柯萨奇病毒B_3诱导小鼠心肌炎心脏胶原变化及其与心功能的相关性研究
摘要
在我国，病毒性心肌炎(viral myocarditis，VMC)的发病逐年增多。随着风湿性等心肌炎的减少，临床大部分心肌炎实际是病毒性的，成为严重危害人民，尤其是小儿和青年人健康的常见病。临床发现，大部分进入慢性期的VMC患者常见有心脏舒张功能不全，如何解释这种现象，成为临床医师所关注的问题。
近年来的研究表明，心脏间质，尤其是Ⅰ型、Ⅲ型胶原的病理表达是心功能障碍的一个重要原因。资料证实VMC慢性期主要病理特点是心脏间质纤维化，用现代观点解释，即心脏胶原网络(Cardiac collagen network，CCN)增生性重建，这可能与VMC心脏舒张功能不全有关。但关于这方面的研究，国内外均未见到报道。本文旨在通过建立柯萨奇B3(CVB3)VMC小鼠模型，观察：①VMC小鼠急性期到慢性期心脏胶原表达变化及其与心脏功能变化间的关系；②血管紧张素Ⅱ(AⅡ)受体拮抗剂losartan干预后，各期VMC小鼠心脏胶原表达与心脏功能的变化；③各期VMC小鼠血浆AII和醛固酮(ALD)浓度变化及其与心脏胶原表达变化间的关系；④CVB3mRNA在各期VMC小鼠心肌中的表达。
总之，本文试图阐明心肌纤维化在VMC发生、发展中的作用，及其与心脏功能变化间的关系，探讨心肌纤维化的机制及药物干预的效果。
方法
1．动物及实验分组
The cases clinically diagnosed as viral myocarditis have been increasing recent years in China. Instead of rheumatic myocarditis, viral myocarditis has become the most common myocarditis which seriously threaten human health, especially in adolescents and children. A feature of viral myocarditis is the cardiac diastolic dysfunction at the chronic stage. However, the molecular mechanism for this remains unclear. Recent studies suggested that pathologic expression of myocardial interstitium, particularly type I and III collagen may be an important reason for cardiac dysfunction. And some literatures suppose that the proliferative remodeling of cardiac interstitial collagen network during viral myocarditis is responsibe for cardiac diastolic dysfunction.But there is no experimental evidence to support the hypothesis so far. In order to illustrate the role of myocardial fibrosis in the pathogenesis and development of VMC, and its relationship to the cardiac function alteration, Coxsackievirus B3 myocarditis models were established, and using the models, the following studies have been done:(1) the myocardial collagen expression and its relation to the cardiac function in the VMC mice from the acute stage to chronic stage;(2)the changes in myocardial collagen expression and the cardiac function in the VMC mice at each stage intervened with losartan,an AII receptor antagonist;(3)the relationship
近年来的研究表明，心脏间质，尤其是Ⅰ型、Ⅲ型胶原的病理表达是心功能障碍的一个重要原因。资料证实VMC慢性期主要病理特点是心脏间质纤维化，用现代观点解释，即心脏胶原网络(Cardiac collagen network，CCN)增生性重建，这可能与VMC心脏舒张功能不全有关。但关于这方面的研究，国内外均未见到报道。本文旨在通过建立柯萨奇B3(CVB3)VMC小鼠模型，观察：①VMC小鼠急性期到慢性期心脏胶原表达变化及其与心脏功能变化间的关系；②血管紧张素Ⅱ(AⅡ)受体拮抗剂losartan干预后，各期VMC小鼠心脏胶原表达与心脏功能的变化；③各期VMC小鼠血浆AII和醛固酮(ALD)浓度变化及其与心脏胶原表达变化间的关系；④CVB3mRNA在各期VMC小鼠心肌中的表达。
总之，本文试图阐明心肌纤维化在VMC发生、发展中的作用，及其与心脏功能变化间的关系，探讨心肌纤维化的机制及药物干预的效果。
方法
1．动物及实验分组
The cases clinically diagnosed as viral myocarditis have been increasing recent years in China. Instead of rheumatic myocarditis, viral myocarditis has become the most common myocarditis which seriously threaten human health, especially in adolescents and children. A feature of viral myocarditis is the cardiac diastolic dysfunction at the chronic stage. However, the molecular mechanism for this remains unclear. Recent studies suggested that pathologic expression of myocardial interstitium, particularly type I and III collagen may be an important reason for cardiac dysfunction. And