The effect of preconditioning on liver regeneration after hepatic resection in cirrhotic rats
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Background/Aims:Ischemic preconditioning (IP) decreases severity of liver necrosis and has anti-apoptotic effects in previous studies using liver regeneration in normal rats. This study assessed the effect of IP on liver regeneration after hepatic resection in cirrhotic rats. Methods:To induce liver cirrhosis, thioacetamide (300 mg/kg) was injected intraperitoneally into Sprague-Dawley rats twice per week for 16 weeks. Animals were divided into four groups: non-clamping (NC), total clamping (TC), IP, and intermittent clamping (IC). Ischemic injury was induced by clamping the left portal pedicle including the portal vein and hepatic artery. Liver enzymes alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured to assess liver damage. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining for apoptosis and proliferating cell nuclear antigen (PCNA) staining for cell replication were also performed. Results:Day-1 ALT and AST were highest in IP, however, levels in NC and IC were comparably low on days 1-7. There was no significant correlation of AST or ALT with experimental groups (P=0.615 and P=0.186). On TUNEL, numbers of apoptotic cells at 100× magnification (cells/field) were 31.8±24.2 in NC, 69.0±72.3 in TC, 80.2±63.1 in IP, and 21.2±20.8 in IC (P<0.05). When regeneration capacity was assessed by PCNA staining, PCNA-positive cells (cells/field) at 400× were 3.4±6.0 in NC, 16.9±69 in TC, 17.0±7.8 in IP and 7.4±7.6 in IC (P<0.05). Conclusions:Although regeneration capacity in IP is higher than IC, the liver is vulnerable to ischemic damage in cirrhotic rats. Careful consideration is needed in applying IP in the clinical setting.
Abstract
Background/Aims:Ischemic preconditioning (IP) decreases severity of liver necrosis and has anti-apoptotic effects in previous studies using liver regeneration in normal rats. This study assessed the effect of IP on liver regeneration after hepatic resection in cirrhotic rats. Methods:To induce liver cirrhosis, thioacetamide (300 mg/kg) was injected intraperitoneally into Sprague-Dawley rats twice per week for 16 weeks. Animals were divided into four groups: non-clamping (NC), total clamping (TC), IP, and intermittent clamping (IC). Ischemic injury was induced by clamping the left portal pedicle including the portal vein and hepatic artery. Liver enzymes alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured to assess liver damage. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining for apoptosis and proliferating cell nuclear antigen (PCNA) staining for cell replication were also performed. Results:Day-1 ALT and AST were highest in IP, however, levels in NC and IC were comparably low on days 1-7. There was no significant correlation of AST or ALT with experimental groups (P=0.615 and P=0.186). On TUNEL, numbers of apoptotic cells at 100× magnification (cells/field) were 31.8±24.2 in NC, 69.0±72.3 in TC, 80.2±63.1 in IP, and 21.2±20.8 in IC (P<0.05). When regeneration capacity was assessed by PCNA staining, PCNA-positive cells (cells/field) at 400× were 3.4±6.0 in NC, 16.9±69 in TC, 17.0±7.8 in IP and 7.4±7.6 in IC (P<0.05). Conclusions:Although regeneration capacity in IP is higher than IC, the liver is vulnerable to ischemic damage in cirrhotic rats. Careful consideration is needed in applying IP in the clinical setting.
