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The Bridge-October 2003
Journal of Hepatology 39 (2003) 465 www.elsevier.com/locate/jhep
The Bridge – October 2003 Directional calcium signaling is mediated by receptor density (pages 489–495) Hormones which mediate calcium signaling via inositol-1,2,3phosphate include vasopressin and norepinephrine. Propagation of a signal with both hormones results in calcium waves which are known to be directional as demonstrated in hepatocytes multiplets or the perfused rat liver. Clair and colleagues provide an explanation for this fascinating (and beautiful to watch) phenomenon: they demonstrated that in hepatocyte triplets vasopressin receptor 1 density differed between cells and was correlated to the magnitude of the calcium wave in this cell. Cells garnished with more receptors also exhibited a longer delay between ligand binding and the increase in intracellular calcium. In vivo immunohistochemistry in whole liver demonstrated a portal – central venous gradient with pericentral hepatocytes expressing more vasopressin 1 receptor but also adrenergic a1 receptors. This neat piece of cell physiology provides a novel explanation for the directionality of calcium waves. Expanding such studies to other hormones will provide us with a better understanding of how hormones – using the same pathway of increase in intracellular calcium – induce differential answers and propagation of signals across tissue. Endothelial dysfunction in cirrhosis is mediated by thromboxane A2 generated by cyclooxygenase 1 (COX1) (pages 515–521) Endothelial dysfunction describes an altered vascular tone due to an imbalance between vasoconstrictors and vasodilators; in the liver it is responsible for the reversible part of increased vascular resistance and therefore an interesting target for pharmacological intervention. Up to now endothelial dysfunction was considered to be due chiefly to a local deficiency in NO formation. Using the vasodilative response to acetylcholine, Graupera et al. demonstrate that inhibition of COX1 (the constitutive form) but not of COX2 or NO synthase restores the response to acetylcholine of the cirrhotic practically to normal. This is a very important observation; personally, I have always believed that targeting the liver with vasodilators was a good approach to treatment (and have been proven wrong most of the time). This important observation by Graupera opens the door to a better understanding of endothelial dysfunction and to new therapeutic approaches. Differential regulation of protein kinases according to cell type and type of tissue injury (pages 528–537) I have commented on many papers exploring signaling in fibrogenesis; most of them were either performed in cultured cells or in whole liver. Being a devout stereologist this often left me somewhat uncomfortable since it is well established that different models used to introduce cirrhosis lead to livers of different composition with respect to hepatocytes, cholangiocytes and hepatic stellate cells. Svegliati-Baroni and his many collaborators make this point in a paper in this issue which represents a real tour de force: they evaluate mitogen activated
Ju¨rg Reichen [email protected] protein kinases – MAPK, key regulators of cell proliferation – and P70 S6K (a kinase central in the control of translation) in dimethylnitrosamine and bile duct ligation-induced liver injury. The former injures primarily hepatocytes, the latter cholangiocytes. What makes this paper so remarkable is that they carefully evaluate protein mass by Western blotting in liver sections and its activity in the main cellular components, namely isolated hepatocytes, cholangiocytes and hepatic stellate cells (HSC). Both MAPK’s were activated in hepatocytes after dimethylnitrosamine, while only extracellular signal-regulated kinase (ERK) was activated in cholangiocytes after bile duct ligation. In HSC, kinase activation preceded transformation as evidenced by appearance of actin. This paper sets a new standard in the study of fibrogenesis. Microorgans and fulminant failure: Will aLIVE prolong life? (pages 552–558) Many different cell-based liver assist devices have been described; some of them have been put to clinical use as a bridge to transplantation. Grad-Itach and colleagues describe yet another such device representing some smart bioengineering: they put 150 mm cubes of liver tissue into a bioreactor. They chose this size because it represents the distance from the portal tract to the central vein and assures also a short diffusion distance for oxygen and nutrients. The idea behind taking cubes rather than isolated cells was to preserve cell-cell and cell-matrix interactions. In this aim they were successful: the organoids remained viable for up to 7 days in culture and maintained hepatic functions such as albumin and urea production. They named their device aLIVE – and indeed it improved coma and prolonged life in rats after 92% hepatectomy. Apparently, the investigators are already scaling up their system to larger animals. If that is successful, we are looking forward to clinical application of a promising new artificial aLIVEr. Mitochondrial glutathione (GSH) content and liver regeneration (pages 571–579) Mitochondria are exposed by their function to oxygen radicals; this exposure dramatically increases after hepatectomy where mitochondria work at their hardest to keep up with the energy demand of rebuilding the liver. To protect themselves, they need glutathione which they import from the cytoplasm using a specific carrier. Grattagliano and collaborators investigated regenerative capacity, mitochondrial function and GSH content after hepatectomy in GSH-depleted or hypothyroid rats. In both conditions, mitochondrial function was impaired after hepatectomy, in the latter – as one would expect – even at baseline. This was associated with a markedly reduced regenerative capacity. Interestingly and potentially of clinical importance is their finding that GSHethylester could restore GSH stores and regenerative capacity in both conditions of GSH depletion. GSH deficiency in man is probably not rare and could be particularly expected in alcoholic and/or malnourished patients. If the findings of Grattagliano et al. can be translated to man, administration of GSH-ester could potentially prevent liver failure after major hepatic resection.
