不同剂量地塞米松对家兔肝脏损伤程度的研究
|
摘要
地塞米松属于糖皮质激素(Glucocorticoids)的一种,具有抗毒素、抗休克、抗感染、抗过敏等特性,随着近年来小动物临床诊疗的迅速发展,地塞米松已经成为不可缺少的药物,对疾病的治疗起着重要的作用,但超生理剂量和长时间的运用地塞米松对肝脏会造成损伤。地塞米松对肝脏的实际损伤程度目前国内外研究还尚未明确。
本研究以健康日本大耳白兔为实验动物,注射不同剂量的地塞米松,观察研究日本大耳白兔血清生化指标值和肝脏病理学变化,探讨不同剂量地塞米松长时间运用于机体,对肝脏组织的损伤程度的影响。
本实验选用25只健康的日本大耳白兔,随机分成5组:对照组、正常剂量组、2倍剂量组、4倍剂量组、10倍剂量组,对照组皮下注射注射用水,其余组别分别皮下注射相应剂量的地塞米松,并与给药前、给药后的第1、4、7、14、21天分别测血清ALT、AST、ALP、TBIL,并于第21天后,剖杀实验兔,进行病理组织切片和电镜切片的制做和观察。得出以下结论。
1不同剂量地塞米松能引起家兔血清ALT、AST、TBIL不同程度的升高,证明超正常剂量地塞米松对肝脏组织有不同程度的损伤,且损伤的程度与剂量成正相关。
2光镜显示:给予超正常剂量地塞米松后,家兔肝脏组织发生病理学变化,正常剂量组,肝细胞结构清晰,无变形与坏死;其他组别,不同程度的显示肝脏组织出现肝细胞空泡样变性,红细胞大量沉积。
3电镜显示,正常剂量组肝细胞线粒体脊正常,超微结构无明显改变;低剂量组出现线粒体嵴肿胀、模糊不清,部分嵴消失,大量的类脂类内含物沉积,而高剂量组出现大量纤维化物质。
Background: dexamethasone is an important glucocorticoids. It is essential for life and regulates or supports a variety of important anti-toxic, anti-shock, anti-anaphylaxis, anti-inflammatory functions. The dexamethasone is more important in clinical application with the develop of animal clinical medical. high dose dexamethasone were used in long time would damage the liver . but several questions on the damage action remain.
Medthod: 25 healthy adult rabbits were randomly divided into 5 grounps, control grounp, basic grounp(0.5 mg/kg), 2 times grounp(1 mg/kg), 4 times grounp(2 mg/kg), and 10times grounp(5 mg/kg) administracted with dexamethasone, After 21 d rabbits were killed and through the measurement of activities of alanine aminotransferase(ALT) and aspartate aminotransferase(AST), alkalinep hosphatase(ALP)and total bilirubin(TBIL) in serum were determined 0d, 1 d, 4d, 7d, 14d and 21d. At the same time, the rabbits’livers were collected and pathological changes of liver were observed under light microscope and election microscope.
Conclusion : 1 there is a significant difference in serum ALT, AST, and TBIL, and the injury degrees is increased with the doses. 2 the different degrees of pathological changes of liver were found, the cell structure of liver in basic group was clear, there was no denaturetion and necrosis. In other groups. The cell structure of disorder, the cells swelling, there were some red cells. 3 under electron microscope, in basic group did not some difference. In lower group. some of the mitochondrial ridges were destroyed, vesiculated and disappeared. Some lipoid substance was appeared. In high group, hepatic fibrosis was appeared in some cells.
