AT_1R、TGF-β1、Ⅰ型及Ⅲ型胶原在OLETF大鼠肺组织中的表达变化
摘要
目的：糖尿病(diabetes millitus, DM)是一种由多因素引起的以慢性高血糖为特征的全身代谢性疾病。目前,人们对DM引起的心、脑、肾、视网膜、神经系统等器官的慢性并发症进行了大量研究,但对于DM引起的慢性肺损害的认识尚不深入。目前国内外对DM肺的研究主要集中在肺功能、肺组织形态学和肺组织超微病理学等方面,对于DM肺组织损害的发病机制研究较少。近年研究发现组织局部肾素-血管紧张素系统(renin-angiotensin system,RAS)的激活在组织纤维化发病机制中起重要作用,但对DM状态下肺组织局部RAS组分变化的研究尚未见文献报道。血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)是RAS中的主要效应分子,AngⅡ主要通过血管紧张素Ⅱ1型受体(angiotensinⅡtype 1 receptor,AT1R)发挥作用。本实验通过用免疫组织化学方法测定DM状态下肺组织AT1R、转化生长因子-β1 (transforming growth factor-β1,TGF-β1)、Ⅰ型及Ⅲ型胶原的表达,探讨DM肺组织AT1R、TGF-β1表达的变化及其在肺纤维化发病机制中的作用,为临床干预提供理论依据。
方法：4周龄自发性2型糖尿病(T2DM)大鼠模型OLETF大鼠30只和其同系非DM对照组LETO大鼠8只,在无特定病原体级(SPF级,specific pathogen-free)条件下单笼饲养,饲以标准饲料。大鼠定期行口服葡萄糖耐量试验(oral glucose tolerance test,OGTT)。至30周龄时,共有成模OLETF大鼠16只,随机选取8只作为模型组(DM组),LETO大鼠为空白对照组(N组)。继续饲养12周后,经股动脉放血处死大鼠,留取肺组织,在10%的中性福尔马林固定、脱水、透明、浸蜡后包埋、切片：①HE染色光镜下观察肺组织结构变化；②Masson染色观察各组肺组织胶原沉积情况；③对肺组织进行AT1R、TGF-β1、I型及Ⅲ型胶原免疫组织化学染色,在光镜下观察AT1R、TGF-β1的染色强度并计算阳性细胞百分数,用图像分析系统测定Ⅰ型及Ⅲ型胶原染色阳性面积比及平均光密度。
结果：(1)OLETF大鼠较LETO大鼠肥胖,活动迟缓、懒动、毛色干枯无光泽。实验周期内,DM组大鼠体重显著高于N组(P<0.01)。(2)HE染色结果：光镜下观察发现,N组大鼠肺泡结构正常,DM组大鼠肺组织结构紊乱,支气管壁、肺泡壁增厚,肺泡上皮细胞显示不清,肺泡萎缩、塌陷,肺间质和血管周围细胞外基质增多,成纤维细胞增多,并有炎症细胞浸润。(3)Masson染色结果：N组大鼠肺间质、血管周围有少量胶原纤维。DM组大鼠肺间质胶原纤维增多,排列紊乱,毛细血管周围胶原物质增多。(4)免疫组织化学分析：①AT1R：DM组大鼠AT1R在支气管上皮细胞、Ⅱ型肺泡上皮细胞、肺间质成纤维细胞、巨噬细胞及少量毛细血管内皮细胞胞浆中可见大量阳性颗粒表达；N组大鼠AT1R在肺泡巨噬细胞、支气管上皮细胞、Ⅱ型肺泡上皮细胞及少量毛细血管内皮细胞胞浆中可见少量阳性颗粒表达。DM组大鼠AT1R表达较N组明显升高(P<0.01),差别具有统计学意义。②TGF-β1:DM组大鼠TGF-β1在支气管粘膜上皮细胞、肺泡上皮细胞、肺间质成纤维细胞、巨噬细胞及少量毛细血管内皮细胞胞浆中可见大量阳性颗粒表达,N组大鼠少数血管内皮细胞、肺泡上皮细胞及支气管粘膜上皮细胞胞浆可见阳性颗粒表达。DM组大鼠TGF-β1表达较N组明显升高(P<0.01),差别具有统计学意义。③Ⅰ型及Ⅲ型胶原：DM组大鼠肺间质可见大量Ⅰ型及Ⅲ胶原阳性表达,N组大鼠肺间质可见少量Ⅰ型及Ⅲ型胶原阳性表达。DM组大鼠Ⅰ型及Ⅲ型胶原染色阳性面积比及平均光密度较N组明显升高(P<0.01),差别具有统计学意义。(5)Pearson相关分析显示：DM组大鼠肺组织AT1R与TGF-β1之间呈正相关(r=0.898,P<0.01)。
结论：(1)DM组大鼠肺组织出现病理改变和胶原纤维成分的沉积,表明DM大鼠肺纤维化增多,肺脏是DM的又一靶器官。(2)DM组大鼠肺组织AT1R表达增多,提示DM组大鼠肺组织存在局部RAS组分的激活,可能在肺纤维化发病机制中起一定的作用。(3)DM组大鼠肺组织中TGF-β1表达增多,且与AT1R的表达呈正相关,提示AngⅡ经由AT1R促进肺纤维化的发生可能部分由TGF-β1介导。
Objectives:Diabetes mellitus (DM) is a metabolic disorder of chronic hyperglycemia which is caused by multitude factors. At present,a lot of studies were done to heart, brain, kidney, retina and nervous system chronic complications of diabetes,but chronic lung damage caused by diabetes was not well understood.The studies about lungs of diabetes at home and abroad were mainly focused on lung function,lung tissue morphology and lung tissue ultrastructural at present and there were few studies about pathogenesis of lung damage caused by diabetes. In recent years studies had found that the local RAS activation in tissue might play an important role in the pathogenesis of fibrosis,but studies about the change of local RAS components in lung tissue of diabetic were not found. AngⅡis the main effector molecule of RAS and it is mainly bound to type 1 receptor.This experiment by immunohistochemistry measured the expression of AT1R、TGF-β1 and collagen typeⅠ、Ⅲin lung tissue of diabetic state in order to explore the changes of AT1R and TGF-β1 and pathogenesis of pulmonary fibrosis and provide a theoretical basis for clinical intervention.