참고문헌 (30)
- Jaeschke H, "Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning", Am J Physiol Gastrointest Liver Physiol, 284, pp.15~26 (2003)
- Adkison D, "Role of free radicals in ischemia-reperfusion injury to the liver", Acta Physiol Scand Suppl, 548, pp.101~107 (1986)
- Jaeschke H, "Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver", Am J Physiol, 260, pp.355~362 (1991)
- González-Flecha B, "Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion", J Clin Invest, 91, pp.456~464 (1993)
- Cutrín JC, "Primary role of Kupffer cell-hepatocyte communication in the expression of oxidative stress in the post- ischaemic liver", Cell Biochem Funct, 16, pp.65~72 (1998)
- Selzner N, "Protective strategies against ischemic injury of the liver", Gastroenterology, 125, pp.917~936 (2003)
- Rüdiger HA, "A cytotoxic drug against reperfusion injury", Hepatology, 31, pp.533~535 (2000)
- Peralta C, "Preconditioning protects against systemic disorders associated with hepatic ischemia-reperfusion through blockade of tumor necrosis factor-induced P-selectin up-regulation in the rat", Hepatology, 33, pp.100~113 (2001)
- Sindram D, "Ischemic preconditioning protects against cold ischemic injury through an oxidative stress dependent mechanism", J Hepatol, 36, pp.78~84 (2002)
- Mannick JB, "Fas-induced caspase denitrosylation", Science, 284, pp.651~654 (1999)
- Natori S, "Apoptosis of sinusoidal endothelial cells occurs during liver preservation injury by a caspase-dependent mechanism", Transplantation, 68, pp.89~96 (1999)
- Cursio R, "A caspase inhibitor fully protects rats against lethal normothermic liver ischemia by inhibition of liver apoptosis", FASEB J, 13, pp.253~261 (1999)
- Wanner GA, "Differential effect of anti-TNF-alpha antibody on proinflammatory cytokine release by Kupffer cells following liver ischemia and reperfusion", Shock, 11, pp.391~395 (1999)
- Peralta C, "Hepatic preconditioning preserves energy metabolism during sustained ischemia", Am J Physiol Gastrointest Liver Physiol, 279, pp.163~171 (2000)
- Arai M, "Ischemic preconditioning in liver pathophysiology", J Gastroenterol Hepatol, 22(1), pp.65~67 (2007)
- 김경식, "효과적인 간경변 백서 모델의 개발", 한국간담췌외과학회지, 11(2), pp.1~7 (2007), 한국간담췌외과학회
- Sindram D, "Platelets induce sinusoidal endothelial cell apoptosis upon reperfusion of the cold ischemic rat liver", Gastroenterology, 118, pp.183~191 (2000)
- Horiuchi T, "Optimal cycles of hepatic ischemia and reperfusion for intermittent pedicle clamping during liver surgery", Arch Surg, 130, pp.754~758 (1995)
- Bishop A, "Induced adaptive resistance to oxidative stress in the CNS: a discussion on possible mechanisms and their therapeutic potential", Curr Drug Metab, 4, pp.171~184 (2003)
- Bishop A, "NO signaling in the CNS: from the physiological to the pathological", Toxicology, 208, pp.193~205 (2005)
- Walker K, "Kinins and kinin receptors in the nervous system", Neurochem Int, 26, pp.1~16 (1995)
- Jawan B, "The protective mechanism of magnolol, a Chinese herb drug, against warm ischemia-reperfusion injury of rat liver", J Surg Res, 110, pp.378~382 (2003)
- Gujral JS, "Mechanism of cell death during warm hepatic ischemia-reperfusion in rats: apoptosis or necrosis", Hepatology, 33, pp.397~405 (2001)
- Jaeschke H, "Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia", Free Radic Res Commun, 15, pp.277~284 (1991)
- Clavien PA, "A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning", Ann Surg, 238, pp.843~850 (2003)
- Stolz DB, "Growth factor signal transduction immediately after two-thirds partial hepatectomy in the rat", Cancer Res, 59, pp.3954~3960 (1999)
- Skarpen E, "Altered regulation of EGF receptor signaling following a partial hepatectomy", J Cell Physiol, 202, pp.707~716 (2005)
- Shen SQ, "Protective effect of curcumin against liver warm ischemia", reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymes, 2007, pp.13, 1953~1961
- Ishii S, "Effects of preconditioning on ischemia", reperfusion injury of hepatocytes determined by immediate early gene transcription, 2001, pp.8, 461~468
- Xiao JS, "Preconditioning effects on expression of proto-oncogenes c-fos and c-jun after hepatic ischemia", reperfusion in rats, 2005, pp.4, 197~202