- Email: [email protected]
The Bridge – June 2002
Journal of Hepatology 36 (2002) 717 www.elsevier.com/locate/jhep
The Bridge – June 2002 Organic anion transporters in a rat model of primary sclerosing cholangitis (pages 718–724) Geier and colleagues use a novel animal model – developed by the same authors – to study regulation of different organic anion transporters in the basolateral (ntcp, oatp 1, 2 and 4) and canalicular (bsep and mrp2) side of hepatocytes. PSC is induced by instilling 2,4,6-trinitrobenzene sulfonic acid (TNBS) into predilated bile ducts (for further details on this model consult their reference 15). One week after TNBS instillation, mRNA for all carriers was down regulated. However, 12 weeks after instillation when there is established biliary fibrosis only ntcp (mediating sodium-dependent bile salt uptake, oatp4 and mrp2 (the canalicular bilirubin carrier) remained down regulated on the mRNA level. On the protein level, only oatp1 and mrp2 were decreased after 12 weeks. The authors ascribe this to cytokines released from inflammatory cells; another explanation could be regeneration since similar changes can be observed after partial hepatectomy. Besides the interest in this as an apparently close model of human PSC the authors should also be commended to give the new nomenclature of anion carriers only in parentheses; who can remember which protein is represented by slc21a5 or abcb11... Inflammatory cytokines: regulation of hepatocyte apoptosis by NF-kB, NO synthase and metabolic effects (pages 742–750, 759–765) Shoemaker et al. use a cytokine mixture to induce apoptosis in cultured hepatocytes as a model of fulminant hepatic failure. Using an array of adenoviral constructs interfering with different signalling pathways they unequivocally demonstrate that NF-kB activation protects from apoptosis; this is, at least in part, mediated by inhibitor of apoptosis protein 2. The IAP family members – of which there are several expressed in hepatocytes – are potent inhibitors of caspases, important effectors of apoptotic cell death. The pivotal role of NFkB as a sensor and effector of apoptosis is reviewed in the accompanying editorial by Schuchmann and Galle (pages 827–828). A similar approach but with another aim is taken by Kitano and colleagues. Using inducible NO synthase knock-out mice and their controls they demonstrate that iNOS or NOS2 mediates the insulindependent pathways altered by the cytokines but not glycogen synthesis. Part of these effects are thought to be due to direct inhibition of mitochondrial respiration by NO. Microwave ablation induces tumor growth in rat hepatoma (pages 774–779) Ohno and coworkers demonstrate that microwave ablation of healthy liver tissue is associated with increased tumor burden and an increase in the proliferation rate of distant hepatic tumor. As suggested by the authors this is most likely due to growth signals due to hepatocyte necrosis. This potentially important observation – together with the recent demonstration by a Spanish group that microwave ablation is associated with increased tumor seeding in man – should lead us to approach this novel therapeutic
Ju¨rg Reichen [email protected] method to hepatic cancer with some caution since it has been introduced into clinical medicine without much scrutiny. However, I would have liked to see an experiment closer to the clinical situation, i.e. does this observation also apply when actual tumor is treated by microwave ablation. Potentially important genes in human cholangiocarcinoma (pages 780–785, 786–792) RCAS1 is an interesting molecule thought to be involved in suppression of the proliferation of activated T-lymphocytes and thereby could be involved in the immune escape of tumors. Initially described in gynecological tumors, it is also expressed in a variety of gastrointestinal tumors. Enjoji and colleagues investigated its expression in cholangiocarcinoma and gallbladder cancer and find that 85 and 96% of intra- and extrahepatic biliary tumors express this protein. Even more interestingly, it is not only found in cancer but also in autoimmune diseases where biliary epithelium is attacked such as primary biliary cirrhosis (74%) and graft-versus-host disease (67%) while in supposedly non-immune mediated forms of cholestasis RCAS1 expression was not observed. I find it very interesting that not only tumors but also immune attacked cells try to mount a defense against invading lymphocytes. If confirmed on a functional level this observation could be very important in judging therapeutic progress in the treatment of autoimmune biliary diseases. Somewhat less surprising is the finding that c-erbB-2 is overexpressed on RNA and protein level in cholangiocarcinoma as reported by Ukita et al. This proto-oncogene expresses a high homology to epidermal growth factor receptor and is known to be overexpressed in many cancers including cholangiocarcinoma. The ‘added value’ of the present investigation is the use of fluorescence in situ hybridization. As in other tumors, there is no correlation between c-erbB-2 expression and other pathological features. Oxidative stress in hepatitis C (pages 805–811) Antioxidants are touted on many websites as adjuncts or sole treatment of hepatitis C. There are even two (albeit small) controlled trials on the use of vitamin E in this disease. Jain and colleagues provide a rationale for such complementary approaches: they find different antioxidants to be decreased in the sera of patients suffering from hepatitis C and conversely, markers of lipid peroxidation to be increased. Although this did correlate with fibrosis score on the biopsy, significant decreases were already found in patients with mild to moderate fibrosis. Individual antioxidants have been investigated before – the merit of the present study is that it studies almost all antioxidants and correlates them with histological severity. While vitamin E and other antioxidants as an adjunct to antiviral therapy (quoted in the paper by Jain) have been disappointing, large-scale and longterm trials of the antifibrotic effect of such treatments are certainly warranted, in particular given the fact that all these substances are cheap and innocuous – and used on a vast scale by patients not involved in clinical trials.