本研究以健康日本大耳白兔为实验动物,注射不同剂量的地塞米松,观察研究日本大耳白兔血清生化指标值和肝脏病理学变化,探讨不同剂量地塞米松长时间运用于机体,对肝脏组织的损伤程度的影响。
本实验选用25只健康的日本大耳白兔,随机分成5组:对照组、正常剂量组、2倍剂量组、4倍剂量组、10倍剂量组,对照组皮下注射注射用水,其余组别分别皮下注射相应剂量的地塞米松,并与给药前、给药后的第1、4、7、14、21天分别测血清ALT、AST、ALP、TBIL,并于第21天后,剖杀实验兔,进行病理组织切片和电镜切片的制做和观察。得出以下结论。
1不同剂量地塞米松能引起家兔血清ALT、AST、TBIL不同程度的升高,证明超正常剂量地塞米松对肝脏组织有不同程度的损伤,且损伤的程度与剂量成正相关。
2光镜显示:给予超正常剂量地塞米松后,家兔肝脏组织发生病理学变化,正常剂量组,肝细胞结构清晰,无变形与坏死;其他组别,不同程度的显示肝脏组织出现肝细胞空泡样变性,红细胞大量沉积。
3电镜显示,正常剂量组肝细胞线粒体脊正常,超微结构无明显改变;低剂量组出现线粒体嵴肿胀、模糊不清,部分嵴消失,大量的类脂类内含物沉积,而高剂量组出现大量纤维化物质。
Background: dexamethasone is an important glucocorticoids. It is essential for life and regulates or supports a variety of important anti-toxic, anti-shock, anti-anaphylaxis, anti-inflammatory functions. The dexamethasone is more important in clinical application with the develop of animal clinical medical. high dose dexamethasone were used in long time would damage the liver . but several questions on the damage action remain.
Medthod: 25 healthy adult rabbits were randomly divided into 5 grounps, control grounp, basic grounp(0.5 mg/kg), 2 times grounp(1 mg/kg), 4 times grounp(2 mg/kg), and 10times grounp(5 mg/kg) administracted with dexamethasone, After 21 d rabbits were killed and through the measurement of activities of alanine aminotransferase(ALT) and aspartate aminotransferase(AST), alkalinep hosphatase(ALP)and total bilirubin(TBIL) in serum were determined 0d, 1 d, 4d, 7d, 14d and 21d. At the same time, the rabbits’livers were collected and pathological changes of liver were observed under light microscope and election microscope.
Conclusion : 1 there is a significant difference in serum ALT, AST, and TBIL, and the injury degrees is increased with the doses. 2 the different degrees of pathological changes of liver were found, the cell structure of liver in basic group was clear, there was no denaturetion and necrosis. In other groups. The cell structure of disorder, the cells swelling, there were some red cells. 3 under electron microscope, in basic group did not some difference. In lower group. some of the mitochondrial ridges were destroyed, vesiculated and disappeared. Some lipoid substance was appeared. In high group, hepatic fibrosis was appeared in some cells.
引文
[1]冯淇辉主编兽医临床药理学[M]北京,科学出版社,1983
[2]冯淇辉主编兽医药物代谢动力学[M]北京科学出版社1987
[3]陈仗榴主编兽医药理学[M]中国农业出版社2002
[4]庄文荣.大剂量地塞米松配合伊维菌素治疗犬疥螨病[J].畜牧与兽医,2006,3(5):53
[5]杨自军,郭世霞,吉朝松等,地塞米松在犬病治疗中的作用[J] .动物科学与兽医医学, 1999, 18(1) :51-52
[6]刘占斌,徐玉生,徐黎用糖皮质激素治疗犬结膜和角膜炎[J].中国工作犬业, 2006, 6: 28
[7]高大柱,胡大勇,王伟等,地塞米松局部应用对犬完全性脊髓横断伤再生的影响[J].安徽医学, 2003, 24(2): 1-3
[8]鲁文,犬猫脊髓损伤的药物治疗[J].中国兽医杂志2002,38(6):49-50
[9]何德华肝胆病理学[M]上海:第二军医大学出版社,1997:1
[10]韩藩五,马学惠,赵元昌,等.齐墩果酸防治实验性肝硬变发生的研究[J].中医杂志,1981,22(3):217
[11]崔婕,薛绍白胞内钙的稳态调节[J].细胞生物学杂志.1995,17(3):97-102
[12] Date M ,Matsuzaki K,Matusushita M ,et al. Differential regulation ofactivin A for hepatocyte growth and fibronectin synthesis in rat liver injury [J]. J Hepatol,2000,32(2) :251-260.
