Caspase 8 Small Interfering RNA Prevents Acute Liver Failure in Mice
A major concern in therapy of acute liver failure is protection of hepatocytes to prevent apoptosis and maintain liver function. Small interfering RNA (siRNA) is a powerful tool to silence gene expression in mammalian cells. To evaluate the therapeutic efficacy of siRNA in vivo we used different mou...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2003-06, Vol.100 (13), p.7797-7802 |
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| creator | Zender, Lars Hütker, Sebastian Liedtke, Christian Tillmann, Hans Ludger Zender, Steffen Mundt, Bettina Waltemathe, Morlen Gösling, Thomas Flemming, Peer Malek, Nisar Peter Trautwein, Christian Manns, Michael Peter Kühnel, Florian Kubicka, Stefan |
| description | A major concern in therapy of acute liver failure is protection of hepatocytes to prevent apoptosis and maintain liver function. Small interfering RNA (siRNA) is a powerful tool to silence gene expression in mammalian cells. To evaluate the therapeutic efficacy of siRNA in vivo we used different mouse models of acute liver failure. We directed 21-nt siRNAs against caspase 8, which is a key enzyme in death receptor-mediated apoptosis. Systemic application of caspase 8 siRNA results in inhibition of caspase 8 gene expression in the liver, thereby preventing Fas (CD95)-mediated apoptosis. Protection of hepatocytes by caspase 8 siRNA significantly attenuated acute liver damage induced by agonistic Fas (CD95) antibody (Jo2) or by adenovirus expressing Fas ligand (AdFasL). However, in a clinical situation the siRNAs most likely would be applied after the onset of acute liver failure. Therefore we injected caspase 8 siRNA at a time point during AdFasL- and adenovirus wild type (Adwt)-mediated liver failure with already elevated liver transaminases. Improvement of survival due to RNA interference was significant even when caspase 8 siRNA was applied during ongoing acute liver failure. In addition, it is of particular interest that caspase 8 siRNA treatment was successful not only in acute liver failure mediated by specific Fas agonistic agents (Jo2 and AdFasL) but also in acute liver failure mediated by Adwt, which is an animal model reflecting multiple molecular mechanisms involved in human acute viral hepatitis. Consequently, our data raise hope for future successful application of siRNA in patients with acute liver failure. |
| doi_str_mv | 10.1073/pnas.1330920100 |
| format | Article |
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Small interfering RNA (siRNA) is a powerful tool to silence gene expression in mammalian cells. To evaluate the therapeutic efficacy of siRNA in vivo we used different mouse models of acute liver failure. We directed 21-nt siRNAs against caspase 8, which is a key enzyme in death receptor-mediated apoptosis. Systemic application of caspase 8 siRNA results in inhibition of caspase 8 gene expression in the liver, thereby preventing Fas (CD95)-mediated apoptosis. Protection of hepatocytes by caspase 8 siRNA significantly attenuated acute liver damage induced by agonistic Fas (CD95) antibody (Jo2) or by adenovirus expressing Fas ligand (AdFasL). However, in a clinical situation the siRNAs most likely would be applied after the onset of acute liver failure. Therefore we injected caspase 8 siRNA at a time point during AdFasL- and adenovirus wild type (Adwt)-mediated liver failure with already elevated liver transaminases. Improvement of survival due to RNA interference was significant even when caspase 8 siRNA was applied during ongoing acute liver failure. In addition, it is of particular interest that caspase 8 siRNA treatment was successful not only in acute liver failure mediated by specific Fas agonistic agents (Jo2 and AdFasL) but also in acute liver failure mediated by Adwt, which is an animal model reflecting multiple molecular mechanisms involved in human acute viral hepatitis. Consequently, our data raise hope for future successful application of siRNA in patients with acute liver failure.