Smad信号通路及CTGF在依那普利抑制高肺血流性肺动脉高压形成中的作用机制
|
摘要
背景与目的小儿左向右分流先天性心脏病的并发症较多,最常见的是高肺血流性肺动脉高压(pulmonary artery hypertension PAH),严重影响患儿的预后。目前治疗主要包括药物治疗、手术治疗。不适合手术或术后功能未得到改善的患儿,多采用药物治疗。其中药物治疗主要包括N0吸入、磷酸二酯酶-5(PDE-5)抑制剂、前列腺素类物质及内皮素抑制剂及各种药物的联合应用。因大量的分子参与了肺动脉高压的发病机制,其发病机制尚不十分清楚,目前仍无比较满意的疗法。因此明确肺动脉高压的发病机制对于寻求更有效的治疗肺动脉高压的方法具有重要意义。
本研究的目的是观察依那普利对大鼠高肺血流性肺动脉高压形成是否有抑制作用,并探讨Smad信号通路及结缔组织生长因子(CTGF)在依那普利抑制肺动脉高压形成中可能的作用机制。
方法45只wistar大鼠随机分为对照组,分流组,依那普利干预组,每组15只。各组于第8周测量右心室平均收缩压(RVSP)右心肥厚指数(RVHI), HE染色观察肺动脉形态学改变,计算血管壁肌层面积与血管总面积比值(WA%)及管壁厚度与血管外径比值(WT%)。分别采用免疫组化法、Western Blot法检测各组大鼠肺动脉平滑肌中Smad7、CTGF蛋白的表达。
结果与对照组相比,分流组大鼠肺动脉管壁明显增厚、狭窄,RVSP、RVHI及WT%、WA%增高(P<0.01),Smad7蛋白表达减弱(P<0.01), CTGF蛋白表达增强(P<0.01)。与分流组相比,依那普利干预组大鼠肺动脉管壁增厚、狭窄程度显著减轻,RVSP、RVHI及WT%、WA%明显降低(P<0.01), Smad7蛋白(P<0.05)表达增高,CTGF蛋白(P<0.05)表达降低。
结论在动物试验中,依那普利具有抑制高肺血流性肺动脉高压形成的作用,Smad信号通路及结缔组织生长因子(CTGF)是其可能发挥抑制作用的机制之一
BACKGROUND Patients with congenital heart disease are usually associated with a lot of neopathy,and pulmonary arterial hypertension is the most common complication which affacts the prognosis of patients. The current treatments mainly includes pharmacotherapy、Surgery. The patients that are not suitable for surgery or their postoperative function are not improved can use drug therapies.The drugs,such as nitric oxide, prostaglandin inhibitors of phosphodiesterase and endothelin antagonists are widely used to treat pulmonary arterial hypertension. Because there are lots of elements involved in the pathogenesis of pulmonary hypertension,its pathogenesis is still unknown. There is no satisfactory therapy for it. Regular monitoring, it's important to Clear the pathogenesis of pulmonary hypertension and seek more effective treatments for pulmonary arterial hypertension treatment.
OBJECTIVE To observe the inhibitive effect of enalapril on high-flow pulmonary hypertension in rats and to explore the mechanism of Smad signaling pathway and connective tissue growth factor(CTGF) in the pulmonary hypertension by enalapril.
METHODS Forty-five famale wistar rats were randomly divided into a shamoperated group,a high-flow pulmonary hypertension group,a enalapril treated group (n=15each). The rat model of pulmonary hypertension was established by underwent abdominal aorta and inferior vena cava shunt operation. Measuring the RVSP and RVHI in each group and calculating WT% and WA% after HE staining the left lung.The small pulmonary arterial morphologic changes in each groups were studied with microscopy for morphometric analysis.The expression of Smad7 and CTGF by pulmanory arteries were determined by immunohistochemistry and western blot.
RESULTS Compared with shamoperated group,the pulmonary arterial morphologic changes in the high-flow pulmonary hypertension group showed that the WT%、WA% and RVSP、RVHI (P<0.01) togther with the expression of CTGF (P<0.05) increased significantly.However in enalapril treated group,they are deceased significantly than the high-flow pulmonary hypertension group (P<0.01).The expression of Smad7 (P<0.05) in high-flow pulmonary hypertension group was increased compared with shamoperated group.Compared with high-flow pulmomary hypertension group,the expression of Smad7 (P<0.05) in enalapril treated group was increased.
CONCLUSIONS Enalapric may partly prevent the development of pulmanory hypertension by affecting CTGF and Smad7 of the pulmonary hypertension rats.
本研究的目的是观察依那普利对大鼠高肺血流性肺动脉高压形成是否有抑制作用,并探讨Smad信号通路及结缔组织生长因子(CTGF)在依那普利抑制肺动脉高压形成中可能的作用机制。
方法45只wistar大鼠随机分为对照组,分流组,依那普利干预组,每组15只。各组于第8周测量右心室平均收缩压(RVSP)右心肥厚指数(RVHI), HE染色观察肺动脉形态学改变,计算血管壁肌层面积与血管总面积比值(WA%)及管壁厚度与血管外径比值(WT%)。分别采用免疫组化法、Western Blot法检测各组大鼠肺动脉平滑肌中Smad7、CTGF蛋白的表达。
结果与对照组相比,分流组大鼠肺动脉管壁明显增厚、狭窄,RVSP、RVHI及WT%、WA%增高(P<0.01),Smad7蛋白表达减弱(P<0.01), CTGF蛋白表达增强(P<0.01)。与分流组相比,依那普利干预组大鼠肺动脉管壁增厚、狭窄程度显著减轻,RVSP、RVHI及WT%、WA%明显降低(P<0.01), Smad7蛋白(P<0.05)表达增高,CTGF蛋白(P<0.05)表达降低。
结论在动物试验中,依那普利具有抑制高肺血流性肺动脉高压形成的作用,Smad信号通路及结缔组织生长因子(CTGF)是其可能发挥抑制作用的机制之一
BACKGROUND Patients with congenital heart disease are usually associated with a lot of neopathy,and pulmonary arterial hypertension is the most common complication which affacts the prognosis of patients. The current treatments mainly includes pharmacotherapy、Surgery. The patients that are not suitable for surgery or their postoperative function are not improved can use drug therapies.The drugs,such as nitric oxide, prostaglandin inhibitors of phosphodiesterase and endothelin antagonists are widely used to treat pulmonary arterial hypertension. Because there are lots of elements involved in the pathogenesis of pulmonary hypertension,its pathogenesis is still unknown. There is no satisfactory therapy for it. Regular monitoring, it's important to Clear the pathogenesis of pulmonary hypertension and seek more effective treatments for pulmonary arterial hypertension treatment.