[13] Geeraerts M D,Ronveaux-Dupul MF,Lemasters JJ.Cytosolicfree Ca and protecolysis in lethal oxidative injury in endothelialceils [J] Am J Physiol, 1991,267(5):889-891
[14]巫协宁急性肝损伤的细胞学机制[J].国外医学.消化系疾病分册,1998,18(1):14-16
[15] Nagata S.Apoptosis by death factor [J].Cell.1997,88(3):355-365
[16] Beyaert R,Vanhaesebroeck B, Declercq W,et al. Casein kinase-lphosphorylates the p75 tumor necrosis factor receptor and negativelyregulates tumor necrosis fator signaling for apoptosis[J].J Biol Chem,1995,270(40):23293-23299
[17] Patel, T,Gores GJ.Apoptosis and hepatobiliary disease [J]. Hepatology,1995,21:1725-1741
[18]孙帅,血清酶AST/ALT比值在肝病中的意义[J]中华医药杂志,2005,5(10)
[19]吴文苑,骨型碱性磷酸酶的检测方法和临床应用.临床生物化学检测学分册,1999,20(2):64-65
[20]刘宏伟,吴织芬骨形成蛋白和(或)甲状旁W激素对牙周膜细胞碱性磷酸酶活性的影响,[J]华西口腔医学杂志,1995,13(1):15
[21]陶文洪羚脯氨酸和碱性磷酸酶检测在骨折、骨病研究中的概况,[J]中华骨科杂志, 1989,9(5):376
[22]张若燕血骨源性碱性磷酸酶临床意义深讨[J],四川省卫生管理干部学院学报,2003,22(3):181
[23]王书林兽医临床诊断学[M]中国农业出版社2001
[24] RAYPD, FOSTER DO, LARDY HA, Mode of action of glucocorticoids Stimulation of glucoconeogenesis independent of synthesis denovo of enzymes. J Biolchem, 1964,239:396-400
[25] Sistre FD, Haynes RC Jr. Acute stimulation by glucocorticoids of gluconeogenesis from lactate/pyruvate in isolated hepatocytes from normal and adrenalectomized rats. J Biolchem, 1985,260:54-60
[26] Egana M,Sancho MJ, Macarulla JM. An early effect of cortisol, previous to its glycogenogenic action. Horm Metab Res,1981,13:609-611
[27] Vallejo A, Trueba M, Sancho MJ, et al. Glycogenolytic effect of cortisol previous to its interaction with the cell nucleus in mouse liver, Exp Clin Endocrinol, 1986,87:201-207
[28] Marino A, Bartolome B, Trueba M,et al. Increased phospholipid methylation and glycogen phosphorylase activation after a single dose of dexamethasone in mouse liver. Exp Clin Endocrinol, 1988,92:314-322
[29] Gomez-Munoz A, Hales P, Brindley DN, et al. Rapid activation of glycogenphosphorylase by steroid hormones in cultured rat hepatocytes. Biochem J, 1989,262:417-423
[30] Baque S, Roca A, Guinovart JJ, et al. Direct activatine effects of dexamethasone on glycogen metabolizing enzymes in primary cultured rat hepatocytes. Eur J Biochem, 1996,236:772-777
[31] Zhou J, Kang Z M,Xie Q M, etal. Rapid nongenomic effect of glucocorticoids on allergic asthma reaction in the guinea pig. J Endocrinol, 2003,177:R1-R4
[32] Sun HW, Miao CY, Liu L,etal. Rapid inhibitory effect of glucocorticoids on airway smooth muscle contraction in guinea pigs. Steroids, 2006,71(2):154-159
[33] Liu L,Wang Y X,Zhou J,et al. Rapid non-genomic inhibitory effects of glucocorticoids on human neu trophil degranulation. Inflamm Res, 2005,54:37-41
[34] Long F, Wang Y X, Liu L, et al. Rapid nongenomic inhibitory effects of glucocorticoids on phagocytosis and superoxide anion production by macrophages. Steroids, 2005,70(1):55-61