Methods:4 weeks spontaneous type 2 diabetes mellitus model 30 OLETF rats and the same department non-diabetic control of them 8 LETO rats were reared in single cage with standard feed in specific pathogen-free conditions.They were made OGTT on a regular basis. To 30 weeks,there were 16 OLETF rats modelled successfully. We selected 8 OLETF rats randomly from them as DM group and the LETO rats as N group. They continued to be fed for 12 weeks,then they were killed by the femoral artery bleeding and the lung samples were obtained. Put them in 10% neutral formalin to fix、anhydrate% transparent dip wax、embed and slice:①Observed the structural changes of lung tissue under light microscope by HE staining;②Observed collagen deposition in lung tissue of each group by Masson staining;③Detected the expression of AT1R、TGF-β1 collagen typeⅠ、Ⅲby immunohistochemistry,then observed staining intensity and calculated the percentage of positive cells of AT1R and TGF-β1 under light microscope and determined collagen typeⅠ、Ⅲratios of the positive reactive area of view and mean optical density by the image analysis system.
Results:(1) Compared with LETO rats, OLETF rats were fatter、acted slowly、lazy and dry dull coat color.During experiment, the body mass of DM group were significantly higher than N group(P<0.01).(2)HE staining:N group had normal alveolar structure.The lung organizational structure of DM group disordered, bronchial wall、alveolar wall thickening,alveolar epithelial cells showed unclear, alveolar atrophy、collapse,extracellular matrix and fibroblasts of pulmonary interstitial and perivascular increased, and there were inflammatory cell infiltration. (3)Masson staining:Pulmonary interstitial and perivascular of N group had little collagen fibers and in DM group they increased and disordered. (4)Immunohistochemistry:①AT1R:In DM group bronchial epithelial cell、typeⅡalveolar epithelial cell、fibroblast、macrophages and little capillary endothelial cells cytoplasm could be seen many positive particles and in N group could be seen little positive particles.AT1R expression in DM group compared with N group was different(P<0.01).②TGF-β1:In DM group bronchial epithelial cells、alveolar epithelial cells、fibroblast、macrophages and little capillary endothelial cells cytoplasm could be seen many positive particles and N group had little. TGF-β1 expression in DM group compared with N group was different(P<0.01).③collagen typeⅠ、Ⅲ:Pulmonary interstitial collagen typeⅠandⅢof DM group could see a lot of positive expression, N group showed little. Collagen typeⅠ、Ⅲratios of the positive reactive area of view and mean optical density in DM group compared with N group was different(P<0.01).(5)Pearson correlation analysis:The expression of AT1R had positive correlation with that of TGF-β1 expression in DM group.