OBJECTIVE To observe the inhibitive effect of enalapril on high-flow pulmonary hypertension in rats and to explore the mechanism of Smad signaling pathway and connective tissue growth factor(CTGF) in the pulmonary hypertension by enalapril.
METHODS Forty-five famale wistar rats were randomly divided into a shamoperated group,a high-flow pulmonary hypertension group,a enalapril treated group (n=15each). The rat model of pulmonary hypertension was established by underwent abdominal aorta and inferior vena cava shunt operation. Measuring the RVSP and RVHI in each group and calculating WT% and WA% after HE staining the left lung.The small pulmonary arterial morphologic changes in each groups were studied with microscopy for morphometric analysis.The expression of Smad7 and CTGF by pulmanory arteries were determined by immunohistochemistry and western blot.
RESULTS Compared with shamoperated group,the pulmonary arterial morphologic changes in the high-flow pulmonary hypertension group showed that the WT%、WA% and RVSP、RVHI (P<0.01) togther with the expression of CTGF (P<0.05) increased significantly.However in enalapril treated group,they are deceased significantly than the high-flow pulmonary hypertension group (P<0.01).The expression of Smad7 (P<0.05) in high-flow pulmonary hypertension group was increased compared with shamoperated group.Compared with high-flow pulmomary hypertension group,the expression of Smad7 (P<0.05) in enalapril treated group was increased.
CONCLUSIONS Enalapric may partly prevent the development of pulmanory hypertension by affecting CTGF and Smad7 of the pulmonary hypertension rats.
引文
[1]Hoffman J I, Rudolph AM. The natural history of ventricular septal defects in infancy [J].Am J Cardiol,1965,16(5):634-653.
[2]Steele P, Fuster V, Cohen M, et al. Isolated atrial septal defect with pulmonary vascular obstructive disease:long-term follow-up and prediction of outcome after surgical correction [J]. Circulation,1987,76(5):1037-1042.
[3]Aesim C, David W, Courman B, et al. Apoptosis(Programmed Cell Death)in arteries of the neonatal lamb[J]. Circulation Reseach,1995,76(2):168-175.
[4]Colwell A S, Phan T T, Kong W. Hypertrophic Scar Fibroblas ts Have Increased Connective Tissue Growth Factor Expression after Transforming Growth Factor-Stimulation[J]. Plast Reconstr Surg,2005,116(5):1387-1390.
[5]Leask A, Sa S, Holmes A, et al. The control of ccn2(ctgf)gene expression in normal and scleroderma fibroblasts. Mol Pathol,2001,54(3):180-183.
[6]Vetuschi A, Sferra R, Latella G, et al. Smad3-null mice lack interstitial cells of Cajal in the colonic wall.Eur J Clin Invest,2006,36(1):41-48.
[7]马松林,赵秋,龚勇.纤维化胰腺组织中TGF-β1、Smad3、 Smad7的表达及意义[J].世界华人消化杂志,2007,15(2)：185-188.
[8]Chen W, Yan H, Mo X. Effect of tetrandrine on expression of bFGF in lung tissue of rat with chronic hypoxic pulmonary hypertension[J]. Hua Xi Yi Ke Da Xue Xue Bao,2001,32(1):12-4,58.
[9]Vieilled-Baron A, Frisdal E, Raffestin B, et al. Inhibition of matrix metall opro-teinase by lung TIMP-1 gene transfer limitsmonocrotaline-induced pulmonary vascular remodeling in rats[J]. Hum GeneTher,2003,14(9):861-869.
[10]Barth P J, Kimpel C, Roy S, et al. An improved mathematical approach for the assessment of the medial thickness of pulmonary arteries [J]. Pathol Res Pract, 1993,189(5):567-576.
[11]Warnecke I, Bucherl E S. The expermental production of a persistent ductus arteriosus for testing catheter closure devices[J]. Anna Thorac Surg,1985,39:441-444.
[12]Ocampo C, Ingram P, Ilbawi M, et al. Revisiting the surgical creation of volume load by aorto-caval shunt in rats[J]. Mol Cell Biochem,2003,251(1-2):139-143.
[13]李晓惠,杜宝军,汤秀英,等.大鼠高肺血流性肺动脉高压形成中肺血管结构的变化[J].中国医学科学院学报,2005,27(4)：446-451.
[14]Bradham D M, Igarashi A, Potter R L, et al. Conective tissue growth factor:a cysteine-rich mitogen secreted by human vascular endothelial cells related to the SRC-induced immediate early gene product CEF-10[J]. J Cell Biol,1991, 114(6):1285-1294.
[15]As ano M, Kubota S, Nakanishi T, et al. Effect of connective tissue growth factor (CCN2/CTGF) on prol iferation and differentiation of mouse periodontal 1 igament-derived cells[J]. Cell Commun Signal,2005,3:11.
[16]Bork P. The modular architecture of a new family of growth regulatorsrelated to connective tissue growth factor[J]. FEBS Lett,1993,327(2):125-130.
[17]Lasky J A, Ortiz L A, Tonthat B, et al. Connective tissue growth factor mRNA expression is upregulated in bleomycir-induced lung fibrosis[J]. Am J Physiol, 1998,275(2ptl):L365-371.
[18]Igrashi A, Okochi H, Bradham D M, et al. Regulation of connective tissue,growth factor gene expression in human skin fibroblasts and duing wound repair [J]. Mol Biol Cell,1993,4(6):637-645.
[19]Hishikawa K, Oemarb S, Nakakit. Static pressure regulates connective tissue growth factor expression in human mesangial cell[J]. J Biol Chem,2001, 276(20):16797-16803.
[20]Shimo T, Kubota S, Kondo S, et al. Connective tissue growth factor as a major angiogenic agent that is induced by hypoxia in a human breast cancer cell line[J]. Cancer Lett,2001,174(1):57-64.
[21]Schild C, Trueb B. Mechanical stress is required for high-level expression of connective tissue growth factor[J]. Exp Cell Res,2002,274(1):83-91.
[22]Fan Wh, Pech M, Kamowsky M J. Connective tissue growth factor (CTGF) stimulates vascular smooth muscle cell growth and migration in vitro[J]. Eur J Cell Biol,2000,79(12):195-923.
[23]Lee Y S, Byun J, Kim J A, et al. Monocrotaline-induced pulmonary hypertension correlates with upregulation of connective growth factor expression in the lung[J]. Exp Mol Med,2005,37(1):27-35.
[24]Grotendorst G R. Connective tissue growth factor:a mediator of TGF-beta action on fibroblasts[J]. Cytokine Growth Factor Rev,1999,10(3):171-179.
[25]Laping N J, Grygielko E, Mathur A, et al. Inhibition of transforming growth factor(TGF)-beta-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity:SB-431542[J]. Mol Pharmacol,2002,62(1):58-64.
[26]贲长恩,于世瀛,金永三.肝纤维化及中药逆转作用[J].中医药通报,2002,1(2)：39-45.