[35] Baccan GC, Oliceira RD, Mantovani B. Stress and immunological phagocytosis:possible nongenomic action of corticosterone. Life Sci,2004,75:1357-1368
[36] Hinz B, Hirschelmann R. Dexamethasone megadoses stabilize rat litivityver lysosmalmembranes by non-genomic and genomic effects. Pharm Res, 2000,17:1489-1493
[37] Berki T, Palinkas L, Boldizsar F, et al. Glucocortcoid(GC) sensitivity and GC receptor expression differ thymocyte subpopulations. Int Immunol, 2002,14:463-469
[38] Bartis D, Boldizsar F, Szabo M, et al. Dexamethasone induces rapid tyrosine-phosphorylation of ZAP-70 in Jukat cells. J Steroid Biochem Mol Biol, 2006,98:147-154
[39] Kapojos JJ, van den Berg A, Borghuis T, et al. Enhanced ecto-apyrase activity of stimulated endothelial or mesangial cells is downregulated by glucocorticoids in vitro. Eur J Pharmacol, 2004,501:191-198
[40] Verriere VA, Hynes D, Faherty S,et al. Rapid effects of dexamethasone on intracellular pH and Na+/H+ exchanger activity in human bronchial epithelial cells. J Biolchem. 2005,280:807-814
[41] Urbach V, Walsh DE, Mainprice B,et al. Rapid non-genomic inhibition of ATP-induced Cl- secretion by dexamethasone in human bronchial epithelium. J Physiol, 2002,545:869-878
[42] Urbach V, Verriere V, Grumbach Y, et al. Rapid anti-secretory effects of glucocorticoids in human airway epithelim. Steroids, 2006,71:323-328
[43] Limbourg FP, Huang Z, Plumier JC, et al. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticostereroids. J Clin Invest,2002,110:1729-1738
[44] Hafezi-Moghadam A, Simoncini T, Yang Z,et al. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med, 2002,8: 473-479
[45] Cifone MG, Migliorati G, Parroni R, et al. Dexamethasone-induced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases. Blood, 1999,93: 2282-96
[46] Marchetti MC, Marco BD, Santini MC, et al. Dexamethasone-induced thymocytes apoptosis requires glucocorticoid receptor nuclear translocation but not mitochondrial membrane potential transition. Toxicol Lett, 2003,139:175-180
[47] Bruscoli S, Di Virgilio R, Donato V, et al. Genomic and non-genomic effects of different glucocorticoids on mouse thymocyte apoptosis. Eur J Pharmacol, 2006,529:63-70
[48] Sionov RV, Kflr S, Zafrir E, etal .Glucocorticoid-induced apoptosis revisited: anovel role for glucocorticoid receptor translocation to the mitochcondria. Cell Cycle.2006,5:1017-1026
[49]Buttgereit F, Krauss S, Brand MD, Methylprednisolone inhibits uptake of Ca2+ and Na+ ions into concanavalin A-stimulated thymocytes, Biochem J, 1997,326:329-332
[50] Buttgereit F, Straub RH, Wehling M, etal. Glucocrticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum, 2004,50:3408-3417
[51] Gametchu B. Glucocorticoid receptor-like antigen in lymphoma cell membranes: correlation to cell lysis. Science, 1987,236: 456-461