Conclusions:(1)Pathological changes and collagen fibers deposition occured in lung tissue of DM group,indicating that DM group had more fibers and the lung was another target organ of diabetes.(2)AT1R expression increased in lung tissue of DM group,suggesting that lung tissue of DM group exist activation of local RAS components.It may be play a role in the pathogenesis of pulmonary fibrosis.(3) TGF-β1 expression in lung tissue of DM group increased and showed positive correlation with the expression of AT1R, suggesting that AngⅡby AT1R for the occurrence of pulmonary interstitial fibrosis may be partly mediated by TGF-β1.
方法：4周龄自发性2型糖尿病(T2DM)大鼠模型OLETF大鼠30只和其同系非DM对照组LETO大鼠8只,在无特定病原体级(SPF级,specific pathogen-free)条件下单笼饲养,饲以标准饲料。大鼠定期行口服葡萄糖耐量试验(oral glucose tolerance test,OGTT)。至30周龄时,共有成模OLETF大鼠16只,随机选取8只作为模型组(DM组),LETO大鼠为空白对照组(N组)。继续饲养12周后,经股动脉放血处死大鼠,留取肺组织,在10%的中性福尔马林固定、脱水、透明、浸蜡后包埋、切片：①HE染色光镜下观察肺组织结构变化；②Masson染色观察各组肺组织胶原沉积情况；③对肺组织进行AT1R、TGF-β1、I型及Ⅲ型胶原免疫组织化学染色,在光镜下观察AT1R、TGF-β1的染色强度并计算阳性细胞百分数,用图像分析系统测定Ⅰ型及Ⅲ型胶原染色阳性面积比及平均光密度。
结果：(1)OLETF大鼠较LETO大鼠肥胖,活动迟缓、懒动、毛色干枯无光泽。实验周期内,DM组大鼠体重显著高于N组(P<0.01)。(2)HE染色结果：光镜下观察发现,N组大鼠肺泡结构正常,DM组大鼠肺组织结构紊乱,支气管壁、肺泡壁增厚,肺泡上皮细胞显示不清,肺泡萎缩、塌陷,肺间质和血管周围细胞外基质增多,成纤维细胞增多,并有炎症细胞浸润。(3)Masson染色结果：N组大鼠肺间质、血管周围有少量胶原纤维。DM组大鼠肺间质胶原纤维增多,排列紊乱,毛细血管周围胶原物质增多。(4)免疫组织化学分析：①AT1R：DM组大鼠AT1R在支气管上皮细胞、Ⅱ型肺泡上皮细胞、肺间质成纤维细胞、巨噬细胞及少量毛细血管内皮细胞胞浆中可见大量阳性颗粒表达；N组大鼠AT1R在肺泡巨噬细胞、支气管上皮细胞、Ⅱ型肺泡上皮细胞及少量毛细血管内皮细胞胞浆中可见少量阳性颗粒表达。DM组大鼠AT1R表达较N组明显升高(P<0.01),差别具有统计学意义。②TGF-β1:DM组大鼠TGF-β1在支气管粘膜上皮细胞、肺泡上皮细胞、肺间质成纤维细胞、巨噬细胞及少量毛细血管内皮细胞胞浆中可见大量阳性颗粒表达,N组大鼠少数血管内皮细胞、肺泡上皮细胞及支气管粘膜上皮细胞胞浆可见阳性颗粒表达。DM组大鼠TGF-β1表达较N组明显升高(P<0.01),差别具有统计学意义。③Ⅰ型及Ⅲ型胶原：DM组大鼠肺间质可见大量Ⅰ型及Ⅲ胶原阳性表达,N组大鼠肺间质可见少量Ⅰ型及Ⅲ型胶原阳性表达。DM组大鼠Ⅰ型及Ⅲ型胶原染色阳性面积比及平均光密度较N组明显升高(P<0.01),差别具有统计学意义。(5)Pearson相关分析显示：DM组大鼠肺组织AT1R与TGF-β1之间呈正相关(r=0.898,P<0.01)。
结论：(1)DM组大鼠肺组织出现病理改变和胶原纤维成分的沉积,表明DM大鼠肺纤维化增多,肺脏是DM的又一靶器官。(2)DM组大鼠肺组织AT1R表达增多,提示DM组大鼠肺组织存在局部RAS组分的激活,可能在肺纤维化发病机制中起一定的作用。(3)DM组大鼠肺组织中TGF-β1表达增多,且与AT1R的表达呈正相关,提示AngⅡ经由AT1R促进肺纤维化的发生可能部分由TGF-β1介导。
Objectives:Diabetes mellitus (DM) is a metabolic disorder of chronic hyperglycemia which is caused by multitude factors. At present,a lot of studies were done to heart, brain, kidney, retina and nervous system chronic complications of diabetes,but chronic lung damage caused by diabetes was not well understood.The studies about lungs of diabetes at home and abroad were mainly focused on lung function,lung tissue morphology and lung tissue ultrastructural at present and there were few studies about pathogenesis of lung damage caused by diabetes. In recent years studies had found that the local RAS activation in tissue might play an important role in the pathogenesis of fibrosis,but studies about the change of local RAS components in lung tissue of diabetic were not found. AngⅡis the main effector molecule of RAS and it is mainly bound to type 1 receptor.This experiment by immunohistochemistry measured the expression of AT1R、TGF-β1 and collagen typeⅠ、Ⅲin lung tissue of diabetic state in order to explore the changes of AT1R and TGF-β1 and pathogenesis of pulmonary fibrosis and provide a theoretical basis for clinical intervention.