0168-8278/02/$20.00 q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S 0168-827 8(02)00151-4
The Bridge – June 2002 Organic anion transporters in a rat model of primary sclerosing cholangitis (pages 718–724) Geier and colleagues use a novel animal model – developed by the same authors – to study regulation of different organic anion transporters in the basolateral (ntcp, oatp 1, 2 and 4) and canalicular (bsep and mrp2) side of hepatocytes. PSC is induced by instilling 2,4,6-trinitrobenzene sulfonic acid (TNBS) into predilated bile ducts (for further details on this model consult their reference 15). One week after TNBS instillation, mRNA for all carriers was down regulated. However, 12 weeks after instillation when there is established biliary fibrosis only ntcp (mediating sodium-dependent bile salt uptake, oatp4 and mrp2 (the canalicular bilirubin carrier) remained down regulated on the mRNA level. On the protein level, only oatp1 and mrp2 were decreased after 12 weeks. The authors ascribe this to cytokines released from inflammatory cells; another explanation could be regeneration since similar changes can be observed after partial hepatectomy. Besides the interest in this as an apparently close model of human PSC the authors should also be commended to give the new nomenclature of anion carriers only in parentheses; who can remember which protein is represented by slc21a5 or abcb11... Inflammatory cytokines: regulation of hepatocyte apoptosis by NF-kB, NO synthase and metabolic effects (pages 742–750, 759–765) Shoemaker et al. use a cytokine mixture to induce apoptosis in cultured hepatocytes as a model of fulminant hepatic failure. Using an array of adenoviral constructs interfering with different signalling pathways they unequivocally demonstrate that NF-kB activation protects from apoptosis; this is, at least in part, mediated by inhibitor of apoptosis protein 2. The IAP family members – of which there are several expressed in hepatocytes – are potent inhibitors of caspases, important effectors of apoptotic cell death. The pivotal role of NFkB as a sensor and effector of apoptosis is reviewed in the accompanying editorial by Schuchmann and Galle (pages 827–828). A similar approach but with another aim is taken by Kitano and colleagues. Using inducible NO synthase knock-out mice and their controls they demonstrate that iNOS or NOS2 mediates the insulindependent pathways altered by the cytokines but not glycogen synthesis. Part of these effects are thought to be due to direct inhibition of mitochondrial respiration by NO. Microwave ablation induces tumor growth in rat hepatoma (pages 774–779) Ohno and coworkers demonstrate that microwave ablation of healthy liver tissue is associated with increased tumor burden and an increase in the proliferation rate of distant hepatic tumor. As suggested by the authors this is most likely due to growth signals due to hepatocyte necrosis. This potentially important observation – together with the recent demonstration by a Spanish group that microwave ablation is associated with increased tumor seeding in man – should lead us to approach this novel therapeutic
Ju¨rg Reichen [email protected] method to hepatic cancer with some caution since it has been introduced into clinical medicine without much scrutiny. However, I would have liked to see an experiment closer to the clinical situation, i.e. does this observation also apply when actual tumor is treated by microwave ablation. Potentially important genes in human cholangiocarcinoma (pages 780–785, 786–792) RCAS1 is an interesting molecule thought to be involved in suppression of the proliferation of activated T-lymphocytes and thereby could be involved in the immune escape of tumors. Initially described in gynecological tumors, it is also expressed in a variety of gastrointestinal tumors. Enjoji and colleagues investigated its expression in cholangiocarcinoma and gallbladder cancer and find that 85 and 96% of intra- and extrahepatic biliary tumors express this protein. Even more interestingly, it is not only found in cancer but also in autoimmune diseases where biliary epithelium is attacked such as primary biliary cirrhosis (74%) and graft-versus-host disease (67%) while in supposedly non-immune mediated forms of cholestasis RCAS1 expression was not observed. I find it very interesting that not only tumors but also immune attacked cells try to mount a defense against invading lymphocytes. If confirmed on a functional level this observation could be very important in judging therapeutic progress in the treatment of autoimmune biliary diseases. Somewhat less surprising is the finding that c-erbB-2 is overexpressed on RNA and protein level in cholangiocarcinoma as reported by Ukita et al. This proto-oncogene expresses a high homology to epidermal growth factor receptor and is known to be overexpressed in many cancers including cholangiocarcinoma. The ‘added value’ of the present investigation is the use of fluorescence in situ hybridization. As in other tumors, there is no correlation between c-erbB-2 expression and other pathological features. Oxidative stress in hepatitis C (pages 805–811) Antioxidants are touted on many websites as adjuncts or sole treatment of hepatitis C. There are even two (albeit small) controlled trials on the use of vitamin E in this disease. Jain and colleagues provide a rationale for such complementary approaches: they find different antioxidants to be decreased in the sera of patients suffering from hepatitis C and conversely, markers of lipid peroxidation to be increased. Although this did correlate with fibrosis score on the biopsy, significant decreases were already found in patients with mild to moderate fibrosis. Individual antioxidants have been investigated before – the merit of the present study is that it studies almost all antioxidants and correlates them with histological severity. While vitamin E and other antioxidants as an adjunct to antiviral therapy (quoted in the paper by Jain) have been disappointing, large-scale and longterm trials of the antifibrotic effect of such treatments are certainly warranted, in particular given the fact that all these substances are cheap and innocuous – and used on a vast scale by patients not involved in clinical trials.
0168-8278/02/$20.00 q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S 0168-827 8(02)00151-4