[27]Gorelik L, Flarell R A. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease[J]. Immunity,2000, 12(2):171-181.
[28]Frenkle S R, Saadeh P B, Mehrara B J, et al. Transforming growth factor beta superfamily members:role in cartilage modeling[J]. Plast Reconstr Surg,2000, 105(3):980-990.
[29]Gressner A M, Weiskirchen R, Breitkopf K, et al. Roles of TGF-beta in hepatic fibrosis[J]. Front Biosci,2002,7:793-807.
[30]Blom I E, Goldschmeding R, Leask A. Gene regulation of connective tissue growth factor:new targets for antifibrotic therapy[J]. Matrix Biol,2002,21(6): 473-482.
[31]Verrecchia F, Maubiel A. Transforming growth factor-beta signaling through the Smad pathway:role in extracellular matrix gene expression and regulation[J]. J Invest Dermatol,2002,118(2):211-215.
[32]Chen W, Fu X, Sheng Z. Review of current progress in the structure and function of Smad proteins[J]. Chin Med J(Engl),2002,115(3):446-450.
[33]Ulloa L, Tabibzadeh S. Lefty inhibits receptor-regulated Smad phosphorylation induced by the activated transforming growth factor-beta receptor [J]. J Biol Chem, 2001,276(24):21397-21404.
[34]Leask A, Sa S, Holmes A, et al. The control of ccn2(ctgf)gene expression in normal and scleroderma fibroblasts[J]. Mol Pathol,2001,54(3):180-183.
[35]Phanish M K, Wahab N A, Hendry B M. TGF-betal-induced connective tissue growth factor(CCN2) expres-sion in human renal proximal tubule epihelial cells requires Ras/MEK/ERK and Smad signalling[J]. Nephron Exp Nephrol,2005, 100(4):e156-e165.
[36]Yokoi H, Mukoyama M, Sugawara A, et al. Role of connective tissue growth factor in fibronectin expression and tubulointers titial fibrosis[J]. Am J Physiol Renal Physiol,2002;282(5):F933-F942.
[37]黄海长,杨敏,李惊子,等.结缔组织生长因子通过活化Erk-1/2信号通路促成纤维细胞生成[J].中华医学杂志,2005,85(19)：1322-1326.
[38]Akman H O, Zhang H, Siddiqui M A, et al. Response to hypoxia involves transforming growth factor-β2 and Smad proteins in humam endothelial cells[J]. Blood,2001,98(12):3324-3331.
[39]Ikedo H, Tamaki K. Smad protein and TGF-beta signaling in vascular smooth cells[J]. Int J Mol Med,2003,11(5):645-650.
[40]Li Y J, Azuma A, Usuki J, et al. EM703 improves bleomycin-induced pulmonary fibrosis in mice by the inhibition of TGF-beta signaling in lung fibroblasts[J]. Respir Res,2006,7(27):16.
[41]Rodriguez-Vita J, Sanchez-Lppez E, Esteban V, et al. Angiotensin Ⅱ activates the Smad pathway in vascular smooth muscule cells by a transforming growth factor-β-independent mechanism[J]. Circulation,2005,111(19):2509-2517.
[42]Dupuis J, Stewart D J. Cernacek P,et al.Human pulmonary circulation is an important site for both cleatance and production of endothlin-1[J]. Circulation,1996, 94(7):1578-1584.
[43]陶慧琳,王怀良,等.几种药物对肺主动脉平滑肌细胞增殖作用影响的比较研究[J].中国现代应用药学杂志,2005,3(22)：187-190.
[44]Shinichi K, Yi-Jen L, Paul C, et al. Angiotensinconverting enzyme inhibitor preserves p21 and endothelial nitric oxide synthase expressionin monocrotaline-induced pulmomary arterial hypertension in rats[J].Circulation,2001,104(9): 945-950.
[45]高修仁,彭龙云,麦炜颐,等.高血压大鼠心肌中MMP-2的蛋白表达及其RAS阻断后的变化[J].中山大学学报：医学科学版,2003,24(1)：30-34.
[46]Dixon I M, Hao J, Reid N L, et al. Effect of chronic AT(1) receptor blockade on cardiac Smad overexpression in hereditary cardiomyopathic hamsters[J]. Cardiovas Res,2000,46(2):286-297.
[47]Sorescu D. Smad3 mediates angiotensin Ⅱ-and TGF-betal-induced vascular fibrosis:Smad3 thickens the plot[J]. Circ Res,2006,98(8):988-989.
[48]李谧,周同甫,刘瀚旻,等.卡托普利对大鼠左向右分流模型肺小动脉重构的影响[J].四川大学学报(医学版),2006,37(2)：242-245.
[49]杨栋,谢燕.西拉普利对缺氧性大鼠肺动脉高压肺血管结构的保护[J].中国临床医学,2008,4(15)：471-473.
[1]Bradham D M, IgarashiA, Potter R L, et al. Conective tissue growth factor:a cysteine-rich mitogen secreted by human vascular endothelial cells related to the SRC-induced immediate early gene product CEF-10[J]. J CellBiol,1991,114(6): 1285-1294.
[2]云云,张红锋.结缔组织生长因子对血管生成和细胞功能调节[J].细胞生物学杂志,2006,28(5)：689-693.
[3]Lau L F, Lam S C. The CCN family of angiogenic regulators:the integrin connection[J]. Exp Cell Res,1999,248(1):44-57.
[4]Wahab N A, Brinkman H, Mason R M. Uptake and intracellular transport of the connective tissue growth factor:a Potential mode of action[J]. Bio Chem J, 2001,359(ptl):89-97.
[5]Kondo S, Kubota S, Eguchi T, et al. Characterization of a mouse ctgf3UTR segment that mediates repressive regulation of gene expression[J]. Biochem Biop Res Commun,2000,278:119-127.
[6]Holmes A, Abraham D J, Sa S, et al. CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling[J]. J Biol Chem, 2001:276(14):10549-601.
[7]Ruperez M, Lorenzo O, Blanco-Colio L M, et al. Connective tissue growth factor is a mediator of angiotensin-inducedfibrosis[J]. Circulation,2003,108(12):1499-1505.
[8]Finckenberg P, Inkinen K, Ahonen J, et al. Angiotensin Ⅱ induces connective tissue growth factor gene expression via calcineurin-dependent pathways[J]. Am J Pathol, 2003,163(1):355-466.
[9]Dimmeier J, Beer H D, Brauehle M, et al. Dexamethasone is a novel potent inducer of connective tissue growth factor expression,implications for glucocorticoid therapy [J]. J Biol Chem,1998,273(29):18185-18190.