Methods:4 weeks spontaneous type 2 diabetes mellitus model 30 OLETF rats and the same department non-diabetic control of them 8 LETO rats were reared in single cage with standard feed in specific pathogen-free conditions.They were made OGTT on a regular basis. To 30 weeks,there were 16 OLETF rats modelled successfully. We selected 8 OLETF rats randomly from them as DM group and the LETO rats as N group. They continued to be fed for 12 weeks,then they were killed by the femoral artery bleeding and the lung samples were obtained. Put them in 10% neutral formalin to fix、anhydrate% transparent dip wax、embed and slice:①Observed the structural changes of lung tissue under light microscope by HE staining;②Observed collagen deposition in lung tissue of each group by Masson staining;③Detected the expression of AT1R、TGF-β1 collagen typeⅠ、Ⅲby immunohistochemistry,then observed staining intensity and calculated the percentage of positive cells of AT1R and TGF-β1 under light microscope and determined collagen typeⅠ、Ⅲratios of the positive reactive area of view and mean optical density by the image analysis system.
Results:(1) Compared with LETO rats, OLETF rats were fatter、acted slowly、lazy and dry dull coat color.During experiment, the body mass of DM group were significantly higher than N group(P<0.01).(2)HE staining:N group had normal alveolar structure.The lung organizational structure of DM group disordered, bronchial wall、alveolar wall thickening,alveolar epithelial cells showed unclear, alveolar atrophy、collapse,extracellular matrix and fibroblasts of pulmonary interstitial and perivascular increased, and there were inflammatory cell infiltration. (3)Masson staining:Pulmonary interstitial and perivascular of N group had little collagen fibers and in DM group they increased and disordered. (4)Immunohistochemistry:①AT1R:In DM group bronchial epithelial cell、typeⅡalveolar epithelial cell、fibroblast、macrophages and little capillary endothelial cells cytoplasm could be seen many positive particles and in N group could be seen little positive particles.AT1R expression in DM group compared with N group was different(P<0.01).②TGF-β1:In DM group bronchial epithelial cells、alveolar epithelial cells、fibroblast、macrophages and little capillary endothelial cells cytoplasm could be seen many positive particles and N group had little. TGF-β1 expression in DM group compared with N group was different(P<0.01).③collagen typeⅠ、Ⅲ:Pulmonary interstitial collagen typeⅠandⅢof DM group could see a lot of positive expression, N group showed little. Collagen typeⅠ、Ⅲratios of the positive reactive area of view and mean optical density in DM group compared with N group was different(P<0.01).(5)Pearson correlation analysis:The expression of AT1R had positive correlation with that of TGF-β1 expression in DM group.
Conclusions:(1)Pathological changes and collagen fibers deposition occured in lung tissue of DM group,indicating that DM group had more fibers and the lung was another target organ of diabetes.(2)AT1R expression increased in lung tissue of DM group,suggesting that lung tissue of DM group exist activation of local RAS components.It may be play a role in the pathogenesis of pulmonary fibrosis.(3) TGF-β1 expression in lung tissue of DM group increased and showed positive correlation with the expression of AT1R, suggesting that AngⅡby AT1R for the occurrence of pulmonary interstitial fibrosis may be partly mediated by TGF-β1.