[52] Chen F, Watson CS, Gametchu B. Association of the glucocorticoid receptor alternatively-spliced transcript 1A with the presence of the high molecular weight membrane glucocorticoid receptor in mouse lymphoma cells. J Cell Biochem, 1999,74: 430-446
[53]杨自军.地塞米松在犬病治疗中的作用[J] .动物科学与兽医医学,1999,
[54]庄文荣.大剂量地塞米松配合伊维菌素治疗犬疥螨病[J].畜牧与兽医,2006,3(5):53
[55]刘占斌,用糖皮质激素治疗犬结膜和角膜炎[J].中国工作犬业,2006,6:28
[56]赵丽云.大剂量地塞米松对犬心肺复苏后脑损伤程度及血浆中兴奋性氨基酸的影响[J].正常医学与临床,2003,23(3):310-313
[57]李正莉,糖皮质激素的抗痫作用及其与γ-氨基酸丁酸的关系[J].中国组织化学与细胞化学杂志1999,8(4):361-365
[58]鲁文,犬猫脊髓损伤的药物治疗[J].中国兽医杂志2002,38(6):49-50
[59] Rogers WA, A retrospective study of probable glucocorticoid-induced hepatopathy in dogs. [J]. J Am Vet Med Assoc,1977,170(6):603-606
[60]杜红伟,地塞米松、生长激素及胰岛素对大鼠肝细胞11β-羟类固醇脱氢酶活性的影响[J].临床儿科杂志2006,24(12):998-1000
[61] Irene B. FeingGold, Effects Of Adrenocorticotropic Hormone And Dexamethasone on Adrenal and Hepatica-Tocopherol Concentrations [J].Free Radical Biology & Medicine,1999,26(5):633-638
[62] Viola Tamasi, The Effect of Dexamethasone on P450 Activities in Regenerating Rat Liver [J].Biochemical and Biophysical Research Communications,2001,6:239-242
[63]王贵民,地塞米松对单层培养的大鼠肝细胞分泌机能的影响[J].中华肝胆外科杂志,2003,9(8): 495-498
[64]杨海峰,地塞米松和利福平对鸡肝CYP450酶系的影响[J].畜牧与兽医,
[65]黄宏奕,张超不同固定液及固定时间对小鼠肝组织结构的影响[J]广州医学院学报,2007,35(2) ,65:68
[66]任成林动物组织HE染色石蜡切片技术的改进[J]河北北方学院学报,2007,23(1),41:45
[67]孙帅,血清酶AST/ALT比值在肝病中的意义[J]中华医药杂志,2005,5(10)
[68] Badylak SF, Van Vleet JR:Sequential morphologic and clinicopathologic alterations in dogs with experimentally induced glucocorticoid hepatopathy. [J]Am J Vet Res 42:1310-1318,1981
[69] Byars,T D, Ling, G. V, Ferris, N. A, and Keeton,K S: Activated Coagulation Time(ACT) of Whole Blood in Normal Dog.Am J Vet Res, 35,(Nov,1976):1359-1361
[70] Thompson, S. W, Sparano, B. M, and Diener, R.M: Vacuoles in the Hepatocytes of Cortisone-Treated Dogs.[J] Am J Pathol, 63,(April,1971):135-145
[71] Dorner, J. J, Hoffmann, W. E, and Long, G.. B.: Corticosteroid Induction of an Isoenzyme of Alkaline Phosphatase in the Dog. [J] Am J Vet Res, 35,(Nov, 1974):1457-1458
[2]冯淇辉主编兽医药物代谢动力学[M]北京科学出版社1987
[3]陈仗榴主编兽医药理学[M]中国农业出版社2002
[4]庄文荣.大剂量地塞米松配合伊维菌素治疗犬疥螨病[J].畜牧与兽医,2006,3(5):53
[5]杨自军,郭世霞,吉朝松等,地塞米松在犬病治疗中的作用[J] .动物科学与兽医医学, 1999, 18(1) :51-52
[6]刘占斌,徐玉生,徐黎用糖皮质激素治疗犬结膜和角膜炎[J].中国工作犬业, 2006, 6: 28
[7]高大柱,胡大勇,王伟等,地塞米松局部应用对犬完全性脊髓横断伤再生的影响[J].安徽医学, 2003, 24(2): 1-3
[8]鲁文,犬猫脊髓损伤的药物治疗[J].中国兽医杂志2002,38(6):49-50
[9]何德华肝胆病理学[M]上海:第二军医大学出版社,1997:1
[10]韩藩五,马学惠,赵元昌,等.齐墩果酸防治实验性肝硬变发生的研究[J].中医杂志,1981,22(3):217
[11]崔婕,薛绍白胞内钙的稳态调节[J].细胞生物学杂志.1995,17(3):97-102
[12] Date M ,Matsuzaki K,Matusushita M ,et al. Differential regulation ofactivin A for hepatocyte growth and fibronectin synthesis in rat liver injury [J]. J Hepatol,2000,32(2) :251-260.