some literatures suppose that the proliferative remodeling of cardiac interstitial collagen network during viral myocarditis is responsibe for cardiac diastolic dysfunction.But there is no experimental evidence to support the hypothesis so far. In order to illustrate the role of myocardial fibrosis in the pathogenesis and development of VMC, and its relationship to the cardiac function alteration, Coxsackievirus B3 myocarditis models were established, and using the models, the following studies have been done:(1) the myocardial collagen expression and its relation to the cardiac function in the VMC mice from the acute stage to chronic stage;(2)the changes in myocardial collagen expression and the cardiac function in the VMC mice at each stage intervened with losartan,an AII receptor antagonist;(3)the relationship
引文
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5．北京儿童医院等．小儿原发性心肌炎208例．中华医学杂志，1974，3：138
6. Zak R. Cell proliferation during cardiac growth. Am J Cardiol, 1973,31: 211
7. Robinson TF, et al. The skeletal framework of mammalian heart muscle: arrangement of inter-and prricellular connective tissue structures. Lab Invest, 1983,49:577
8．荆志成等．心脏胶原网络及其病理学意义．中国循环杂志，1998，13(3)：187
9. Poole-Wilson PA eds. Heart Failure. Ed 1. New York: Churchill Livingstone, 1997, p14-15
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11. Weber KT, et al. Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension. Am J Cardiol, 1990;65:1G
12. Haisong Ju, et al. Effect of AT1 receptor bolckade on cardiac collagen remodeling after myocardial infarction. Cardiovascular Research, 1997,35:223
13. Matthias P.,et al. Differential myocardial abundance of collagen??type Ⅰ and type Ⅲ mRNA in dilated cardiomyopathy: effects of myocardial inflammation. Cardiovascular Research, 1998,37:123
14. Gunter K.,et al. Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol, 1995,75:913
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2．上海二医大仁济医院等．30年来39774例心脏病住院病例的比较患病率．中华心血管病杂志，1986，14：326
3．中华内科杂志编委会．全国心肌炎心肌病专题座谈会纪要．中华内科学杂志，1987，26：597
4．李佩娟等．急性心肌炎19例临床病理分析．中华儿科学杂志，1981，19：148
5．北京儿童医院等．小儿原发性心肌炎208例．中华医学杂志，1974，3：138
6. Zak R. Cell proliferation during cardiac growth. Am J Cardiol, 1973,31: 211
7. Robinson TF, et al. The skeletal framework of mammalian heart muscle: arrangement of inter-and prricellular connective tissue structures. Lab Invest, 1983,49:577
8．荆志成等．心脏胶原网络及其病理学意义．中国循环杂志，1998，13(3)：187
9. Poole-Wilson PA eds. Heart Failure. Ed 1. New York: Churchill Livingstone, 1997, p14-15
10. Weber KT et al.. Nonclassic actins of angiotensin Ⅱ and aldosterone in nonclassic target tissue(the heart):relevance to hupertensice heart disease. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management, vol. 2,2nd ed, New York: Raven Press, 1995:2203
11. Weber KT, et al. Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension. Am J Cardiol, 1990;65:1G
12. Haisong Ju, et al. Effect of AT1 receptor bolckade on cardiac collagen remodeling after myocardial infarction. Cardiovascular Research, 1997,35:223