引文
[1]郝新忠,陈隽,蒋幼凡.糖尿病肺损害研究进展[J].重庆医学,2004,33(4)：626-628.
[2]Enomoto T,Usuki J,Azuma A,et al. Diabetes mellitus may increase risk for idiopathic pulmonary fibrosis[J].Chest,2003,123(6):2007-2011.
[3]刘松平,张宏.糖尿病肺损害[J].国际内分泌代谢杂志,2004,24(5)：341-343.
[4]张宏,白景文,于振涛,等.2型糖尿病患者慢性肺损伤的超微病理改变及临床意义[J].解剖学报,2005,36(6)：656-659.
[5]赵伟,张宏,谢云,等.2型糖尿病患者支气管黏膜超微结构的病理变化[J].解剖学报,2006,37(6)：685-688.
[6]张宏,白景文,曹泽伟,等.糖尿病家兔早期肺组织超微结构的改变及中药干预治疗的影响[J].中国中西医结合急救杂志,2005,12(3)：170-172.
[7]Wang R,Ibarra-Sunga O,Verlinski I,et al.Abrogation of bleomycin-induced Epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor[J].Am J Physiol Lung Cell Mol Physiol,2000,279(1):L143-L151.
[8]Marshall RP.The pulmonary rennin-angiotensin system[J]. Current Pharmaceutical Design,2003,9(9):715-722.
[9]Otsuka M,Takahashi H,Shiratori M,et al.Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist[J]. Thorax.2004,59(1):31-38.
[10]Bullock GR,Steyaert I,Bilbe GDistribution of type-1 and type-2 angiotensin rece-ptors in the normal human lung and in lungs from patients with chronic obstructi-ve pulmonary disease[J].Histochem Cell Biol,2001,115(2):117-124.
[11]Sarkar S,Vellaichamy E,Young D,et al.Influence of cytokines and growth factors in ANG II-mediated collagen upregulation by fibroblasts in rats:role of myocytes[J].Am J Physiol Heart Circ Physiol,2004,287(1):H107-H117.
[12]Davis TM,KnuimanM,Kendall P,et al.Reduced pulmonary function and its associations in type 2 diabetes:the Fremantle Diabetes Study[J].Diabetes Res Clin Pract,2000,50(2):153-159.
[13]Goldman MD.Lung dysfunction in diabetes[J].Diabetes Care,2003,26(6): 1915-1918.
[14]沈轶,尹福在,姚立新,等.2型糖尿病患者的肺功能研究[J].中国糖尿病杂志,2000,8(6)：370-379.
[15]孙玉桂,张秀玲,张继安.糖尿病肺功能改变的临床价值[J].辽宁实用糖尿病杂志,2001,(1)：23-24.
[16]江山平,黄莉文,李依群,等.2型糖尿病患者的肺功能改变[J].中华结核和呼吸杂志,2005,28(1)：65-66.
[17]Popov D,Simioneseu M.Alterations of lung structure in experimental diabetes,and diabetes associated with hyperlipidaemia in hamsters[J].Eur Respir,1997,10(8):1850-1858.
[18]Weyrand B Jonchneere A,Fraus A, et al. Diabetes mellitus induees a thickning of the pulmonary basal lamina[J].Respiration,1999,66(1):14-19.
[19]Ofulue F,Kida K,Thurllbeck WM.Experimental diabetes and the iung [J].Am Rev Respir Dis,1988,137(1):162-166.
[20]Sahebjami H,Denhnolm D.Lung mechanies and conneelive tissue proteins in diabetic Bio-Breeding/Woreester Wistar rats[J].J Appi Physiol,1987,62(4): 1430-1435.
[21]Plopper CG,Morishige WK.Alterations in granular (type II) pneumoreyte ultrastructure by streptozotocin induced dibetes in the rals [J]. Lab Invest,1987, 38(2):143-148.
[22]沈兴平,舒昌达,张佐才,等.实验性糖尿病肺形态学及氧自由基研究[J].中国病理生理杂志,2000,16(6)：552-556.
[23]Kawano K,Hirashima T,Mori S,et al.Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty(OLETF) strain[J].Diabetes,1992,41(11):1422-1428.
