Adenoviral expression of a transforming growth factor-β1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated rats
<p>Abstract</p> <p>Background</p> <p>Transforming growth factor-β (TGF-β) is a key mediator in establishing liver fibrosis. Therefore, TGF-β as a causative agent may serve as a primary target for antifibrotic gene therapy approaches. We have previously shown that the ad...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2003-10-01
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| Series: | BMC Gastroenterology |
| Online Access: | http://www.biomedcentral.com/1471-230X/3/29 |
| _version_ | 1818826847425658880 |
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| author | Buettner Reinhard Theuerkauf Ingo Janoschek Nora Treptau Jens Sauer-Lehnen Sibille Arias Monica Gressner Axel M Weiskirchen Ralf |
| author_facet | Buettner Reinhard Theuerkauf Ingo Janoschek Nora Treptau Jens Sauer-Lehnen Sibille Arias Monica Gressner Axel M Weiskirchen Ralf |
| author_sort | Buettner Reinhard |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Transforming growth factor-β (TGF-β) is a key mediator in establishing liver fibrosis. Therefore, TGF-β as a causative agent may serve as a primary target for antifibrotic gene therapy approaches. We have previously shown that the adenoviral delivery of a transgene constitutively expressing a TGF-β1 antisense mRNA blocks TGF-β synthesis in culture-activated hepatic stellate cells and effectively abolishes ongoing fibrogenesis <it>in vitro</it>.</p> <p>Methods</p> <p>Ligature of the common bile duct was used to induce liver fibrosis in rats. The effect of the TGF-β1 antisense on fibrogenesis was analyzed in this model of liver injury.</p> <p>Results</p> <p>In the present study, we demonstrate that the adenoviral vector directs the synthesis of mRNA quantities that are approximately 8000-fold more abundant than endogenous TGF-β1 mRNA. In experimentally injured rat livers induced by ligature of the common bile duct, a model for persistent fibrogenesis and cirrhosis, administration of the adenoviral vector abrogates TGF-β-enhanced production of collagen and α-smooth muscle actin. Furthermore, the number of cells positive for α-smooth muscle actin resulting from active recruitment of activated hepatic stellate cells around the bile ductular structures was significantly reduced in animals after application of Ad5-CMV-AS-TGF-β1. However, the observed elevated serum levels of aspartate aminotransferase, alanine aminotransferase, and bilirubin induced in this obstructive liver injury model were not significantly altered in the presence of the TGF-β antagonist.</p> <p>Conclusion</p> <p>Taken together, our data provides <it>in vivo </it>evidence that the delivery of TGF-β1 antisense mRNA specifically abolishes the diverse effects of direct TGF-β function in ongoing liver fibrogenesis. Therefore, we conclude that the expressed transgene is therapeutically useful for inhibition of TGF-β effects in diverse applications, ranging from clarification of TGF-β function in the course of liver injury to the development of novel gene therapeutic approaches.</p> |
| first_indexed | 2024-12-19T00:34:10Z |
| format | Article |
| id | doaj.art-f9eb2514d253457cb7b5d8b266f9b296 |
| institution | Directory Open Access Journal |
| issn | 1471-230X |
| language | English |
| last_indexed | 2024-12-19T00:34:10Z |
| publishDate | 2003-10-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Gastroenterology |
| spelling | doaj.art-f9eb2514d253457cb7b5d8b266f9b2962022-12-21T20:44:54ZengBMCBMC Gastroenterology1471-230X2003-10-01312910.1186/1471-230X-3-29Adenoviral expression of a transforming growth factor-β1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated ratsBuettner ReinhardTheuerkauf IngoJanoschek NoraTreptau JensSauer-Lehnen SibilleArias MonicaGressner Axel MWeiskirchen Ralf<p>Abstract</p> <p>Background</p> <p>Transforming growth factor-β (TGF-β) is a key mediator in establishing liver fibrosis. Therefore, TGF-β as a causative agent may serve as a primary target for antifibrotic gene therapy approaches. We have previously shown that the adenoviral delivery of a transgene constitutively expressing a TGF-β1 antisense mRNA blocks TGF-β synthesis in culture-activated hepatic stellate cells and effectively abolishes ongoing fibrogenesis <it>in vitro</it>.</p> <p>Methods</p> <p>Ligature of the common bile duct was used to induce liver fibrosis in rats. The effect of the TGF-β1 antisense on fibrogenesis was analyzed in this model of liver injury.</p> <p>Results</p> <p>In the present study, we demonstrate that the adenoviral vector directs the synthesis of mRNA quantities that are approximately 8000-fold more abundant than endogenous TGF-β1 mRNA. In experimentally injured rat livers induced by ligature of the common bile duct, a model for persistent fibrogenesis and cirrhosis, administration of the adenoviral vector abrogates TGF-β-enhanced production of collagen and α-smooth muscle actin. Furthermore, the number of cells positive for α-smooth muscle actin resulting from active recruitment of activated hepatic stellate cells around the bile ductular structures was significantly reduced in animals after application of Ad5-CMV-AS-TGF-β1. However, the observed elevated serum levels of aspartate aminotransferase, alanine aminotransferase, and bilirubin induced in this obstructive liver injury model were not significantly altered in the presence of the TGF-β antagonist.</p> <p>Conclusion</p> <p>Taken together, our data provides <it>in vivo </it>evidence that the delivery of TGF-β1 antisense mRNA specifically abolishes the diverse effects of direct TGF-β function in ongoing liver fibrogenesis. Therefore, we conclude that the expressed transgene is therapeutically useful for inhibition of TGF-β effects in diverse applications, ranging from clarification of TGF-β function in the course of liver injury to the development of novel gene therapeutic approaches.</p>http://www.biomedcentral.com/1471-230X/3/29 |
| spellingShingle | Buettner Reinhard Theuerkauf Ingo Janoschek Nora Treptau Jens Sauer-Lehnen Sibille Arias Monica Gressner Axel M Weiskirchen Ralf Adenoviral expression of a transforming growth factor-β1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated rats BMC Gastroenterology |
| title | Adenoviral expression of a transforming growth factor-β1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated rats |
| title_full | Adenoviral expression of a transforming growth factor-β1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated rats |
| title_fullStr | Adenoviral expression of a transforming growth factor-β1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated rats |
| title_full_unstemmed | Adenoviral expression of a transforming growth factor-β1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated rats |
| title_short | Adenoviral expression of a transforming growth factor-β1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated rats |
| title_sort | adenoviral expression of a transforming growth factor β1 antisense mrna is effective in preventing liver fibrosis in bile duct ligated rats |
| url | http://www.biomedcentral.com/1471-230X/3/29 |
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