[10]Suzuma K, Naruse K, Suzuma I, et al. Vascular endothelial growth factor induces expression of connective tissue growth factor via KDR, Fltl, and phosphatidylinositol 3-kinase-akt-dependent pathways in retinal vascular cells[J]. J Biol Chem,2000, 275(52):40725-40731.
[11]Kazi A S, Lotfi E A, Goncharova O, et al. Vascular endothelial growth factor-induced secretion of fibroaectin is ERK dependent[J]. Am J Physiol Lung Cell Mol Physiol,2004,286(3):L539-L545.
[12]Kessler D, Dethlefsen S, Haase I, et al. Fibroblasts in mechanically stressed collagen lattices assume a'synthetic'phenotype[J]. J Biol Chem,2001,276(39): 36575-36585.
[13]Hishikawa K, Oemar B S, Nakaki T. Static pressure regulates connective tissue growth factor expression in human mesangial cells[J]. J Biol chem,2001,276(18): 16797-16803.
[14]Schild C, Trueb B. Mechanical stress is required for high-level expression of connective tissue growth factor[J]. Exp Cell Res,2002,274(1):83-91.
[15]Albraham D J, Shiwen X, Black C M, et al. Tumor necrosis factor alpha suppresses the induction of connective tissue growth factor by transforming growth factor-beta in normal and sclerodema fibroblasts [J]. Jbiol Chem,2000,275(20):15220.
[16]Roll Ziescbe, Elisabeth Hofbauer, Karin Wittmann, et al. A Preliminary study of Long-Term Treatment with Interferon Gamma-lb and Low-Dose Prednisolone in Patients with Idiopathic Pulmonary Fibrosis[J]. The New England Journal of Medinice,1999,21 (341):1264-1269.
[17]Iin BR, Chang CC, Chen T F, et al. Connective Tissue Growth Factor Inhibits Metastasis and Acts as an Independent Prognostic Marker in Colorectal Cancer[J]. Gastroenterology,2005,128(1):9-23.
[18]Planyue N, Perbal B. A Structural Approach to the Role of CCN (Cyr16/CTGF /NOV), Proteins in Tumorigenesis[J]. Cancer Cell Int,2003,3(1):15.
[19]Moritani NH, Kubota S, Nishisa T, et al. Suppressive Effect of Overexpressed Connective Tissue Growth Factor on Tumor Cell Growth in a Human Oral Squamous Cell Carcinoma Derived Cell Line[J]. Cancer lett,2003,192(1):205-214.
[20]Kolipany A, Friess H, Dimola F F, et al. Connective Tissue Growth Factor Gene Expressional Alters Tumor Progression in Esophageal Cancer [J]. World J Surg, 2002,26(4):420-427.
[21]曾志军,杨连粤,王伟,等.Cyr61,CTGF和Nov基因在孤立性大肝癌中的表达及意义[J].肝胆外科杂志,2006,14(5)：395-397.
[22]曾志军,杨连粤,王伟,等Cyr61,CTGF和Nov基因在肝癌细胞中的表达及与临床特征的关系[J].中华肝胆外科杂志,2005,11(7)：452-424.
[23]肖在鹏,胡祥,杨佩满,等.结缔组织生长因子在胃硬癌形成机制中的作用[J].中国医师进修杂志,2007,30(6)：8-11.
[24]杨常春,王穗暖,张一,等.结缔组织生长因子在脑胶质瘤组织中的表达和肿瘤级别的关系[J].临床神经外科杂志,2006,3(3)：89-101.
[25]Koliopanos A, Friess H, diMola F F, et al. Connective tissue Growth Factor Gene Exprssion Alters Tumor Progression in Esophageal Cancer[J]. World J Surg,2002, 26(4):420-427.
[26]Shakunaga T, Ozaki T, Ohara N, et al. Takigawa M and Inoue H:Expression of connective tissue growth factor in cartilaginous tumours[J]. Cancer,2000,89(7): 1466-1473.
[27]Rimon E, Sasson R, Dantes A, et al. Gonadotropin-induced gene regulation in human granulosa cells obtained from IVF pations modulation of genes coding for growth factors and their receptors and genes involved in cancer and other diseases [J]. Int J Oncol,2004,24(5):1325-1338.
[28]陶秀平,张裕华,刘福云.甲状腺癌CTGF、TGFβ1表达及临床病理意义[J].医学临床研究,2005,22(7)：936-938.
[29]杨竹林,黄生福,苗雄鹰,等.胰腺癌组织中CCN家族基因和转化生长因子-β1表达及其临床病理意义[J].中华实验外科杂志,2005,22(10)：1276.
[30]李友忠,卢永德,曾益慈,等.喉鳞状细胞癌组织中CTGF和OPN的表达及其临床意义[J].临床耳鼻咽喉头颈外科杂志,2007,21(3)：121-123.
[31]崔玲玲,孙锦峰,王旗,等.人肺癌组织中富含酪氨酸61和结缔组织生长因子的表达[J].郑州大学学报,2007,42(3)：453-457.
[32]董秀明.结缔组织生长因子科降低结直肠癌转移率[J].中华放射肿瘤学杂志,2005,14(3)：176.
[33]Chang C C, Shih J Y, Jeng Y M, et al. Connective tissue growth factor and its role in lung adenocarcinoma invasion and metastasis[J]. J Natl Cancer Inst,2004,96(5): 364-375.
[34]]Lee Y S, Byun J'Kim J A, et al. Monocrotaline-induced pulmonary hypertension correlates with upregulation of connective tissue growth factor expression in the lung[J]. Experiment and Molecuar Medicine,2005,37(1):27-35.
[35]何立英,刘静,刘亚敏CTGF在低氧性肺动脉高压大鼠肺血管重构中的作用[J].武警医学院学报,2010,19(5)：351-353.
[36]崔茂香,陈晓玲,霍春玲,等.结缔组织生长因子在肺纤维化初期肺动脉中的表达[J].生理学报,2008,60(4)：535-540.
[37]李晓惠,杜宝军,唐朝枢.硫化氢供体对大鼠高肺血流性肺动脉高压中内皮素-1及结缔组织生长因子表达的影响[J].中国病理生理学志,2008,24(3)：446-450.
[38]Evgenov O V, Pacher P, Schmidt P M, et al. NO-independent stimulators and activators of soluble guanylate cyclase:discovery and therapeutic potential [J]. Nat Rev Drug Discov,2006,5(9):755-768.
[39]Fan W H, Pech M, Karnovsky M J, et al. Connective tissue factor (CTGF) stimulates vascular smooth muscle cell growth and migration in vitro[J].Eur J Cell Biol,2000,79 (12):915-923.
[40]Suzuma K, Naruse K, Suzuma I, et al. Vascular Endothelial Growth Factor Induces Expression of Connective Tissue Growth Factor via KDR,Fit1,and Phosphatidylin- ositol 3-Kinase-Akt-dependent Pathways in Retinal Vascular Cells[J]. J Biol Chem.2000.275(52):40725-40731.
