In vivo study, the hydroxyproline content in liver and serum AST, ALT were also detected. In vitro study, AAV vector could mediated efficient expression of human INF-gamma, which inhibit the activation of hepatic stellate cells, decrease the expression of alpha-SMA and mRNA of TIMP-1, TGF-beta, with the MMP-13 unchanged. In vivo study, the histological examination revealed that rAAV- INF-gamma could inhibit the progression of the hepatic fibrosis. In the rAAV-INF-gamma induced group, the hydroxyproline content and serum AST, ALT level were decreased to 177+/-28 microg/g wet liver, 668.5+/-140.0, 458.4+/-123.5 U/L, compare with the fibrosis control group 236+/-31 microg/g wet liver, 1 019.1+/-276.3, 770.5+/-154.3 U/L, respectively (P&lt;0.01). mRNA expression of TIMP-1 in the rAAV-INF-gamma induced rat liver was decreased while no significant change was observed in TGF-beta and MMP-13. All these results indicated that rAAV-INF-gamma has potential effects for gene therapy of hepatic fibrosis, which could inhibit the progression of hepatic fibrosis.</description><identifier>ISSN: 1007-9327</identifier><identifier>EISSN: 2219-2840</identifier><identifier>DOI: 10.3748/wjg.v11.i26.4045</identifier><identifier>PMID: 15996030</identifier><language>eng</language><publisher>United States: Jiangsu Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, No.24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China%Gene Therapy Laboratory, Genome Research Center,The University of Hong Kong, 8S-01, Kadoorie BioScience Bldg,Pokfulam Road, Hong Kong, China</publisher><subject>Animals ; Basic Research ; Carbon Tetrachloride Poisoning - prevention &amp; control ; Cells, Cultured ; Collagenases - genetics ; Dependovirus - genetics ; Dependovirus - immunology ; Disease Models, Animal ; Disease Progression ; Humans ; Interferon-gamma - pharmacology ; Liver - cytology ; Liver - drug effects ; Liver - immunology ; Liver Cirrhosis, Experimental - prevention &amp; control ; Liver Function Tests ; Matrix Metalloproteinase 13 ; Rats ; Recombinant Proteins ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; Tissue Inhibitor of Metalloproteinase-1 - genetics ; Transforming Growth Factor beta - genetics ; Virion - immunology</subject><ispartof>World journal of gastroenterology : WJG, 2005-07, Vol.11 (26), p.4045-4051</ispartof><rights>Copyright © Wanfang Data Co. Ltd. All Rights Reserved.</rights><rights>The Author(s) 2005. Published by Baishideng Publishing Group Inc. All rights reserved. 2005</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c381t-23417be2ee0585baf2811840483171e3be636abc4e507a1acb1bf76587edd9493</citedby><cites>FETCH-LOGICAL-c381t-23417be2ee0585baf2811840483171e3be636abc4e507a1acb1bf76587edd9493</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.wanfangdata.com.cn/images/PeriodicalImages/wjg/wjg.jpg</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502101/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502101/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15996030$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Miao</creatorcontrib><creatorcontrib>Wang, Guang-Ji</creatorcontrib><creatorcontrib>Diao, Yong</creatorcontrib><creatorcontrib>Xu, Rui-An</creatorcontrib><creatorcontrib>Xie, Hai-Tang</creatorcontrib><creatorcontrib>Li, Xin-Yan</creatorcontrib><creatorcontrib>Sun, Jian-Guo</creatorcontrib><title>Adeno-associated virus mediated interferon-gamma inhibits the progression of hepatic fibrosis in vitro and in vivo</title><title>World journal of gastroenterology : WJG</title><addtitle>World J Gastroenterol</addtitle><description>To investigate the effects of adeno-associated virus (AAV) mediated expression of human interferon-gamma for gene therapy in experimental hepatic fibrosis in vitro and in vivo. We constructed the recombinant AAV encoding human INF-gamma (rAAV- INF-gamma) and took the primary rat hepatic stellate cells and carbon tetrachloride induced rats as the experimental hepatic fibrosis model in vitro and in vivo. Immunocytochemistry analysis was used to reveal the expression of alpha-SMA, the marker protein expressed in hepatic stellate cells. The mRNA expression of TGF-beta, TIMP-1, and MMP-13 were analyzed by RT-PCR method. In vivo study, the hydroxyproline content in liver and serum AST, ALT were also detected. In vitro study, AAV vector could mediated efficient expression of human INF-gamma, which inhibit the activation of hepatic stellate cells, decrease the expression of alpha-SMA and mRNA of TIMP-1, TGF-beta, with the MMP-13 unchanged. In vivo study, the histological examination revealed that rAAV- INF-gamma could inhibit the progression of the hepatic fibrosis. In the rAAV-INF-gamma induced group, the hydroxyproline content and serum AST, ALT level were decreased to 177+/-28 microg/g wet liver, 668.5+/-140.0, 458.4+/-123.5 U/L, compare with the fibrosis control group 236+/-31 microg/g wet liver, 1 019.1+/-276.3, 770.5+/-154.3 U/L, respectively (P&lt;0.01). mRNA expression of TIMP-1 in the rAAV-INF-gamma induced rat liver was decreased while no significant change was observed in TGF-beta and MMP-13. All these results indicated that rAAV-INF-gamma has potential effects for gene therapy of hepatic fibrosis, which could inhibit the progression of hepatic fibrosis.