已酮可可碱对内毒素诱导大鼠心肌细胞生成TNF-α的影响
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摘要
目的肿瘤坏死因子α(TNF-α)在心力衰竭发生发展中具有重要作用,已证实慢性心力衰竭患者血浆TNF-α水平明显升高。已酮可可碱是一种黄嘌呤衍生物,临床试验证实它可以改善心力衰竭患者的临床状况;动物实验亦报道已酮可可碱作为一种免疫调节剂可以抑制人类单核细胞生成肿瘤坏死因子-α。因此我们假设在心肌细胞中它有相似的作用机制。此实验旨在通过观察已酮可可碱对内毒素诱导新生大鼠心肌细胞生成TNF-α的影响,探讨已酮可可碱对大鼠心肌细胞可能的保护机制。
材料与方法取新生大鼠的心肌细胞加以培养,按不同的药物处理分为四组:对照组(A组)、1μg/ml已酮可可碱组(B组)、10μg/ml已酮可可碱组(C组)、100μg/ml已酮可可碱组(D组)。加入生理盐水(A组)和不同浓度的已酮可可碱(B、C、D组)作用一定时间后,再加入内毒素刺激TNF-α生成。作用6小时后,采用酶联免疫吸附法(ELISA)法测定新生大鼠心肌细胞TNF-α的生成,用逆转录聚合酶链式反应(RT-PCR)法检测TNF-αmRNA的表达。
结果已酮可可碱干预后,新生大鼠心肌细胞培养液中TNF-α的生成受到不同程度的抑制,且与预处理的已酮可可碱浓度呈正相关。其中1μg/ml已酮可可碱组、10μg/ml已酮可可碱组、100μg/ml已酮可可碱组的TNF-α的生成[(83.37±16.39)pg/ml,(35.43±2.60)pg/ml,(19.72±5.19)pg/ml]都显著低于对照组[(98.50±7.99)pg/ml](P<0.05);已酮可可碱干预后,新生大鼠心肌细胞TNF-αmRNA的表达均受到不同程度的抑制,且与已酮可可碱浓度呈正相关。其中1μg/ml已酮可可碱组、10μg/ml已酮可可碱组、100μg/ml已酮可可碱组心肌细胞TNF-αmRNA表达(0.78±0.02,0.71±0.04,0.62±0.04)都显著低于对照组(0.90±0.02) (P<0.05)。
结论已酮可可碱能有效抑制内毒素诱导的新生大鼠心肌细胞产生TNF-α,并能有效减少内毒素诱导的新生大鼠心肌细胞TNF-αmRNA的表达,且这些效应呈剂量依赖性。本实验结果表明已酮可可碱能有效调节TNF-α的生成,而且这一过程至少部分发生在转录水平。这一结果为已酮可可碱应用于治疗心力衰竭提供了实验依据。
Objective TNF-αhas played important roles in the development and progression of chronic heart failure. Several lines of reports indicated that the levels of circulating TNF-αwere elevated in patients with congestive heart failure. Pentoxifylline, a xanthin-derived agent, has been showed to improve clinical status in chornic heart failure patients by several clinical trials. Animal studies has showed that pentoxifylline reduced TNF-αproduction in human macrophages as an immunomodulatory agent. Therefore, we studied the effects of pentoxifylline on TNF-αproduction in neonatal rat cardiac myocytes stimulated with lipopplysaccharide to valuate the mechanism underlying pentoxifylline on the protection of rat hearts.
Materials and methods Neonatal rats cardiomyocytes were cultured and divided into four groups as follows: control group (A group, cells pretreated with diluent), 1μg/ml pentoxifylline group (B group), 10μg/ml pentoxifylline group (C group) and 100μg/ml pentoxifylline group (D group). Primary cultured cells were pretreated with diluent or various concentration of pentoxifylline for indicated times, then stimulated with lipopplysaccharide for another 6 hours. Then the culture medium and cells were collected for analysis. The level of secreted TNF-αwas measured by enzyme-linked immunosorbent assay (ELISA) and TNF-αmRNA expression was determined by semiquantitative reverse transcriptional polymerase chain reaction(RT-PCR).