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1330920100</identifier><identifier>PMID: 12810955</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Acute Disease ; Adenoviridae - genetics ; Animals ; Apoptosis ; Biological Sciences ; Blotting, Northern ; Caspase 8 ; Caspase 9 ; Caspases - genetics ; Cell Line ; Fas Ligand Protein ; fas Receptor - metabolism ; Gene Expression Regulation - drug effects ; Hepatocytes ; Hepatocytes - metabolism ; Humans ; Infections ; Kidneys ; Liver ; Liver - pathology ; Liver failure ; Liver Failure - prevention & control ; Medical treatment ; Membrane Glycoproteins - genetics ; Messenger RNA ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Prevention ; Ribonucleic acid ; RNA ; RNA, Small Interfering - genetics ; Rodents ; Small interfering RNA ; Time Factors ; Transfection ; Tumor Cells, Cultured</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2003-06, Vol.100 (13), p.7797-7802</ispartof><rights>Copyright 1993-2003 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Jun 24, 2003</rights><rights>Copyright © 2003, The National Academy of Sciences 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c590t-3c23e2239e7c4cb50936e9217464444205a1e50fdbc04fff157a02e85bedf7c73</citedby><cites>FETCH-LOGICAL-c590t-3c23e2239e7c4cb50936e9217464444205a1e50fdbc04fff157a02e85bedf7c73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/100/13.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3139826$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3139826$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12810955$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zender, Lars</creatorcontrib><creatorcontrib>Hütker, Sebastian</creatorcontrib><creatorcontrib>Liedtke, Christian</creatorcontrib><creatorcontrib>Tillmann, Hans Ludger</creatorcontrib><creatorcontrib>Zender, Steffen</creatorcontrib><creatorcontrib>Mundt, Bettina</creatorcontrib><creatorcontrib>Waltemathe, Morlen</creatorcontrib><creatorcontrib>Gösling, Thomas</creatorcontrib><creatorcontrib>Flemming, Peer</creatorcontrib><creatorcontrib>Malek, Nisar Peter</creatorcontrib><creatorcontrib>Trautwein, Christian</creatorcontrib><creatorcontrib>Manns, Michael Peter</creatorcontrib><creatorcontrib>Kühnel, Florian</creatorcontrib><creatorcontrib>Kubicka, Stefan</creatorcontrib><title>Caspase 8 Small Interfering RNA Prevents Acute Liver Failure in Mice</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>A major concern in therapy of acute liver failure is protection of hepatocytes to prevent apoptosis and maintain liver function. Small interfering RNA (siRNA) is a powerful tool to silence gene expression in mammalian cells. To evaluate the therapeutic efficacy of siRNA in vivo we used different mouse models of acute liver failure. We directed 21-nt siRNAs against caspase 8, which is a key enzyme in death receptor-mediated apoptosis. Systemic application of caspase 8 siRNA results in inhibition of caspase 8 gene expression in the liver, thereby preventing Fas (CD95)-mediated apoptosis. Protection of hepatocytes by caspase 8 siRNA significantly attenuated acute liver damage induced by agonistic Fas (CD95) antibody (Jo2) or by adenovirus expressing Fas ligand (AdFasL). However, in a clinical situation the siRNAs most likely would be applied after the onset of acute liver failure. Therefore we injected caspase 8 siRNA at a time point during AdFasL- and adenovirus wild type (Adwt)-mediated liver failure with already elevated liver transaminases. Improvement of survival due to RNA interference was significant even when caspase 8 siRNA was applied during ongoing acute liver failure. In addition, it is of particular interest that caspase 8 siRNA treatment was successful not only in acute liver failure mediated by specific Fas agonistic agents (Jo2 and AdFasL) but also in acute liver failure mediated by Adwt, which is an animal model reflecting multiple molecular mechanisms involved in human acute viral hepatitis. Consequently, our data raise hope for future successful application of siRNA in patients with acute liver failure.