Abstract
The aim of this study was to examine the effect of the antithrombotic drugs aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of liver cirrhosis and to determine if these two drugs are beneficial in animals with advanced fibrosis or with established cirrhosis undergoing partial hepatectomy. Thioacetamide-induced cirrhotic rats received saline (N=10), aspirin (N=7), or enoxaparin (N=11) for a 5-week treatment period. Hepatic fibrosis was assessed according to METAVIR score. Liver regeneration was monitored using PCNA immunostaining. Compared to untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the aspirin (43%; χ2=54, P < 0.001) and enoxaparin (36%; χ2=43, P < 0.001) treated groups. Postoperatively, total serum bilirubin levels were lower in the aspirin (1.4±0.18 mg/dl; P < 0.01) and enoxaparin (1.8±0.35 mg/dl; P < 0.05)-treated groups compared to untreated cirrhotic controls (3.2±0.6 mg/dl). Hepatic regenerative activity was significantly improved in the aspirin group (57.3%±6.8%, versus 34.2%±7.2% in untreated cirrhotic controls; P < 0.01) but unchanged in the enoxaparin group. We conclude that aspirin and enoxaparin hold promise as a useful therapy for patients with extensive fibrosis.
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References
Olaso E, Friedman SL (1998) Molecular regulation of hepatic fibrogenesis. J Hepatol 29:836–847
Wanless IR, Liu JJ, Butany J (1995) Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis). Hepatology 21:1232–1237
Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G (1995) Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 21:1238–1247
Shimamatsu K, Wanless IR (1997) Role of ischemia in causing apoptosis, atrophy, and nodular hyperplasia in human liver. Hepatology 26:343–350
Papatheodoridis GV, Papakonstantinou E, Andrioti E, Cholongitas E, Petraki K, Kontopoulou I, Hadziyannis SJ (2003) Thrombotic risk factors and extent of liver fibrosis in chronic viral hepatitis. Gut 52:404–409
Moser MA, Kneteman NM, Minuk GY (2000) Research toward safer resection of the cirrhotic liver. HPB Surg 11:285–297
Friedman SL (1997) Molecular mechanisms of hepatic fibrosis and principles of therapy. J Gastroenterol 32:424–430
Abu-Hajir M, Mazzeo AJ (1999) Perioperative use of anticoagulants and thrombolytics. Anest Clin North Am 17:750–785
Kalkman EA, van Suylen RJ, van Dijk JP, Saxena PR, Schoemaker RG (1995) Chronic aspirin treatment affects collagen deposit in noninfarcted myocardium during remodeling after coronary artery ligation in the rat. J Mol Cell Cardiol 27:2483–2494
Denda A, Tang Q, Endoh T, Tsujiuchi T, Horiguchi K, Noguchi O, Mizumoto Y, Nakae D, Konishi Y (1994) Prevention by acetylsalicylic acid of liver cirrhosis and carcinogenesis as well as generations of 8-hydroxydeoxyguanosine and thiobarbituric acid-reactive substances caused by a choline-deficient, L-amino acid-defined diet in rats. Carcinogenesis 15:1279–1283
Frizelle S, Schwarz J, Huber SA, Leslie K (1992) Evaluation of the effects of low molecular weight heparin on inflammation and collagen deposit in chronic coxsackievirus B3-induced myocarditis in A/J mice. Am J Pathol 141:203–209
Dashti H, Jeppsson B, Haggerstrand I, Hutberg B, Srinivas U, Abdulla M, Bengmark S (1989) Thioacetamide and carbon tetrachloride-induced liver cirrhosis. Eur Surg Res 21:83–91
Higgens CM, Anderson RM (1931) Experimental pathology of the liver of the white rat following partial surgical removal. Arch Pathol 12:186–202
Brunt EM (2000) Grading and staging the histological lesions of chronic hepatitis: the Knodell histology activity index and beyond. Hepatology 31:241–246
MacIntosh E, Gauthier T, Pettigrew N, Minuk G (1992) Liver regeneration and the effect of exogenous putrescine on regenerative activity after partial hepatectomy in cirrhotic rats. Hepatology 16:1428–1433
Assy N, Minuk GY (1997) Liver regeneration: methods for monitoring and their applications. J Hepatol 26:945–952
Assy N, Gong Y, Zhang M, Pettigrew NM, Pashniak D, Minuk GY (1998) Use of proliferating cell nuclear antigen as a marker of liver regeneration after partial hepatectomy in rats. J Lab Clin Med 131:251–256
Friedman SL (1993) The molecular basis of hepatic fibrosis. Mechanism and treatment strategies. N Engl J Med 328:1282–1835
Marnett LJ (1992) Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 52:5575–5589
Gordring MB, Krane SM (1987) Modulation by recombinant interleukin 1 of synthesis of type 1 and 111 collagens and associated procollagen RNA levels in cultured human cells. J Biol Chem 262:16724–16729
Miura Y, Fukui N (1979) Prostaglandins as possible triggers for liver regeneration after partial hepatectomy. A review. Cell Mol Biol 25:179–184
Mochida S, Ohno A, Arai M, Fujiwara K (1995) Role of adhesion between activated macrophages and endothelial cells in the development of two types of massive hepatic necrosis in rats. J Gastroenterol Hepatol 10:S38–S42
Laxer U (1999) The effect of enoxaparin on bleomycin induced lung injury in mice. Exp Lung Res 25:531–541
Li Y, Wang HY, Cho CH (1999) Effects of heparin on hepatic regeneration and function after partial hepatectomy in rats. World J Gastroenterol 5:213–217
Matsumoto K, Nakamura T (1996) Heparin functions as a hepatotrophic factor by inducing production of hepatocyte growth factor. Biochem Biophy Res Commun 227:455–461
Schuppan D, Ruehl M, Somasundaram R, Hahn EG (2001) Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis 21:351–372
Benyon RC, Iredale JP (2000) Is liver fibrosis reversible? Gut 46:443–446
Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, Hovell C, Arthur MJ (1998) Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 102:538–549
Zimmermann H, Reichen J, Zimmermann A, Sagesser H, Thenisch B, Hoflin F (1992) Reversibility of secondary biliary fibrosis by biliodigestive anastomosis in the rat. Gastroenterology 103:579–589
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Assy, N., Hussein, O., Khalil, A. et al. The Beneficial Effect of Aspirin and Enoxaparin on Fibrosis Progression and Regenerative Activity in a Rat Model of Cirrhosis. Dig Dis Sci 52, 1187–1193 (2007). https://doi.org/10.1007/s10620-006-9595-1
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DOI: https://doi.org/10.1007/s10620-006-9595-1