[41]Orphanides C, Fine L, Norman J T. Hypoxia stimulates proximal tubular cell matrix production via a TGF-β1-independent mechanism[J]. Kidney Int, 1997,52(5):637-647.
[42]Honq K H, Yoo S A, Kang S S, et al. Hypoxia induces expression of connective tissue growth in scleroderma skin fibroblasts[J]. Clin Exp Immunol,2006,146(2): 362-370.
[43]Olbry M, Jarzab M, Jazowiecka-Rakus J, et al. Gene expression profile of B 16(FIO) murine melanoma cells exposed to hypoxic conditions in vitro[J]. Gene Expr, 2006,13(3):191-203.
[44]Paradis V, Dargere D, Bonvoust F, et al. Effects and regulation of connective tissue growth factor on hepatic stellate cells[J]. Lab Invest,2002,82(6):767-774.
[45]Paradis V, Dargere D, Vidaud M, et al. Expression of connective tissue growth factor in experimental rat and human liver fibrosis[J].Hepatology,1999,30(4):968-976.
[46]Hayashi N, Kakimuma T, Soma Y, et al. Connective tissue growth factor is directly related to liver fibrosis[J]. Hepatogastroenterology,2002,49(43):133-135.
[47]Yokoi H, Mukoyama M, Nagac T, et al. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstital fibrosis[J]. Am Soc Nephrol,2004,15(6):1430-1440.
[48]Riser B L, Cortes P. Connective tissue growth factor and its regulation:a new element in diabetic glomerulosclerosis[J]. Ren Fail,2001,23(3-4):459-470.
[49]Hishikawa K, Nakaki T, Oemar B S, et al. Static pressure regulates connective tissue growth factor expression in human mesangial cells[J]. Biol Chem,2001, 276(20):1797-1803.
[50]Gore-Hyer E, Shegogue D, Markiewics M, et al. TGF-beta and CTGF have overlapping and distinct fibrogenic effects on human renal cells[J]. Am J Physiol, 2002,283(5):F707-716.
[51]Szeto C C, LaiK B, Chow K M, et al. Differential effects of transforming growth factor-beta on the synthes is of connective tissue growth factor and vascular endothelial growth factor by periton ealmesothelial cell[J]. Nephron Exp Nephrol, 2005,99(4):95-104.
[52]Liu F Y, Xiao L, Peng Y M, et al. Inhibition effect of small interfering RNA of connective tissue growth factor on the expression of vascular endothelial growth factor and connective tissue growth factor in cultured human periton ealmesothelial cells[J]. Chin Med J(Eng I),2007,120(3):231-236.
[53]Ebisawa T, Fukuchi M, Murakami G, et al. Smurfl interacts with transforming growth factor-beta type Ⅰ receptor through Smad7 and induces receptor degradation[J]. J Biol Chem,2001,276(16):12477-12480.
[54]张浩,刘伏友,刘映红,等.转化生长因子-β1对人腹膜间皮细胞结缔组织生长因子的影响[J].中华肾脏病杂志,2004,20(4)：282-285.
[55]Sakamoto N, Sugimura K, Kawashima H, et al. Influence of glucose and inflammatory cytokines on TGF-betal and CTGF mRNA expressions in human peritoneal mesothelial cells[J]. Int J Mol Med,2005,15(6):907-911.
[56]Thaler K, Mack J A, Berho M, et al. Coincidence of connective tissue growth factor expression with fibrosis and angiogenesis in post-operative peritoneal adhesion fomation[J]. Eur Surg Res,2005,37(4):235-241.
[57]Ogawa E, Elliott W M, Hughes F, et al. Latent adenoviral infection induces production of growth factors relevant to airway remodeling in COPD[J]. Am J Physiol Lung Cel Mol Physiol,2004,286(1):L189-197.
[58]Watts K L, Sampson E M, Schultz G S, et al. Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts[J]. Am J Respir Cell Mol Biol,2005,32(4):290-300.
[59]Watts K L, Sampson E M, Schultz G S, et al. Simvastatin inhibits growth factor expression and modulates profibrogenic markers in 1 ung fibroblasts[J]. Am J Respir Cell Mol Biol,2005,32(4):290-300.
[2]Steele P, Fuster V, Cohen M, et al. Isolated atrial septal defect with pulmonary vascular obstructive disease:long-term follow-up and prediction of outcome after surgical correction [J]. Circulation,1987,76(5):1037-1042.
[3]Aesim C, David W, Courman B, et al. Apoptosis(Programmed Cell Death)in arteries of the neonatal lamb[J]. Circulation Reseach,1995,76(2):168-175.
[4]Colwell A S, Phan T T, Kong W. Hypertrophic Scar Fibroblas ts Have Increased Connective Tissue Growth Factor Expression after Transforming Growth Factor-Stimulation[J]. Plast Reconstr Surg,2005,116(5):1387-1390.
[5]Leask A, Sa S, Holmes A, et al. The control of ccn2(ctgf)gene expression in normal and scleroderma fibroblasts. Mol Pathol,2001,54(3):180-183.
[6]Vetuschi A, Sferra R, Latella G, et al. Smad3-null mice lack interstitial cells of Cajal in the colonic wall.Eur J Clin Invest,2006,36(1):41-48.
[7]马松林,赵秋,龚勇.纤维化胰腺组织中TGF-β1、Smad3、 Smad7的表达及意义[J].世界华人消化杂志,2007,15(2)：185-188.
[8]Chen W, Yan H, Mo X. Effect of tetrandrine on expression of bFGF in lung tissue of rat with chronic hypoxic pulmonary hypertension[J]. Hua Xi Yi Ke Da Xue Xue Bao,2001,32(1):12-4,58.
[9]Vieilled-Baron A, Frisdal E, Raffestin B, et al. Inhibition of matrix metall opro-teinase by lung TIMP-1 gene transfer limitsmonocrotaline-induced pulmonary vascular remodeling in rats[J]. Hum GeneTher,2003,14(9):861-869.
[10]Barth P J, Kimpel C, Roy S, et al. An improved mathematical approach for the assessment of the medial thickness of pulmonary arteries [J]. Pathol Res Pract, 1993,189(5):567-576.
[11]Warnecke I, Bucherl E S. The expermental production of a persistent ductus arteriosus for testing catheter closure devices[J]. Anna Thorac Surg,1985,39:441-444.
[12]Ocampo C, Ingram P, Ilbawi M, et al. Revisiting the surgical creation of volume load by aorto-caval shunt in rats[J]. Mol Cell Biochem,2003,251(1-2):139-143.
[13]李晓惠,杜宝军,汤秀英,等.大鼠高肺血流性肺动脉高压形成中肺血管结构的变化[J].中国医学科学院学报,2005,27(4)：446-451.