13. Matthias P.,et al. Differential myocardial abundance of collagen??type Ⅰ and type Ⅲ mRNA in dilated cardiomyopathy: effects of myocardial inflammation. Cardiovascular Research, 1998,37:123
14. Gunter K.,et al. Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol, 1995,75:913
15．李广生等主编．心肌病理学．上海科学技术出版社，1985年第一版，p174
16．董承琅等主编．实用心脏病学．上海科学技术出版社，1962年第一版，p836
17. Sun Y, et al. Angiotendin convertin enzyme myocradial fibrosis in the rat receivingangiotensin Ⅱ or aldosteone. J Lab Clin Med, 1993, 12:395
18. Kato H, et al. Angiotensin Ⅱ stimulates collagen synthesis in cccultured vascular smooth muscle cells. J Hypertens 1991,9:17
19. Ganten D, et al. Effect of angiotensin and an angiotensin antagonist on iso-renin and cell growth in 3T3 mouse cells. IRCS J Med Sci, 1975,3:327
20．李家宜主编．小儿病毒性心肌炎．黑龙江科学技术出版社，1993年第一版，p24
21．杨英珍主编．病毒性心肌炎．上海医科大学出版社，1991年第一版，p118
22．荆志成等．阻抗微分法测量小鼠心排血量的实验研究，基础医学与临床，1998(1)：70
23．A．G．E．皮尔斯著．组织化学理论和实用．中国医药科技出版社，1990年第一版，p117
24．许增禄．显示胶原及其类型的苦味酸天狼星红—偏振光方法．基础医学与临床，1996，16(1)：75
25. Whittaker P, et al. Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light. Basic Res Cardiol, 1994,89:397.
26. Weiss LM, et al. Detection of Coxsackievirus B3 RNA in myocardial tissues dy the polymerase chain reaction. Am J of Pathol, 1991, 138(2):49727.Webb ML, et al. Molecular characterization of angiotersin Ⅱ type Ⅱ receptor in rat pheochromocytoma cells. Peptides, 1992,13:499
28. Rens-Domiano S, et al. Pharmacological properties of two cloned somatostatin receptors. Mol Pharmacol, 1992,42:28
29. Pan MG,et al.G-protein activation of hormonestimulated phosphatase in human tumor cells.Science,1992,256:21527.
30．谷伯起主编．心血管病理学．人民卫生出版社，1992年第一版，p98
31．谷伯起主编．心血管病理学．人民卫生出版社，1992年第一版，p100
32. Braunwald. Heart Disease ,the fifth edition, 1437
33. Kishimoto C, et al. Immunoligic behavior of lymphocytes experimental viral myocarditis: significance of T lymphocytes I the severity of myocarditis and silent myocarditis in BALB/C-nu/nu mice. Lab Invest 1985,71:1247
34. Barson WJ et al. Survival following myocarditis and myocardial calcification associated with infection by coxsackie virus B4. Pediatrics, 1981,68:79
35. Morita H. Experimental coxsackie 83 vurus myocarditis in golden hamsters. Light and electron microscope findings in a long-term follow-up study. Jpn Cire J, 1981,45:713
36. Paque RE, et al. Assessment of cell-mediated immunity against coxsackievurus B3-induced myocarditis in a primate model. Infect Immun, 1981,31:470
37. Hori H, et al. The role of cell mediated immunity in coxsackie B vural myocarditis. Jpn Cire J, 1981,45:1409
38. Slawsky MT, et al. Procine model of myocarditis leading to dilated cardiomyopathy. J Am Coll Cardiol, 1989,13:253A
39. Woodruff JF, et al. Cytotoxic T cells in coxsackieviral disease, Immune Effector Mechanisms in Disease. Weksler ME, Litwin SO, Riggio RR, Siskind GW, eds. New York, Grune and stratton, 1977, p207.40．武忠弼主编．病理学．人民卫生出版社，1979年第一版，p100
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