Results After pretreated with pentoxifylline, TNF-αrelease was significantly decreased in pentoxifylline group. Pentoxifylline reduced TNF–αproduction in a dose dependent manner. With increasing concentration of pentoxifylline (1μg/ml, 10μg/ml, 100μg/ml), TNF-αsecretion showed a liner decrease: (83.37±16.39) pg/ml, (35.43±2.60) pg/ml, (19.72±5.19) pg/ml, lower than control group (98.50±7.99) pg/ml (P<0.05). Pentoxifylline also inhibited TNF-αmRNA expression in neonatal rat cardiomyocytes. There is an inverse relationship between TNF-αmRNA expression and pentoxifylline concentration. Pretreated with different concentration (1μg/ml, 10μg/ml, 100μg/ml ) of pentoxifylline, the TNF-αmRNA expression determined by semi-quantitive RT-PCR was [(0.78±0.02) , (0.71±0.04), (0.62±0.04)], lower than control group (0.90±0.02) (P<0.05).
Conclusions Pentoxifylline can effectively inhibit the production of TNF–αand reduced TNF-αmRNA expression in neonatal rat cardiomyocytes stimulated with lipopplysaccharide in a dose-dependent manner. It showed that pentoxifylline reduced TNF–αproduction at least by blocking transcriptional activation, which may provide the experimental basis for the use of pentoxifylline in the therapy of chronic heart failure.
材料与方法取新生大鼠的心肌细胞加以培养,按不同的药物处理分为四组:对照组(A组)、1μg/ml已酮可可碱组(B组)、10μg/ml已酮可可碱组(C组)、100μg/ml已酮可可碱组(D组)。加入生理盐水(A组)和不同浓度的已酮可可碱(B、C、D组)作用一定时间后,再加入内毒素刺激TNF-α生成。作用6小时后,采用酶联免疫吸附法(ELISA)法测定新生大鼠心肌细胞TNF-α的生成,用逆转录聚合酶链式反应(RT-PCR)法检测TNF-αmRNA的表达。
结果已酮可可碱干预后,新生大鼠心肌细胞培养液中TNF-α的生成受到不同程度的抑制,且与预处理的已酮可可碱浓度呈正相关。其中1μg/ml已酮可可碱组、10μg/ml已酮可可碱组、100μg/ml已酮可可碱组的TNF-α的生成[(83.37±16.39)pg/ml,(35.43±2.60)pg/ml,(19.72±5.19)pg/ml]都显著低于对照组[(98.50±7.99)pg/ml](P<0.05);已酮可可碱干预后,新生大鼠心肌细胞TNF-αmRNA的表达均受到不同程度的抑制,且与已酮可可碱浓度呈正相关。其中1μg/ml已酮可可碱组、10μg/ml已酮可可碱组、100μg/ml已酮可可碱组心肌细胞TNF-αmRNA表达(0.78±0.02,0.71±0.04,0.62±0.04)都显著低于对照组(0.90±0.02) (P<0.05)。
结论已酮可可碱能有效抑制内毒素诱导的新生大鼠心肌细胞产生TNF-α,并能有效减少内毒素诱导的新生大鼠心肌细胞TNF-αmRNA的表达,且这些效应呈剂量依赖性。本实验结果表明已酮可可碱能有效调节TNF-α的生成,而且这一过程至少部分发生在转录水平。这一结果为已酮可可碱应用于治疗心力衰竭提供了实验依据。
Objective TNF-αhas played important roles in the development and progression of chronic heart failure. Several lines of reports indicated that the levels of circulating TNF-αwere elevated in patients with congestive heart failure. Pentoxifylline, a xanthin-derived agent, has been showed to improve clinical status in chornic heart failure patients by several clinical trials. Animal studies has showed that pentoxifylline reduced TNF-αproduction in human macrophages as an immunomodulatory agent. Therefore, we studied the effects of pentoxifylline on TNF-αproduction in neonatal rat cardiac myocytes stimulated with lipopplysaccharide to valuate the mechanism underlying pentoxifylline on the protection of rat hearts.
Materials and methods Neonatal rats cardiomyocytes were cultured and divided into four groups as follows: control group (A group, cells pretreated with diluent), 1μg/ml pentoxifylline group (B group), 10μg/ml pentoxifylline group (C group) and 100μg/ml pentoxifylline group (D group). Primary cultured cells were pretreated with diluent or various concentration of pentoxifylline for indicated times, then stimulated with lipopplysaccharide for another 6 hours. Then the culture medium and cells were collected for analysis. The level of secreted TNF-αwas measured by enzyme-linked immunosorbent assay (ELISA) and TNF-αmRNA expression was determined by semiquantitative reverse transcriptional polymerase chain reaction(RT-PCR).