0168-8278/03/$30.00 q 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/S0168-8278(03)00422-7
The Bridge – October 2003 Directional calcium signaling is mediated by receptor density (pages 489–495) Hormones which mediate calcium signaling via inositol-1,2,3phosphate include vasopressin and norepinephrine. Propagation of a signal with both hormones results in calcium waves which are known to be directional as demonstrated in hepatocytes multiplets or the perfused rat liver. Clair and colleagues provide an explanation for this fascinating (and beautiful to watch) phenomenon: they demonstrated that in hepatocyte triplets vasopressin receptor 1 density differed between cells and was correlated to the magnitude of the calcium wave in this cell. Cells garnished with more receptors also exhibited a longer delay between ligand binding and the increase in intracellular calcium. In vivo immunohistochemistry in whole liver demonstrated a portal – central venous gradient with pericentral hepatocytes expressing more vasopressin 1 receptor but also adrenergic a1 receptors. This neat piece of cell physiology provides a novel explanation for the directionality of calcium waves. Expanding such studies to other hormones will provide us with a better understanding of how hormones – using the same pathway of increase in intracellular calcium – induce differential answers and propagation of signals across tissue. Endothelial dysfunction in cirrhosis is mediated by thromboxane A2 generated by cyclooxygenase 1 (COX1) (pages 515–521) Endothelial dysfunction describes an altered vascular tone due to an imbalance between vasoconstrictors and vasodilators; in the liver it is responsible for the reversible part of increased vascular resistance and therefore an interesting target for pharmacological intervention. Up to now endothelial dysfunction was considered to be due chiefly to a local deficiency in NO formation. Using the vasodilative response to acetylcholine, Graupera et al. demonstrate that inhibition of COX1 (the constitutive form) but not of COX2 or NO synthase restores the response to acetylcholine of the cirrhotic practically to normal. This is a very important observation; personally, I have always believed that targeting the liver with vasodilators was a good approach to treatment (and have been proven wrong most of the time). This important observation by Graupera opens the door to a better understanding of endothelial dysfunction and to new therapeutic approaches. Differential regulation of protein kinases according to cell type and type of tissue injury (pages 528–537) I have commented on many papers exploring signaling in fibrogenesis; most of them were either performed in cultured cells or in whole liver. Being a devout stereologist this often left me somewhat uncomfortable since it is well established that different models used to introduce cirrhosis lead to livers of different composition with respect to hepatocytes, cholangiocytes and hepatic stellate cells. Svegliati-Baroni and his many collaborators make this point in a paper in this issue which represents a real tour de force: they evaluate mitogen activated
Ju¨rg Reichen [email protected] protein kinases – MAPK, key regulators of cell proliferation – and P70 S6K (a kinase central in the control of translation) in dimethylnitrosamine and bile duct ligation-induced liver injury. The former injures primarily hepatocytes, the latter cholangiocytes. What makes this paper so remarkable is that they carefully evaluate protein mass by Western blotting in liver sections and its activity in the main cellular components, namely isolated hepatocytes, cholangiocytes and hepatic stellate cells (HSC). Both MAPK’s were activated in hepatocytes after dimethylnitrosamine, while only extracellular signal-regulated kinase (ERK) was activated in cholangiocytes after bile duct ligation. In HSC, kinase activation preceded transformation as evidenced by appearance of actin. This paper sets a new standard in the study of fibrogenesis. Microorgans and fulminant failure: Will aLIVE prolong life? (pages 552–558) Many different cell-based liver assist devices have been described; some of them have been put to clinical use as a bridge to transplantation. Grad-Itach and colleagues describe yet another such device representing some smart bioengineering: they put 150 mm cubes of liver tissue into a bioreactor. They chose this size because it represents the distance from the portal tract to the central vein and assures also a short diffusion distance for oxygen and nutrients. The idea behind taking cubes rather than isolated cells was to preserve cell-cell and cell-matrix interactions. In this aim they were successful: the organoids remained viable for up to 7 days in culture and maintained hepatic functions such as albumin and urea production. They named their device aLIVE – and indeed it improved coma and prolonged life in rats after 92% hepatectomy. Apparently, the investigators are already scaling up their system to larger animals. If that is successful, we are looking forward to clinical application of a promising new artificial aLIVEr. Mitochondrial glutathione (GSH) content and liver regeneration (pages 571–579) Mitochondria are exposed by their function to oxygen radicals; this exposure dramatically increases after hepatectomy where mitochondria work at their hardest to keep up with the energy demand of rebuilding the liver. To protect themselves, they need glutathione which they import from the cytoplasm using a specific carrier. Grattagliano and collaborators investigated regenerative capacity, mitochondrial function and GSH content after hepatectomy in GSH-depleted or hypothyroid rats. In both conditions, mitochondrial function was impaired after hepatectomy, in the latter – as one would expect – even at baseline. This was associated with a markedly reduced regenerative capacity. Interestingly and potentially of clinical importance is their finding that GSHethylester could restore GSH stores and regenerative capacity in both conditions of GSH depletion. GSH deficiency in man is probably not rare and could be particularly expected in alcoholic and/or malnourished patients. If the findings of Grattagliano et al. can be translated to man, administration of GSH-ester could potentially prevent liver failure after major hepatic resection.
0168-8278/03/$30.00 q 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/S0168-8278(03)00422-7