[14]Bradham D M, Igarashi A, Potter R L, et al. Conective tissue growth factor:a cysteine-rich mitogen secreted by human vascular endothelial cells related to the SRC-induced immediate early gene product CEF-10[J]. J Cell Biol,1991, 114(6):1285-1294.
[15]As ano M, Kubota S, Nakanishi T, et al. Effect of connective tissue growth factor (CCN2/CTGF) on prol iferation and differentiation of mouse periodontal 1 igament-derived cells[J]. Cell Commun Signal,2005,3:11.
[16]Bork P. The modular architecture of a new family of growth regulatorsrelated to connective tissue growth factor[J]. FEBS Lett,1993,327(2):125-130.
[17]Lasky J A, Ortiz L A, Tonthat B, et al. Connective tissue growth factor mRNA expression is upregulated in bleomycir-induced lung fibrosis[J]. Am J Physiol, 1998,275(2ptl):L365-371.
[18]Igrashi A, Okochi H, Bradham D M, et al. Regulation of connective tissue,growth factor gene expression in human skin fibroblasts and duing wound repair [J]. Mol Biol Cell,1993,4(6):637-645.
[19]Hishikawa K, Oemarb S, Nakakit. Static pressure regulates connective tissue growth factor expression in human mesangial cell[J]. J Biol Chem,2001, 276(20):16797-16803.
[20]Shimo T, Kubota S, Kondo S, et al. Connective tissue growth factor as a major angiogenic agent that is induced by hypoxia in a human breast cancer cell line[J]. Cancer Lett,2001,174(1):57-64.
[21]Schild C, Trueb B. Mechanical stress is required for high-level expression of connective tissue growth factor[J]. Exp Cell Res,2002,274(1):83-91.
[22]Fan Wh, Pech M, Kamowsky M J. Connective tissue growth factor (CTGF) stimulates vascular smooth muscle cell growth and migration in vitro[J]. Eur J Cell Biol,2000,79(12):195-923.
[23]Lee Y S, Byun J, Kim J A, et al. Monocrotaline-induced pulmonary hypertension correlates with upregulation of connective growth factor expression in the lung[J]. Exp Mol Med,2005,37(1):27-35.
[24]Grotendorst G R. Connective tissue growth factor:a mediator of TGF-beta action on fibroblasts[J]. Cytokine Growth Factor Rev,1999,10(3):171-179.
[25]Laping N J, Grygielko E, Mathur A, et al. Inhibition of transforming growth factor(TGF)-beta-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity:SB-431542[J]. Mol Pharmacol,2002,62(1):58-64.
[26]贲长恩,于世瀛,金永三.肝纤维化及中药逆转作用[J].中医药通报,2002,1(2)：39-45.
[27]Gorelik L, Flarell R A. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease[J]. Immunity,2000, 12(2):171-181.
[28]Frenkle S R, Saadeh P B, Mehrara B J, et al. Transforming growth factor beta superfamily members:role in cartilage modeling[J]. Plast Reconstr Surg,2000, 105(3):980-990.
[29]Gressner A M, Weiskirchen R, Breitkopf K, et al. Roles of TGF-beta in hepatic fibrosis[J]. Front Biosci,2002,7:793-807.
[30]Blom I E, Goldschmeding R, Leask A. Gene regulation of connective tissue growth factor:new targets for antifibrotic therapy[J]. Matrix Biol,2002,21(6): 473-482.
[31]Verrecchia F, Maubiel A. Transforming growth factor-beta signaling through the Smad pathway:role in extracellular matrix gene expression and regulation[J]. J Invest Dermatol,2002,118(2):211-215.
[32]Chen W, Fu X, Sheng Z. Review of current progress in the structure and function of Smad proteins[J]. Chin Med J(Engl),2002,115(3):446-450.
[33]Ulloa L, Tabibzadeh S. Lefty inhibits receptor-regulated Smad phosphorylation induced by the activated transforming growth factor-beta receptor [J]. J Biol Chem, 2001,276(24):21397-21404.
[34]Leask A, Sa S, Holmes A, et al. The control of ccn2(ctgf)gene expression in normal and scleroderma fibroblasts[J]. Mol Pathol,2001,54(3):180-183.
[35]Phanish M K, Wahab N A, Hendry B M. TGF-betal-induced connective tissue growth factor(CCN2) expres-sion in human renal proximal tubule epihelial cells requires Ras/MEK/ERK and Smad signalling[J]. Nephron Exp Nephrol,2005, 100(4):e156-e165.
[36]Yokoi H, Mukoyama M, Sugawara A, et al. Role of connective tissue growth factor in fibronectin expression and tubulointers titial fibrosis[J]. Am J Physiol Renal Physiol,2002;282(5):F933-F942.
[37]黄海长,杨敏,李惊子,等.结缔组织生长因子通过活化Erk-1/2信号通路促成纤维细胞生成[J].中华医学杂志,2005,85(19)：1322-1326.
[38]Akman H O, Zhang H, Siddiqui M A, et al. Response to hypoxia involves transforming growth factor-β2 and Smad proteins in humam endothelial cells[J]. Blood,2001,98(12):3324-3331.
[39]Ikedo H, Tamaki K. Smad protein and TGF-beta signaling in vascular smooth cells[J]. Int J Mol Med,2003,11(5):645-650.
[40]Li Y J, Azuma A, Usuki J, et al. EM703 improves bleomycin-induced pulmonary fibrosis in mice by the inhibition of TGF-beta signaling in lung fibroblasts[J]. Respir Res,2006,7(27):16.
[41]Rodriguez-Vita J, Sanchez-Lppez E, Esteban V, et al. Angiotensin Ⅱ activates the Smad pathway in vascular smooth muscule cells by a transforming growth factor-β-independent mechanism[J]. Circulation,2005,111(19):2509-2517.
[42]Dupuis J, Stewart D J. Cernacek P,et al.Human pulmonary circulation is an important site for both cleatance and production of endothlin-1[J]. Circulation,1996, 94(7):1578-1584.
[43]陶慧琳,王怀良,等.几种药物对肺主动脉平滑肌细胞增殖作用影响的比较研究[J].中国现代应用药学杂志,2005,3(22)：187-190.
[44]Shinichi K, Yi-Jen L, Paul C, et al. Angiotensinconverting enzyme inhibitor preserves p21 and endothelial nitric oxide synthase expressionin monocrotaline-induced pulmomary arterial hypertension in rats[J].Circulation,2001,104(9): 945-950.
[45]高修仁,彭龙云,麦炜颐,等.高血压大鼠心肌中MMP-2的蛋白表达及其RAS阻断后的变化[J].中山大学学报：医学科学版,2003,24(1)：30-34.
[46]Dixon I M, Hao J, Reid N L, et al. Effect of chronic AT(1) receptor blockade on cardiac Smad overexpression in hereditary cardiomyopathic hamsters[J]. Cardiovas Res,2000,46(2):286-297.