Results After pretreated with pentoxifylline, TNF-αrelease was significantly decreased in pentoxifylline group. Pentoxifylline reduced TNF–αproduction in a dose dependent manner. With increasing concentration of pentoxifylline (1μg/ml, 10μg/ml, 100μg/ml), TNF-αsecretion showed a liner decrease: (83.37±16.39) pg/ml, (35.43±2.60) pg/ml, (19.72±5.19) pg/ml, lower than control group (98.50±7.99) pg/ml (P<0.05). Pentoxifylline also inhibited TNF-αmRNA expression in neonatal rat cardiomyocytes. There is an inverse relationship between TNF-αmRNA expression and pentoxifylline concentration. Pretreated with different concentration (1μg/ml, 10μg/ml, 100μg/ml ) of pentoxifylline, the TNF-αmRNA expression determined by semi-quantitive RT-PCR was [(0.78±0.02) , (0.71±0.04), (0.62±0.04)], lower than control group (0.90±0.02) (P<0.05).
Conclusions Pentoxifylline can effectively inhibit the production of TNF–αand reduced TNF-αmRNA expression in neonatal rat cardiomyocytes stimulated with lipopplysaccharide in a dose-dependent manner. It showed that pentoxifylline reduced TNF–αproduction at least by blocking transcriptional activation, which may provide the experimental basis for the use of pentoxifylline in the therapy of chronic heart failure.
引文
1 Rauchhaus M, Doehner W, Francis D P. Plasma cytokine parameter and mortality in patients with chornic heart failure. Circulation 2000, 102: 3060-3067.
2 Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor alpha and tumor necrosis factor receptors in the failing human heart. Circulation 1996: 93: 704-711.
3 Grandel U, Fink L, Blum A et al. Endotoxin-induced myocardial tumor necrosis factor-alpha synthesis depresses contractility of isolated rat hearts:evidence for a role of sphingosine and cyclooxgenase-2-derived thromboxane production. Circulation 2002; 102: 2758-2764.
4 Aikawa R, Nitta-Komatsubara Y, Kudoh S, et al. Reactive oxygen species induce cardiomyocytes apoptosis partly through TNF-alpha. Cytokine 2002; 18: 179-183.
5 Bradham WS, Bozkurt B, Gunasinghe H, et al. Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective. Cardiovasc Res 2002; 53: 822-830.
6 Waage A, Sorensen M, Stordal B. Differential effect of oxpentifylline on tumor necrosis factor and interlerkin-6 production. Lancet 1990;3: 335-543.
7 Newner P, Klosner G, Schaver E, et al. Pentoxifylline in vivo down-regulates the release of IL-1β, IL-6, IL-8 and tumor necrosis factor-alpha by human peripheral blood mononuclear cells. Immunology 1994; 83: 262-267.
8 Munger MA, Johnson B, Amber U, et al. Circulating concentration of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic oridiopathic dilated cardiomyopathy. Am J Cardiol 1996; 77: 723-727.
9 Deswal A, Bozkurt B, Seta Y, et al. Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation 1999; 99: 3224-3226.
10 Bozkurt B, Torre-Amione G, Warren MS, et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (Enbrel) in patients with advanced heart failure. Circulation 2001; 103: 1044-1047.
11 Fichtlscherer S, Rossig L, Breuer S, et al. Tumor necrosis factor antagonism with etanercept improves systemic endothelial vasoreactivity in patients with advanced heart failure. Circulation 2001; 104: 3023-3025.
12 Coletta AP, Clark AL, Banarjee P, et al. Clinical trials update: RENEWAL (RENAISSANCE and RECOVER) and ATTACH. Eur J Heart Fail 2002;4: 559- 561.
13 Chung ES, Packer Milton, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure. Circulation 2003; 107: 3133.
14 Anker SD, Coats AJ. How to RECOVER from RENAISSANCE? The significance of results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol, 2002, 86:123-130.
15 Staudt A, Landsberger M, Stault Y, et al. Cytokines-causes, players or bystanders in heart failure. Herz, 2002, 27:691-698.
16 Takehana H,Inomate T,Niwana H. Immunodulatory effect of pentoxifylline insuppressing experimental autoimmune myoarditis. Circ J 2002, 66(5): 499-504.