</description><subject>Animals</subject><subject>Basic Research</subject><subject>Carbon Tetrachloride Poisoning - prevention &amp; control</subject><subject>Cells, Cultured</subject><subject>Collagenases - genetics</subject><subject>Dependovirus - genetics</subject><subject>Dependovirus - immunology</subject><subject>Disease Models, Animal</subject><subject>Disease Progression</subject><subject>Humans</subject><subject>Interferon-gamma - pharmacology</subject><subject>Liver - cytology</subject><subject>Liver - drug effects</subject><subject>Liver - immunology</subject><subject>Liver Cirrhosis, Experimental - prevention &amp; control</subject><subject>Liver Function Tests</subject><subject>Matrix Metalloproteinase 13</subject><subject>Rats</subject><subject>Recombinant Proteins</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>Tissue Inhibitor of Metalloproteinase-1 - genetics</subject><subject>Transforming Growth Factor beta - genetics</subject><subject>Virion - immunology</subject><issn>1007-9327</issn><issn>2219-2840</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><recordid>eNpVkc1rGzEQxUVoaJyk95zKHnpdd0Yf-3EpBNMmhUAvyVlIu7NrGVsy0tqm_31l1rTpSYz0mzfz9Bh7QFiKWjZfT5txeURcOl4tJUh1xRacY1vyRsIHtkCAumwFr2_YbUobAC6E4h_ZDaq2rUDAgsXHnnwoTUqhc2aivji6eEjFjvq5dH6iOFAMvhzNbmfyxdpZN6ViWlOxj2GMlJILvghDsaa9mVxXDM7GkFzKcNabYiiM7-fiGO7Z9WC2iT5dzjv29uP76-q5fPn19HP1-FJ2osGp5EJibYkTgWqUNQNvELMv2QiskYSlSlTGdpIU1AZNZ9EOdaWamvq-la24Y99m3f3BZjsd-Smard5HtzPxtw7G6f9fvFvrMRy1VMARMAt8mQVOxg_Gj3oTDtHnlXX-dw6geJWpjMGMddlzijT8HYGgzzGdcZ1j0jkmfY4pt3x-v9q_hksu4g9id5I-</recordid><startdate>20050714</startdate><enddate>20050714</enddate><creator>Chen, Miao</creator><creator>Wang, Guang-Ji</creator><creator>Diao, Yong</creator><creator>Xu, Rui-An</creator><creator>Xie, Hai-Tang</creator><creator>Li, Xin-Yan</creator><creator>Sun, Jian-Guo</creator><general>Jiangsu Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, No.24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China%Gene Therapy Laboratory, Genome Research Center,The University of Hong Kong, 8S-01, Kadoorie BioScience Bldg,Pokfulam Road, Hong Kong, China</general><general>Baishideng Publishing Group Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>2B.</scope><scope>4A8</scope><scope>92I</scope><scope>93N</scope><scope>PSX</scope><scope>TCJ</scope><scope>5PM</scope></search><sort><creationdate>20050714</creationdate><title>Adeno-associated virus mediated interferon-gamma inhibits the progression of hepatic fibrosis in vitro and in vivo</title><author>Chen, Miao ; 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We constructed the recombinant AAV encoding human INF-gamma (rAAV- INF-gamma) and took the primary rat hepatic stellate cells and carbon tetrachloride induced rats as the experimental hepatic fibrosis model in vitro and in vivo. Immunocytochemistry analysis was used to reveal the expression of alpha-SMA, the marker protein expressed in hepatic stellate cells. The mRNA expression of TGF-beta, TIMP-1, and MMP-13 were analyzed by RT-PCR method. In vivo study, the hydroxyproline content in liver and serum AST, ALT were also detected. In vitro study, AAV vector could mediated efficient expression of human INF-gamma, which inhibit the activation of hepatic stellate cells, decrease the expression of alpha-SMA and mRNA of TIMP-1, TGF-beta, with the MMP-13 unchanged. In vivo study, the histological examination revealed that rAAV- INF-gamma could inhibit the progression of the hepatic fibrosis. In the rAAV-INF-gamma induced group, the hydroxyproline content and serum AST, ALT level were decreased to 177+/-28 microg/g wet liver, 668.5+/-140.0, 458.4+/-123.5 U/L, compare with the fibrosis control group 236+/-31 microg/g wet liver, 1 019.1+/-276.3, 770.5+/-154.3 U/L, respectively (P&lt;0.01). mRNA expression of TIMP-1 in the rAAV-INF-gamma induced rat liver was decreased while no significant change was observed in TGF-beta and MMP-13. All these results indicated that rAAV-INF-gamma has potential effects for gene therapy of hepatic fibrosis, which could inhibit the progression of hepatic fibrosis.</abstract><cop>United States</cop><pub>Jiangsu Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, No.24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China%Gene Therapy Laboratory, Genome Research Center,The University of Hong Kong, 8S-01, Kadoorie BioScience Bldg,Pokfulam Road, Hong Kong, China</pub><pmid>15996030</pmid><doi>10.3748/wjg.v11.i26.4045</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
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ispartof World journal of gastroenterology : WJG, 2005-07, Vol.11 (26), p.4045-4051
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source Open Access: PubMed Central
subjects Animals
Basic Research
Carbon Tetrachloride Poisoning - prevention & control
Cells, Cultured
Collagenases - genetics
Dependovirus - genetics
Dependovirus - immunology
Disease Models, Animal
Disease Progression
Humans
Interferon-gamma - pharmacology
Liver - cytology
Liver - drug effects
Liver - immunology
Liver Cirrhosis, Experimental - prevention & control
Liver Function Tests
Matrix Metalloproteinase 13
Rats
Recombinant Proteins
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
Tissue Inhibitor of Metalloproteinase-1 - genetics
Transforming Growth Factor beta - genetics
Virion - immunology
title Adeno-associated virus mediated interferon-gamma inhibits the progression of hepatic fibrosis in vitro and in vivo
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