[24]Kawano K.OLETF(Otsuka Long-Evans Tokushima Fatty) rat:a new NIDDM rat strain[J].Diabetes Res Clin Pract,1994,24(suppl):S317-S320.
[25]Funakoshi A.Little or noexpression of the cholecystokin A receptor gene in the pancreas of diabetic rats(Otsuka Long-Evans Tokushima Fatty=OLETF Rats) [J].Biochem Biophys Res Commun,1994(2),199:482-488.
[26]Hirashima G.A diabetogenic gene(ODB-1)assigned to the X chromosome in OLETF rats[J].Diabtes Res Clin Pract,1995,27(2):91-96.
[27]Hirashima T,Kawano K Mori S, et al.A diabetogenic gene,ODB2, identified on chromosome 14 of the OLETF rat and its synergistic action with ODBl[J].Biochem Biophys Res Commun,1996,224(2):420-425.
[28]Bumpus FM,Schwarts H and Page IH.Synthesis and pharmacology of the octapeptide angiotonin[J].Science,1957,125(3253):886-887.
[29]Rittel W,Iselin B,Kappeler H,et al.Synthesis of a highly effective Angiotensin Ⅱ amide(L-asparagynyl-L-arginyl-L-valyl-L4yrosyl-L-isoleucyl-L-hi stidyl-L-prolyl-L-phenylalanine) [J].Helv Chim Acta,1957,40(4):614-624.
[30]Mento PF,Wiikes BM.Plasma angiotensins and blood pressure during converting enzyme inhibition[J].Hypertension,1987,9(6 Pt 2):Ⅲ42-Ⅲ48.
[31]Urata H,et al.Wide spread tissue distribution of human chymase[J].J Hyperten.1994,12(9):S17-S22.
[32]Rosendorff C.The rennin angiotensin system and vascular hypertrophy[J].J Am Coll Cardial.1996,28(4):803-812.
[33]Timmermans PB,Duncia JV,Carini DJ,et al.Discovery of losartan,the first angiotensin II receptor antagonist[J].Hum Hypertens,1995,9(suppl 5):S3-S18.
[34]Michael E,Knauss TC,Pierce GF,et al.The importance of tyrosine phosphorylation in angiotensin Ⅱ type 1 receptor signaling[J].Hypertension, 1996,27(3 Pt 2):476-480.
[35]Khosla MC,Smeby RR,Bumpus FM.Structure activity relationship in angiotensin Ⅱ analogs,in Handbook of Experimental Pharmacology[J].Springer-Verlag,1974: 126-156.
[36]Martin MM,Victor X,Zhao X,et al.Identification and characterization of functional angiotensin II type 1 receptors on immortalized human fetal aortic vascular smooth muscle cells[J].Molecular and Cellular Endocrinology, 2001,183(1-2):81-91.
[37]Moore SA,Patel AS,Huang N,et al.Effects of mutations in the highly concerved DRY motif on binding affinity,expression,and Gprotein recruitment of the human angiotensin Ⅱ type-2 receptor[J].Molecular Brain Res.2002,109(1-2):161-167.
[38]Sasaki K,Yamano Y,Bardhan S,et al.Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin Ⅱ type-1 receptor[J].Nature. 1991,351 (6323):230-233.
[39]Murphy TJ,Alexander RW,Griendling KK,et al.Isolation of a cDNA encoding the vascular type-1 angiotensin Ⅱ receptor[J].Nature.1991,351(6323):233-236.
[40]Bergsma DJ,Ellis C,Kumar C,et al.Cloning and characterization of a human angiotensin Ⅱ type 1 receptor[J].Biochem Biophys Res Commun,1992,183(3): 989-995.
[41]Guo DF,Furuta H,Mizukoshi M,et al.The genomic organization of human angiotensin Ⅱ type 1 receptor[J]. Biochem Biophys Res Commun,1994, 200(1):313-319.
[42]Curnow KM,Pasoe L,Davies E,et al.Alternatively spliced human type 1 angiotensin Ⅱ receptor mRNAs are translated at different efficiencies and encode two receptor isoforms[J].Mol Endocrinol,1995,9(9):1250-1262.
[43]Jayadev S,Smith RD,Jagadeesh G,et al.N-linked glycosylation is required for optimal AT1a angiotensin receptor expression in COS-7 cells[J].Endocrinology, 1999,140(5):2010-2017.
[44]Ohyama K,Yamano Y,Sano T,et al.Disulfide bridges in extracellular domains of angiotensin Ⅱ receptor type Ⅰ A[J].Regul Pept,1995,57(2):141-147.