17 Belloc F, Jaloustre C, Dumain P, et al. Effect of pentoxifylline on apoptosis of cultured cells. J Cardiovas Pharmcol 1995; 25(suppl 2): S71-S74.
18 Sliwa K, Skudicky D, Candy G. Randomised investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy. Lancet 1998, 351: 1091-1093.
19 Skudicky D, Bergemann A, Sliwa K. Beneficial effects of pentoxifylline in patients with idiopathic dilated cardomyopathy treated with angiotensin-converting enzyme inhibitors and carvedilol. Results of a randomized study. Circulation 2001, 103: 1083-1088.
20 Karen Sliwa, Angela Woodiwiss, Geoffrey Candy, et al. Effects of pentoxifylline on cytokine profiles and left ventricular performance in patients with decompensated congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol 2002; 90: 1118-1122.
21 Sliwa K, Woodiniss A, Kone VN. Therapy of ischemic cardiomyopathy with the immunomodulating agent pentoxifylline: results of a randomized study. Circulation 2004, 109(6): 750-755.
22 Batchelder K, Mayosi BM. Pentoxifylline for heart failure: a systematic review. S Afr Med J 2005; 95: 171-175.
23 Zhang M, Xu YJ, Saini HK, et al. Pentoxifylline attenuates cardiac dysfunction and reduces TNF-alpha level in ischemic-reperfused heart. Am J Physiol Heart Circ Physiol. 2005; 289: H832-9.
1 Braunwald E, Bristow M R. Congestive heart failure: Fifty years of progress. Circulation, 2002, 102:Ⅳ14-Ⅳ23.
2 Munger MA, Johnson B, Amber U, et al. Circulating concentration of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1996, 77: 723- 727.
3 Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor alpha and tumor necrosis factor receptors in the failing human heart. Circulation, 1996: 93:704-711.
4 Cain B, Meldrum D, Dinarello D R, et al.Tumor necrosis factor alpha and interleukin-1 beta synergistically depress human myocardial function. Crit Care Med 1999, 27: 1319-1318.
5 Bloger AP, Anker SD. Tumor necrosis factor in chronic heart failure: a peripheral view on pathogenesis, clinical manifestation and therapeutic implications. Drugs 2000,60:1245-1257.
6 Bradham WS, Bozkurt B, Gunasinghe H, et al. Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective. Cardiovasc Res 2002, 53: 822-830.
7 Bozkurt B, Kribbs S, Clubb F, et al. Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1988, 97: 1382-2-1391.
8 Ono K, Matsumori A, Shioi T, et al. Cytokine gene expression in rat hearts: possible implication in left ventricular remodeling. Circulation 1998, 98:149-156.
9 Bradham WS, Moe G, Wendt KA, et al. Tumor necrosis factor-α and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling. Am J Physiol Heart Circ Physiol 2002, 282: H1288-H1295.
10 Suematsu N, Tsutsui H, Jing Wen, et al. Oxidative stress mediates tumor necrosis factor- α -induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 2003, 107: 1418-1423.
11 Song W, La X, Feng Q. Tumor necrosis factor-alpha induces apoptosis via inducible nitric oxide synthase in neonatal mouse cardiomyocytes. Cardiovas Res 2000, 45: 595-602.
12 Douglas J. Ing, Jie Zang, Victor J. Dzau, et al. Modulation of cytokine-induced cardiac myocyte apoptosis by nitric oxide, Bak, and Bcl-x. Circ Res 1999; 84: 21-33.
13 Condorelli G, Morisco C, Latronica MV, et al. TNF –α signal transudation in rat neonatal cardiac myocytes: definition of pathways generating from the alpha receptor. FASEB J 2002; 16: 1732-37.
14 Deswal A, Bozkurt B, Seta Y, et al. Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation 1999; 99: 224-3226.
15 Bozkurt B, Torre-Amione G, Warren MS, et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (Enbrel) in patients with advanced heartfailure. Circulation 2001; 103: 1044-1047.
16 Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the randomized etanercept worldwide evaluation (RENEWAL). Circulation 2004: 109: 1594-1602.
17 Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation 2003, 107: 3133-3140.
18 Shioi T, Matsumori A, Matoba Y, et al. Inhibition of cytokine production by a new inotropic agent vesnarinone, in human lymphocytes, T cell line, and monocytic cell line. Life Sci 1994,54:PL11-16.