</description><subject>Acute Disease</subject><subject>Adenoviridae - genetics</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological Sciences</subject><subject>Blotting, Northern</subject><subject>Caspase 8</subject><subject>Caspase 9</subject><subject>Caspases - genetics</subject><subject>Cell Line</subject><subject>Fas Ligand Protein</subject><subject>fas Receptor - metabolism</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Hepatocytes</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Infections</subject><subject>Kidneys</subject><subject>Liver</subject><subject>Liver - pathology</subject><subject>Liver failure</subject><subject>Liver Failure - prevention & control</subject><subject>Medical treatment</subject><subject>Membrane Glycoproteins - genetics</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred C57BL</subject><subject>Prevention</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Small Interfering - genetics</subject><subject>Rodents</subject><subject>Small interfering RNA</subject><subject>Time Factors</subject><subject>Transfection</subject><subject>Tumor Cells, Cultured</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0ctvEzEQB2ALgWgonLkgsDhUXLYdv9brA4cotFApPMTjbDnObHHk7Kb2bgT_PY4SNcABfPHB34xm_CPkKYNzBlpcbDqXz5kQYDgwgHtkwsCwqpYG7pMJANdVI7k8IY9yXgGAUQ08JCeMN8UpNSFvZi5vXEba0C9rFyO97gZMLabQ3dDPH6b0U8ItdkOmUz8OSOdhi4leuRDHhDR09H3w-Jg8aF3M-ORwn5JvV5dfZ--q-ce317PpvPLKwFAJzwVyLgxqL_1CgRE1Gs60rGU5HJRjqKBdLjzItm2Z0g44NmqBy1Z7LU7J633fzbhY49KXuZKLdpPC2qWftnfB_vnShe_2pt9aVsu63tWfHepTfztiHuw6ZI8xug77MVstJOPGyP9C1mjDmKoLfPkXXPVj6son2BII12VDU9DFHvnU55ywvZuYgd3FaHcx2mOMpeL574se_SG3Al4dwK7y2K70E1Zro207xjjgj6HQF_-mRTzbi1Ue-nRHBBOm4bX4BYWquK4</recordid><startdate>20030624</startdate><enddate>20030624</enddate><creator>Zender, Lars</creator><creator>Hütker, Sebastian</creator><creator>Liedtke, Christian</creator><creator>Tillmann, Hans Ludger</creator><creator>Zender, Steffen</creator><creator>Mundt, Bettina</creator><creator>Waltemathe, Morlen</creator><creator>Gösling, Thomas</creator><creator>Flemming, Peer</creator><creator>Malek, Nisar Peter</creator><creator>Trautwein, Christian</creator><creator>Manns, Michael Peter</creator><creator>Kühnel, Florian</creator><creator>Kubicka, Stefan</creator><general>National Academy of Sciences</general><general>National Acad Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20030624</creationdate><title>Caspase 8 Small Interfering RNA Prevents Acute Liver Failure in Mice</title><author>Zender, Lars ; 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Small interfering RNA (siRNA) is a powerful tool to silence gene expression in mammalian cells. To evaluate the therapeutic efficacy of siRNA in vivo we used different mouse models of acute liver failure. We directed 21-nt siRNAs against caspase 8, which is a key enzyme in death receptor-mediated apoptosis. Systemic application of caspase 8 siRNA results in inhibition of caspase 8 gene expression in the liver, thereby preventing Fas (CD95)-mediated apoptosis. Protection of hepatocytes by caspase 8 siRNA significantly attenuated acute liver damage induced by agonistic Fas (CD95) antibody (Jo2) or by adenovirus expressing Fas ligand (AdFasL). However, in a clinical situation the siRNAs most likely would be applied after the onset of acute liver failure. Therefore we injected caspase 8 siRNA at a time point during AdFasL- and adenovirus wild type (Adwt)-mediated liver failure with already elevated liver transaminases. Improvement of survival due to RNA interference was significant even when caspase 8 siRNA was applied during ongoing acute liver failure. In addition, it is of particular interest that caspase 8 siRNA treatment was successful not only in acute liver failure mediated by specific Fas agonistic agents (Jo2 and AdFasL) but also in acute liver failure mediated by Adwt, which is an animal model reflecting multiple molecular mechanisms involved in human acute viral hepatitis. Consequently, our data raise hope for future successful application of siRNA in patients with acute liver failure.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>12810955</pmid><doi>10.1073/pnas.1330920100</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acute Disease Adenoviridae - genetics Animals Apoptosis Biological Sciences Blotting, Northern Caspase 8 Caspase 9 Caspases - genetics Cell Line Fas Ligand Protein fas Receptor - metabolism Gene Expression Regulation - drug effects Hepatocytes Hepatocytes - metabolism Humans Infections Kidneys Liver Liver - pathology Liver failure Liver Failure - prevention & control Medical treatment Membrane Glycoproteins - genetics Messenger RNA Mice Mice, Inbred BALB C Mice, Inbred C57BL Prevention Ribonucleic acid RNA RNA, Small Interfering - genetics Rodents Small interfering RNA Time Factors Transfection Tumor Cells, Cultured |
| title | Caspase 8 Small Interfering RNA Prevents Acute Liver Failure in Mice |
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