[13] Geeraerts M D,Ronveaux-Dupul MF,Lemasters JJ.Cytosolicfree Ca and protecolysis in lethal oxidative injury in endothelialceils [J] Am J Physiol, 1991,267(5):889-891
[14]巫协宁急性肝损伤的细胞学机制[J].国外医学.消化系疾病分册,1998,18(1):14-16
[15] Nagata S.Apoptosis by death factor [J].Cell.1997,88(3):355-365
[16] Beyaert R,Vanhaesebroeck B, Declercq W,et al. Casein kinase-lphosphorylates the p75 tumor necrosis factor receptor and negativelyregulates tumor necrosis fator signaling for apoptosis[J].J Biol Chem,1995,270(40):23293-23299
[17] Patel, T,Gores GJ.Apoptosis and hepatobiliary disease [J]. Hepatology,1995,21:1725-1741
[18]孙帅,血清酶AST/ALT比值在肝病中的意义[J]中华医药杂志,2005,5(10)
[19]吴文苑,骨型碱性磷酸酶的检测方法和临床应用.临床生物化学检测学分册,1999,20(2):64-65
[20]刘宏伟,吴织芬骨形成蛋白和(或)甲状旁W激素对牙周膜细胞碱性磷酸酶活性的影响,[J]华西口腔医学杂志,1995,13(1):15
[21]陶文洪羚脯氨酸和碱性磷酸酶检测在骨折、骨病研究中的概况,[J]中华骨科杂志, 1989,9(5):376
[22]张若燕血骨源性碱性磷酸酶临床意义深讨[J],四川省卫生管理干部学院学报,2003,22(3):181
[23]王书林兽医临床诊断学[M]中国农业出版社2001
[24] RAYPD, FOSTER DO, LARDY HA, Mode of action of glucocorticoids Stimulation of glucoconeogenesis independent of synthesis denovo of enzymes. J Biolchem, 1964,239:396-400
[25] Sistre FD, Haynes RC Jr. Acute stimulation by glucocorticoids of gluconeogenesis from lactate/pyruvate in isolated hepatocytes from normal and adrenalectomized rats. J Biolchem, 1985,260:54-60
[26] Egana M,Sancho MJ, Macarulla JM. An early effect of cortisol, previous to its glycogenogenic action. Horm Metab Res,1981,13:609-611
[27] Vallejo A, Trueba M, Sancho MJ, et al. Glycogenolytic effect of cortisol previous to its interaction with the cell nucleus in mouse liver, Exp Clin Endocrinol, 1986,87:201-207
[28] Marino A, Bartolome B, Trueba M,et al. Increased phospholipid methylation and glycogen phosphorylase activation after a single dose of dexamethasone in mouse liver. Exp Clin Endocrinol, 1988,92:314-322
[29] Gomez-Munoz A, Hales P, Brindley DN, et al. Rapid activation of glycogenphosphorylase by steroid hormones in cultured rat hepatocytes. Biochem J, 1989,262:417-423
[30] Baque S, Roca A, Guinovart JJ, et al. Direct activatine effects of dexamethasone on glycogen metabolizing enzymes in primary cultured rat hepatocytes. Eur J Biochem, 1996,236:772-777
[31] Zhou J, Kang Z M,Xie Q M, etal. Rapid nongenomic effect of glucocorticoids on allergic asthma reaction in the guinea pig. J Endocrinol, 2003,177:R1-R4
[32] Sun HW, Miao CY, Liu L,etal. Rapid inhibitory effect of glucocorticoids on airway smooth muscle contraction in guinea pigs. Steroids, 2006,71(2):154-159
[33] Liu L,Wang Y X,Zhou J,et al. Rapid non-genomic inhibitory effects of glucocorticoids on human neu trophil degranulation. Inflamm Res, 2005,54:37-41