[47]Sorescu D. Smad3 mediates angiotensin Ⅱ-and TGF-betal-induced vascular fibrosis:Smad3 thickens the plot[J]. Circ Res,2006,98(8):988-989.
[48]李谧,周同甫,刘瀚旻,等.卡托普利对大鼠左向右分流模型肺小动脉重构的影响[J].四川大学学报(医学版),2006,37(2)：242-245.
[49]杨栋,谢燕.西拉普利对缺氧性大鼠肺动脉高压肺血管结构的保护[J].中国临床医学,2008,4(15)：471-473.
[1]Bradham D M, IgarashiA, Potter R L, et al. Conective tissue growth factor:a cysteine-rich mitogen secreted by human vascular endothelial cells related to the SRC-induced immediate early gene product CEF-10[J]. J CellBiol,1991,114(6): 1285-1294.
[2]云云,张红锋.结缔组织生长因子对血管生成和细胞功能调节[J].细胞生物学杂志,2006,28(5)：689-693.
[3]Lau L F, Lam S C. The CCN family of angiogenic regulators:the integrin connection[J]. Exp Cell Res,1999,248(1):44-57.
[4]Wahab N A, Brinkman H, Mason R M. Uptake and intracellular transport of the connective tissue growth factor:a Potential mode of action[J]. Bio Chem J, 2001,359(ptl):89-97.
[5]Kondo S, Kubota S, Eguchi T, et al. Characterization of a mouse ctgf3UTR segment that mediates repressive regulation of gene expression[J]. Biochem Biop Res Commun,2000,278:119-127.
[6]Holmes A, Abraham D J, Sa S, et al. CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling[J]. J Biol Chem, 2001:276(14):10549-601.
[7]Ruperez M, Lorenzo O, Blanco-Colio L M, et al. Connective tissue growth factor is a mediator of angiotensin-inducedfibrosis[J]. Circulation,2003,108(12):1499-1505.
[8]Finckenberg P, Inkinen K, Ahonen J, et al. Angiotensin Ⅱ induces connective tissue growth factor gene expression via calcineurin-dependent pathways[J]. Am J Pathol, 2003,163(1):355-466.
[9]Dimmeier J, Beer H D, Brauehle M, et al. Dexamethasone is a novel potent inducer of connective tissue growth factor expression,implications for glucocorticoid therapy [J]. J Biol Chem,1998,273(29):18185-18190.
[10]Suzuma K, Naruse K, Suzuma I, et al. Vascular endothelial growth factor induces expression of connective tissue growth factor via KDR, Fltl, and phosphatidylinositol 3-kinase-akt-dependent pathways in retinal vascular cells[J]. J Biol Chem,2000, 275(52):40725-40731.
[11]Kazi A S, Lotfi E A, Goncharova O, et al. Vascular endothelial growth factor-induced secretion of fibroaectin is ERK dependent[J]. Am J Physiol Lung Cell Mol Physiol,2004,286(3):L539-L545.
[12]Kessler D, Dethlefsen S, Haase I, et al. Fibroblasts in mechanically stressed collagen lattices assume a'synthetic'phenotype[J]. J Biol Chem,2001,276(39): 36575-36585.
[13]Hishikawa K, Oemar B S, Nakaki T. Static pressure regulates connective tissue growth factor expression in human mesangial cells[J]. J Biol chem,2001,276(18): 16797-16803.
[14]Schild C, Trueb B. Mechanical stress is required for high-level expression of connective tissue growth factor[J]. Exp Cell Res,2002,274(1):83-91.
[15]Albraham D J, Shiwen X, Black C M, et al. Tumor necrosis factor alpha suppresses the induction of connective tissue growth factor by transforming growth factor-beta in normal and sclerodema fibroblasts [J]. Jbiol Chem,2000,275(20):15220.
[16]Roll Ziescbe, Elisabeth Hofbauer, Karin Wittmann, et al. A Preliminary study of Long-Term Treatment with Interferon Gamma-lb and Low-Dose Prednisolone in Patients with Idiopathic Pulmonary Fibrosis[J]. The New England Journal of Medinice,1999,21 (341):1264-1269.
[17]Iin BR, Chang CC, Chen T F, et al. Connective Tissue Growth Factor Inhibits Metastasis and Acts as an Independent Prognostic Marker in Colorectal Cancer[J]. Gastroenterology,2005,128(1):9-23.
[18]Planyue N, Perbal B. A Structural Approach to the Role of CCN (Cyr16/CTGF /NOV), Proteins in Tumorigenesis[J]. Cancer Cell Int,2003,3(1):15.
[19]Moritani NH, Kubota S, Nishisa T, et al. Suppressive Effect of Overexpressed Connective Tissue Growth Factor on Tumor Cell Growth in a Human Oral Squamous Cell Carcinoma Derived Cell Line[J]. Cancer lett,2003,192(1):205-214.
[20]Kolipany A, Friess H, Dimola F F, et al. Connective Tissue Growth Factor Gene Expressional Alters Tumor Progression in Esophageal Cancer [J]. World J Surg, 2002,26(4):420-427.
[21]曾志军,杨连粤,王伟,等.Cyr61,CTGF和Nov基因在孤立性大肝癌中的表达及意义[J].肝胆外科杂志,2006,14(5)：395-397.
[22]曾志军,杨连粤,王伟,等Cyr61,CTGF和Nov基因在肝癌细胞中的表达及与临床特征的关系[J].中华肝胆外科杂志,2005,11(7)：452-424.
[23]肖在鹏,胡祥,杨佩满,等.结缔组织生长因子在胃硬癌形成机制中的作用[J].中国医师进修杂志,2007,30(6)：8-11.
[24]杨常春,王穗暖,张一,等.结缔组织生长因子在脑胶质瘤组织中的表达和肿瘤级别的关系[J].临床神经外科杂志,2006,3(3)：89-101.
[25]Koliopanos A, Friess H, diMola F F, et al. Connective tissue Growth Factor Gene Exprssion Alters Tumor Progression in Esophageal Cancer[J]. World J Surg,2002, 26(4):420-427.
[26]Shakunaga T, Ozaki T, Ohara N, et al. Takigawa M and Inoue H:Expression of connective tissue growth factor in cartilaginous tumours[J]. Cancer,2000,89(7): 1466-1473.
[27]Rimon E, Sasson R, Dantes A, et al. Gonadotropin-induced gene regulation in human granulosa cells obtained from IVF pations modulation of genes coding for growth factors and their receptors and genes involved in cancer and other diseases [J]. Int J Oncol,2004,24(5):1325-1338.
[28]陶秀平,张裕华,刘福云.甲状腺癌CTGF、TGFβ1表达及临床病理意义[J].医学临床研究,2005,22(7)：936-938.