[45]Sadoshima J.Cytokine actions of angiotensin Ⅱ [J].Circ Res,2000,86(12):1187-1189.
[46]Parsons KK,Coffman TM,The rennin-angiotensin system:it's all in your head[J].J Clin Invest.2007,117(4):873-876.
[47]Po Sing Leung.The physiology of a local rennin-angiotensin system in the pancreas[J].Physiol.2007,580(Pt1):31-37.
[48]Rodgers KE,Abiko M,Girgis W,et al.Acceleration of dermis tissue repair by angiotensin Ⅱ [J].Wound Rep Reg,1997,5(4):175-183.
[49]Phillips MI,Speakman EA,Kimura B.Levels of angiotensin and molecular biology of the tissue rennin angiotensin systems[J].Regul Pept,1993,43(1-2): 1-20.
[50]Peters Jand Clausmeyer S. Intracellular sorting of renin:cell type specific differences and their consequences[J].J-Mol-Cell-Cardiol,2002,34(12):1561-1568.
[51]MacKenzie SM,Fraser R,Connell JM,et al.Local renin-angiotensin systems and their interactions with extra-adrenal corticosteroid production[J].J-Renin-Angiotensin-Aldosterone-Syst,2002,3 (4):214-221.
[52]Zhou J, Pavel J,Macova MA,et al.ATl receptor blockade regulates the local angiotensin Ⅱ system in cerebral microvessels from spontaneously hypertensive rats[J].Stroke,2006,37(5):1271-1276.
[53]Garcia MJ,Martinez-Martos JM,Mayas MD,et al.Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of male mice[J].Life-Sci,2003, 73 (5):525-538.
[54]马骥,林善淡,朱依纯.当代肾脏病学[M].上海：上海教育出版社,2001,第1版,63-74.
[55]Schauser KH,Nielsen AH,Winther H,et al.Localization of the renin-angiotensin System in the bovine ovary:Cyclic variation of the angiotensin Ⅱ receptor expression[J].Biol Reprod,2001,65(6):1672-1680.
[56]Mitsube K,Mikuni M,Matousek M,et al.Role of the angiotensin Ⅱ system in regulation of ovulation and blood flow in the rat ovary[J].Repreduction,2003, 125(3):425-435.
[57]Shutttleworth G,Pipkin FB,Hunter MG.In vitro development of pig preantral follieieles cultured in a serum-free medium and the effect of angiotensin Ⅱ[J]. Reproduction,2002,123(6):807-818.
[58]Leung PS,Sernia C.The renin-angiotensin system and male reproduction:new functions for old hormones[J].J Mol Endocrinol,2003,30(3):263-270.
[59]Franke FE,Pauls K,Metzger R,et al.Agiotensin I-converting enzyme and potential substrates in human testis and testicular tumours[J].APMIS,2003, 111(1):234-244.
[60]Dinh DT,Frauman AG,Johnston CI,et al.Agiotensin receptors:distribution, signaling and function[J].Clinical Science,2001,100(5):481-492.
[61]Stegbauer J,Vonend O,Oberhauser V,et al.Effects of angiotensin-(1-7) and other bioactive components of the renin-angiotensin system on vascular resistance and noradrenaline release in rat kidney[J].Journal of Hypertension,2003,21(7):1391- 1399.
[62]Rodgers K,Xiong S,Felix J,et al.Development of angiotensin(1-7) as an agent to accelerate dermal repair[J].Wound Repair Regen,2001,9(3):238-247.
[63]Batlle M,Roig E,Perez-Villa F,et al.Increased expression of the renin-angiotensin system and mast cell density but not of angiotensin-converting enzyme Ⅱ in late stages of human heart failure[J].J-Heart-Lung-Transplant,2006, 25(9):1117-1125.
[64]Nabeshima Y,Tazuma S,Kanno K,et al.Anti-fibrogenic function of angiotensin II type 2 receptor in CC14-induced liver fibrosis[J].Biochem-Biophys-Res-Commun,2006,346(3):658-664.
[65]Bataller R,Sancho-Bru P,Gines P,et al.Liver fibrogenesis:a new role for the renin-angiotensin system[J].Antioxid-Redox-Signal,2005,7(9-10):1346-1355.
[66]Yang L,Bataller R,Dulyx J,et al.Attenuated hepatic inflammation and fibrosis in Angiotensin type 1a receptor deficient mice[J].J- Hepatol,2005,43(2):317-323.