[34] Long F, Wang Y X, Liu L, et al. Rapid nongenomic inhibitory effects of glucocorticoids on phagocytosis and superoxide anion production by macrophages. Steroids, 2005,70(1):55-61
[35] Baccan GC, Oliceira RD, Mantovani B. Stress and immunological phagocytosis:possible nongenomic action of corticosterone. Life Sci,2004,75:1357-1368
[36] Hinz B, Hirschelmann R. Dexamethasone megadoses stabilize rat litivityver lysosmalmembranes by non-genomic and genomic effects. Pharm Res, 2000,17:1489-1493
[37] Berki T, Palinkas L, Boldizsar F, et al. Glucocortcoid(GC) sensitivity and GC receptor expression differ thymocyte subpopulations. Int Immunol, 2002,14:463-469
[38] Bartis D, Boldizsar F, Szabo M, et al. Dexamethasone induces rapid tyrosine-phosphorylation of ZAP-70 in Jukat cells. J Steroid Biochem Mol Biol, 2006,98:147-154
[39] Kapojos JJ, van den Berg A, Borghuis T, et al. Enhanced ecto-apyrase activity of stimulated endothelial or mesangial cells is downregulated by glucocorticoids in vitro. Eur J Pharmacol, 2004,501:191-198
[40] Verriere VA, Hynes D, Faherty S,et al. Rapid effects of dexamethasone on intracellular pH and Na+/H+ exchanger activity in human bronchial epithelial cells. J Biolchem. 2005,280:807-814
[41] Urbach V, Walsh DE, Mainprice B,et al. Rapid non-genomic inhibition of ATP-induced Cl- secretion by dexamethasone in human bronchial epithelium. J Physiol, 2002,545:869-878
[42] Urbach V, Verriere V, Grumbach Y, et al. Rapid anti-secretory effects of glucocorticoids in human airway epithelim. Steroids, 2006,71:323-328
[43] Limbourg FP, Huang Z, Plumier JC, et al. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticostereroids. J Clin Invest,2002,110:1729-1738
[44] Hafezi-Moghadam A, Simoncini T, Yang Z,et al. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med, 2002,8: 473-479
[45] Cifone MG, Migliorati G, Parroni R, et al. Dexamethasone-induced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases. Blood, 1999,93: 2282-96
[46] Marchetti MC, Marco BD, Santini MC, et al. Dexamethasone-induced thymocytes apoptosis requires glucocorticoid receptor nuclear translocation but not mitochondrial membrane potential transition. Toxicol Lett, 2003,139:175-180
[47] Bruscoli S, Di Virgilio R, Donato V, et al. Genomic and non-genomic effects of different glucocorticoids on mouse thymocyte apoptosis. Eur J Pharmacol, 2006,529:63-70
[48] Sionov RV, Kflr S, Zafrir E, etal .Glucocorticoid-induced apoptosis revisited: anovel role for glucocorticoid receptor translocation to the mitochcondria. Cell Cycle.2006,5:1017-1026