19 Cohn J N, Goldsrein S D, Greenberg B H, et al. For the Vesnarinone Trial Investigators. A dose-dependent increase in mortality with vesnarinone among patients with severe heart heart failure. N Eng J Med 1998, 339:1810-1816.
20 Agoston I, Dibbs II, Wang F, et al. Preclinical and clinical assessment of the safety and potential efficacy of healidomide in heart failure. J Card Fail 2002, 85: 306-314.
21 Takehana H,Inomate T,Niwana H. Immunodulatory effect of pentoxifylline in suppressing experimental autoimmune myoarditis. Circ J 2002, 66: 499-504.
22 Belloc F, Jaloustre C, Dumain P, et al. Effect of pentoxifylline on apoptosis of cultured cells. J Cardiovas Pharmcol 1995, 25(suppl 2): S71-S74.
23 Zhang M, Xu YJ, Saini HK, et al. TNF-alpha as a potential mediator of cardiac dysfunction due to intracellular Ca2+-overload. Biochem Biophys Res Commun 2005, 327: 57-63.
24 Sliwa K, Skudicky D, Candy G. Randomised investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy. Lancet 1998; 351: 1091-1093.
25 Skudicky D, Bergemann A, Sliwa K. Beneficial effects of pentoxifylline in patients with idiopathic dilated cardomyopathy treated with angiotensin-converting enzyme inhibitors and carvedilol. Results of a randomized study. Circulation 2001; 103: 1083-1088.
26 Karen Sliwa, Angela Woodiwiss, Geoffrey Candy, et al. Effects of pentoxifylline of cytokine profiles and left ventricular performance in patients with decompensated congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol 2002; 90: 1118- 1122.
27 Sliwa K, Woodiniss A, Kone VN. Therapy of ischemic cardiomyopathy with the immunomodulating agent pentoxifylline: results of a randomized study. Circulation 2004; 109: 750-755.
28 The EPOCH Study Group. Effects of pimobendan on adverse cardiac events and physical activities in patients with mild to moderate chronic heart failure: the effects of pimobendan on chronic heart failure study. Circ J 2002; 66:149-157.
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30 Li B, Liao YH, Huang YX et al. Effect of Carvedilol on plasma cytokines network in patients with congestive heart failure. J HK Coll Cardiol, 2004,12(Suppl 1):A57.
31 Ohtsuka T, Hamada M, Hiasa G et al. Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy. J Am Coll Cardiol, 2001,37:412-417.
32 Node K, Fujita M, Kitakaze M, et al. Short –term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation 2003; 108: 839-843.
33 Cheng X, Liao YH, Li B et al. Atorvastatin reduces Th1 development in patients with acute myocardial infarction. Circulation, 2004,110 (Supplement III): 696-697.
34 Ito H, Ono K, Nishio R, et al. Amiodarone inhibits interleukin 6 production and attenuates myocardial injury induced by viral myocarditis in mice. Cytokine 2002; 17: 197-202.
2 Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor alpha and tumor necrosis factor receptors in the failing human heart. Circulation 1996: 93: 704-711.
3 Grandel U, Fink L, Blum A et al. Endotoxin-induced myocardial tumor necrosis factor-alpha synthesis depresses contractility of isolated rat hearts:evidence for a role of sphingosine and cyclooxgenase-2-derived thromboxane production. Circulation 2002; 102: 2758-2764.
4 Aikawa R, Nitta-Komatsubara Y, Kudoh S, et al. Reactive oxygen species induce cardiomyocytes apoptosis partly through TNF-alpha. Cytokine 2002; 18: 179-183.
5 Bradham WS, Bozkurt B, Gunasinghe H, et al. Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective. Cardiovasc Res 2002; 53: 822-830.
6 Waage A, Sorensen M, Stordal B. Differential effect of oxpentifylline on tumor necrosis factor and interlerkin-6 production. Lancet 1990;3: 335-543.
7 Newner P, Klosner G, Schaver E, et al. Pentoxifylline in vivo down-regulates the release of IL-1β, IL-6, IL-8 and tumor necrosis factor-alpha by human peripheral blood mononuclear cells. Immunology 1994; 83: 262-267.
8 Munger MA, Johnson B, Amber U, et al. Circulating concentration of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic oridiopathic dilated cardiomyopathy. Am J Cardiol 1996; 77: 723-727.