[29]杨竹林,黄生福,苗雄鹰,等.胰腺癌组织中CCN家族基因和转化生长因子-β1表达及其临床病理意义[J].中华实验外科杂志,2005,22(10)：1276.
[30]李友忠,卢永德,曾益慈,等.喉鳞状细胞癌组织中CTGF和OPN的表达及其临床意义[J].临床耳鼻咽喉头颈外科杂志,2007,21(3)：121-123.
[31]崔玲玲,孙锦峰,王旗,等.人肺癌组织中富含酪氨酸61和结缔组织生长因子的表达[J].郑州大学学报,2007,42(3)：453-457.
[32]董秀明.结缔组织生长因子科降低结直肠癌转移率[J].中华放射肿瘤学杂志,2005,14(3)：176.
[33]Chang C C, Shih J Y, Jeng Y M, et al. Connective tissue growth factor and its role in lung adenocarcinoma invasion and metastasis[J]. J Natl Cancer Inst,2004,96(5): 364-375.
[34]]Lee Y S, Byun J'Kim J A, et al. Monocrotaline-induced pulmonary hypertension correlates with upregulation of connective tissue growth factor expression in the lung[J]. Experiment and Molecuar Medicine,2005,37(1):27-35.
[35]何立英,刘静,刘亚敏CTGF在低氧性肺动脉高压大鼠肺血管重构中的作用[J].武警医学院学报,2010,19(5)：351-353.
[36]崔茂香,陈晓玲,霍春玲,等.结缔组织生长因子在肺纤维化初期肺动脉中的表达[J].生理学报,2008,60(4)：535-540.
[37]李晓惠,杜宝军,唐朝枢.硫化氢供体对大鼠高肺血流性肺动脉高压中内皮素-1及结缔组织生长因子表达的影响[J].中国病理生理学志,2008,24(3)：446-450.
[38]Evgenov O V, Pacher P, Schmidt P M, et al. NO-independent stimulators and activators of soluble guanylate cyclase:discovery and therapeutic potential [J]. Nat Rev Drug Discov,2006,5(9):755-768.
[39]Fan W H, Pech M, Karnovsky M J, et al. Connective tissue factor (CTGF) stimulates vascular smooth muscle cell growth and migration in vitro[J].Eur J Cell Biol,2000,79 (12):915-923.
[40]Suzuma K, Naruse K, Suzuma I, et al. Vascular Endothelial Growth Factor Induces Expression of Connective Tissue Growth Factor via KDR,Fit1,and Phosphatidylin- ositol 3-Kinase-Akt-dependent Pathways in Retinal Vascular Cells[J]. J Biol Chem.2000.275(52):40725-40731.
[41]Orphanides C, Fine L, Norman J T. Hypoxia stimulates proximal tubular cell matrix production via a TGF-β1-independent mechanism[J]. Kidney Int, 1997,52(5):637-647.
[42]Honq K H, Yoo S A, Kang S S, et al. Hypoxia induces expression of connective tissue growth in scleroderma skin fibroblasts[J]. Clin Exp Immunol,2006,146(2): 362-370.
[43]Olbry M, Jarzab M, Jazowiecka-Rakus J, et al. Gene expression profile of B 16(FIO) murine melanoma cells exposed to hypoxic conditions in vitro[J]. Gene Expr, 2006,13(3):191-203.
[44]Paradis V, Dargere D, Bonvoust F, et al. Effects and regulation of connective tissue growth factor on hepatic stellate cells[J]. Lab Invest,2002,82(6):767-774.
[45]Paradis V, Dargere D, Vidaud M, et al. Expression of connective tissue growth factor in experimental rat and human liver fibrosis[J].Hepatology,1999,30(4):968-976.
[46]Hayashi N, Kakimuma T, Soma Y, et al. Connective tissue growth factor is directly related to liver fibrosis[J]. Hepatogastroenterology,2002,49(43):133-135.
[47]Yokoi H, Mukoyama M, Nagac T, et al. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstital fibrosis[J]. Am Soc Nephrol,2004,15(6):1430-1440.
[48]Riser B L, Cortes P. Connective tissue growth factor and its regulation:a new element in diabetic glomerulosclerosis[J]. Ren Fail,2001,23(3-4):459-470.
[49]Hishikawa K, Nakaki T, Oemar B S, et al. Static pressure regulates connective tissue growth factor expression in human mesangial cells[J]. Biol Chem,2001, 276(20):1797-1803.
[50]Gore-Hyer E, Shegogue D, Markiewics M, et al. TGF-beta and CTGF have overlapping and distinct fibrogenic effects on human renal cells[J]. Am J Physiol, 2002,283(5):F707-716.
[51]Szeto C C, LaiK B, Chow K M, et al. Differential effects of transforming growth factor-beta on the synthes is of connective tissue growth factor and vascular endothelial growth factor by periton ealmesothelial cell[J]. Nephron Exp Nephrol, 2005,99(4):95-104.
[52]Liu F Y, Xiao L, Peng Y M, et al. Inhibition effect of small interfering RNA of connective tissue growth factor on the expression of vascular endothelial growth factor and connective tissue growth factor in cultured human periton ealmesothelial cells[J]. Chin Med J(Eng I),2007,120(3):231-236.
[53]Ebisawa T, Fukuchi M, Murakami G, et al. Smurfl interacts with transforming growth factor-beta type Ⅰ receptor through Smad7 and induces receptor degradation[J]. J Biol Chem,2001,276(16):12477-12480.
[54]张浩,刘伏友,刘映红,等.转化生长因子-β1对人腹膜间皮细胞结缔组织生长因子的影响[J].中华肾脏病杂志,2004,20(4)：282-285.
[55]Sakamoto N, Sugimura K, Kawashima H, et al. Influence of glucose and inflammatory cytokines on TGF-betal and CTGF mRNA expressions in human peritoneal mesothelial cells[J]. Int J Mol Med,2005,15(6):907-911.
[56]Thaler K, Mack J A, Berho M, et al. Coincidence of connective tissue growth factor expression with fibrosis and angiogenesis in post-operative peritoneal adhesion fomation[J]. Eur Surg Res,2005,37(4):235-241.
[57]Ogawa E, Elliott W M, Hughes F, et al. Latent adenoviral infection induces production of growth factors relevant to airway remodeling in COPD[J]. Am J Physiol Lung Cel Mol Physiol,2004,286(1):L189-197.
[58]Watts K L, Sampson E M, Schultz G S, et al. Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts[J]. Am J Respir Cell Mol Biol,2005,32(4):290-300.
[59]Watts K L, Sampson E M, Schultz G S, et al. Simvastatin inhibits growth factor expression and modulates profibrogenic markers in 1 ung fibroblasts[J]. Am J Respir Cell Mol Biol,2005,32(4):290-300.