[49]Buttgereit F, Krauss S, Brand MD, Methylprednisolone inhibits uptake of Ca2+ and Na+ ions into concanavalin A-stimulated thymocytes, Biochem J, 1997,326:329-332
[50] Buttgereit F, Straub RH, Wehling M, etal. Glucocrticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum, 2004,50:3408-3417
[51] Gametchu B. Glucocorticoid receptor-like antigen in lymphoma cell membranes: correlation to cell lysis. Science, 1987,236: 456-461
[52] Chen F, Watson CS, Gametchu B. Association of the glucocorticoid receptor alternatively-spliced transcript 1A with the presence of the high molecular weight membrane glucocorticoid receptor in mouse lymphoma cells. J Cell Biochem, 1999,74: 430-446
[53]杨自军.地塞米松在犬病治疗中的作用[J] .动物科学与兽医医学,1999,
[54]庄文荣.大剂量地塞米松配合伊维菌素治疗犬疥螨病[J].畜牧与兽医,2006,3(5):53
[55]刘占斌,用糖皮质激素治疗犬结膜和角膜炎[J].中国工作犬业,2006,6:28
[56]赵丽云.大剂量地塞米松对犬心肺复苏后脑损伤程度及血浆中兴奋性氨基酸的影响[J].正常医学与临床,2003,23(3):310-313
[57]李正莉,糖皮质激素的抗痫作用及其与γ-氨基酸丁酸的关系[J].中国组织化学与细胞化学杂志1999,8(4):361-365
[58]鲁文,犬猫脊髓损伤的药物治疗[J].中国兽医杂志2002,38(6):49-50
[59] Rogers WA, A retrospective study of probable glucocorticoid-induced hepatopathy in dogs. [J]. J Am Vet Med Assoc,1977,170(6):603-606
[60]杜红伟,地塞米松、生长激素及胰岛素对大鼠肝细胞11β-羟类固醇脱氢酶活性的影响[J].临床儿科杂志2006,24(12):998-1000
[61] Irene B. FeingGold, Effects Of Adrenocorticotropic Hormone And Dexamethasone on Adrenal and Hepatica-Tocopherol Concentrations [J].Free Radical Biology & Medicine,1999,26(5):633-638
[62] Viola Tamasi, The Effect of Dexamethasone on P450 Activities in Regenerating Rat Liver [J].Biochemical and Biophysical Research Communications,2001,6:239-242
[63]王贵民,地塞米松对单层培养的大鼠肝细胞分泌机能的影响[J].中华肝胆外科杂志,2003,9(8): 495-498
[64]杨海峰,地塞米松和利福平对鸡肝CYP450酶系的影响[J].畜牧与兽医,
[65]黄宏奕,张超不同固定液及固定时间对小鼠肝组织结构的影响[J]广州医学院学报,2007,35(2) ,65:68
[66]任成林动物组织HE染色石蜡切片技术的改进[J]河北北方学院学报,2007,23(1),41:45
[67]孙帅,血清酶AST/ALT比值在肝病中的意义[J]中华医药杂志,2005,5(10)
[68] Badylak SF, Van Vleet JR:Sequential morphologic and clinicopathologic alterations in dogs with experimentally induced glucocorticoid hepatopathy. [J]Am J Vet Res 42:1310-1318,1981
[69] Byars,T D, Ling, G. V, Ferris, N. A, and Keeton,K S: Activated Coagulation Time(ACT) of Whole Blood in Normal Dog.Am J Vet Res, 35,(Nov,1976):1359-1361
[70] Thompson, S. W, Sparano, B. M, and Diener, R.M: Vacuoles in the Hepatocytes of Cortisone-Treated Dogs.[J] Am J Pathol, 63,(April,1971):135-145
[71] Dorner, J. J, Hoffmann, W. E, and Long, G.. B.: Corticosteroid Induction of an Isoenzyme of Alkaline Phosphatase in the Dog. [J] Am J Vet Res, 35,(Nov, 1974):1457-1458