9 Deswal A, Bozkurt B, Seta Y, et al. Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation 1999; 99: 3224-3226.
10 Bozkurt B, Torre-Amione G, Warren MS, et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (Enbrel) in patients with advanced heart failure. Circulation 2001; 103: 1044-1047.
11 Fichtlscherer S, Rossig L, Breuer S, et al. Tumor necrosis factor antagonism with etanercept improves systemic endothelial vasoreactivity in patients with advanced heart failure. Circulation 2001; 104: 3023-3025.
12 Coletta AP, Clark AL, Banarjee P, et al. Clinical trials update: RENEWAL (RENAISSANCE and RECOVER) and ATTACH. Eur J Heart Fail 2002;4: 559- 561.
13 Chung ES, Packer Milton, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure. Circulation 2003; 107: 3133.
14 Anker SD, Coats AJ. How to RECOVER from RENAISSANCE? The significance of results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol, 2002, 86:123-130.
15 Staudt A, Landsberger M, Stault Y, et al. Cytokines-causes, players or bystanders in heart failure. Herz, 2002, 27:691-698.
16 Takehana H,Inomate T,Niwana H. Immunodulatory effect of pentoxifylline insuppressing experimental autoimmune myoarditis. Circ J 2002, 66(5): 499-504.
17 Belloc F, Jaloustre C, Dumain P, et al. Effect of pentoxifylline on apoptosis of cultured cells. J Cardiovas Pharmcol 1995; 25(suppl 2): S71-S74.
18 Sliwa K, Skudicky D, Candy G. Randomised investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy. Lancet 1998, 351: 1091-1093.
19 Skudicky D, Bergemann A, Sliwa K. Beneficial effects of pentoxifylline in patients with idiopathic dilated cardomyopathy treated with angiotensin-converting enzyme inhibitors and carvedilol. Results of a randomized study. Circulation 2001, 103: 1083-1088.
20 Karen Sliwa, Angela Woodiwiss, Geoffrey Candy, et al. Effects of pentoxifylline on cytokine profiles and left ventricular performance in patients with decompensated congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol 2002; 90: 1118-1122.
21 Sliwa K, Woodiniss A, Kone VN. Therapy of ischemic cardiomyopathy with the immunomodulating agent pentoxifylline: results of a randomized study. Circulation 2004, 109(6): 750-755.
22 Batchelder K, Mayosi BM. Pentoxifylline for heart failure: a systematic review. S Afr Med J 2005; 95: 171-175.
23 Zhang M, Xu YJ, Saini HK, et al. Pentoxifylline attenuates cardiac dysfunction and reduces TNF-alpha level in ischemic-reperfused heart. Am J Physiol Heart Circ Physiol. 2005; 289: H832-9.
1 Braunwald E, Bristow M R. Congestive heart failure: Fifty years of progress. Circulation, 2002, 102:Ⅳ14-Ⅳ23.
2 Munger MA, Johnson B, Amber U, et al. Circulating concentration of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1996, 77: 723- 727.
3 Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor alpha and tumor necrosis factor receptors in the failing human heart. Circulation, 1996: 93:704-711.
4 Cain B, Meldrum D, Dinarello D R, et al.Tumor necrosis factor alpha and interleukin-1 beta synergistically depress human myocardial function. Crit Care Med 1999, 27: 1319-1318.
5 Bloger AP, Anker SD. Tumor necrosis factor in chronic heart failure: a peripheral view on pathogenesis, clinical manifestation and therapeutic implications. Drugs 2000,60:1245-1257.
6 Bradham WS, Bozkurt B, Gunasinghe H, et al. Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective. Cardiovasc Res 2002, 53: 822-830.
7 Bozkurt B, Kribbs S, Clubb F, et al. Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1988, 97: 1382-2-1391.
8 Ono K, Matsumori A, Shioi T, et al. Cytokine gene expression in rat hearts: possible implication in left ventricular remodeling. Circulation 1998, 98:149-156.
9 Bradham WS, Moe G, Wendt KA, et al. Tumor necrosis factor-α and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling. Am J Physiol Heart Circ Physiol 2002, 282: H1288-H1295.
10 Suematsu N, Tsutsui H, Jing Wen, et al. Oxidative stress mediates tumor necrosis factor- α -induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 2003, 107: 1418-1423.
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