[67]Mahmood J,Khan F,Okada S,et al.Local delivery of angiotensin receptor blocker into the kidney ameliorates progression of experimental glomerulonephritis[J].Kidney-Int,2006,70(9):1591-1598.
[68]Yao HW,Zhu JP,Zhao MH,et al.Losartan attenuates bleomycin-induced pulmonary fibrosis in rats[J].Respiration,2006,73 (2):236-242.
[69]Chen CM,Chou HC,Hsu H,et al.Transforming growth factor-betal upregulation is independent of angiotensin in paraquat-induced lung fibrosis[J].Toxicology, 2005,216(2-3):181-187.
[70]Morihara K,Takai S,Takenaka H,et al.Cutaneous tissue agiotensin-converting enzyme may participate in pathologic scar formation in human skin[J].J Am Acad Dermatol,2006,54(2):251-257.
[71]Hitoshi Y,Shigeki K,Ryuichi N,et al.A ngiotensin-Ⅱ and vascular endothelial growth factor interaction plays an important role in rat liver fibrosis development[J].Hepatology Research,2006,36(2):124-129.
[72]De Gasparo M,Catt KJ.International Union of Pharmacology.ⅩⅩⅢ.The Angiotensin II Receptor[J].Pharmacol.Rev,2000,52(3):415-472.
[73]Le Cras TD,Spitzmiller RE,Albertine KH,et al.VEGF causes pulmonary hemorrhage,hemosiderosis,and air space enlargement in neonatal mice[J].Am J Physiol Lung Cell Mol Physiol,2004,287(1):L134-L142.
[74]李春晖,谭茗月,张新超.激活过氧化物酶增殖物激活受体对血管紧张素1I诱导内皮细胞中单核细胞趋化因子-1表达的影响[J].中华老年医学杂志,2006,25(9)：664-667.
[75]Inoshima I,Kuwano K,Hamada N,et al.Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary fibrosis in mice[J].Am J Physiol Lung Cell Mol Physiol,2004,286(5):L1038-L1044.
[76]方向群,朱元珏,胡晓玲,等.氯沙坦对大鼠肺纤维化模型的干预作用及对MCP-1和bFGF表达的影响[J].中华结核和呼吸杂志,2002,25(5)：268-272.
[77]何平平,李杰平,张书杰,等.阻断肾素-血管紧张素-醛固酮系统对大鼠肺维化的干预作用及对MCP-1表达的影响[J].南华大学学报·医学版,2007,35(2)：186-191.
[78]Page EL,Robitaille GA,Pouyssegur,Richard DE:Induction of Hypoxia-Inducible Factor 1-α by Transcriptional and Translation Mechanisms[J]JBC,2002,277(50): 48403-48409.
[79]He M,He X,Xie Q,et al. Angiotensin II induces the expression of tissue factor and its mechanism in human monocytes[J].Thromb Res,2006,117(5):579-590.
[80]Mahrouf M,Ouslimani N,Peynet J,et al.Metformin reduces angiotensin-mediated intracellular production of reactive oxygen species in endothelial cells through the inhibition of protein kinase c[J].Biochem Pharmacol,2006,72(2):176-183.
[81]FeenerEP,Nurthrup JM,Aiello LP,et al.Angiotensin II induces plasminogen activator inhibitor-1 and-2 expression in vascular endothelial and smooth Muscle cells[J].J Clin Invest,1995,95(3):1353-1362.
[82]王利,罗义,杨阳.缬沙坦对血管紧张素II诱导人脐静脉内皮细胞分泌tPA、PA I-1抗原的影响[J].广州医学院学报,2007,35(3)：1-5.
[83]王大志,张书瑜,杨晓璐.缬沙坦和依那普利对自发性高血压大鼠血浆sICAM-1和PAI-1的影响[J].山东医药,2005,45(34)：：23-24.
[84]鹿育萨,王萍芝,王瑞英,等.血管紧张素Ⅱ和卡托普利、缬沙坦对人脐静脉内皮细胞PAI-1、tPA蛋白表达的影响[J].高血压杂志,2005,13(10)：637-641.
[85]施志明,钱晓明,许瑞吉,等.实验性糖尿病大鼠心肌ATⅡ和心肌超微结构的研究[J].中国糖尿病杂志,1996,4(1)：28-30.
[86]Gotzsche LB,Rosenqvist N, Gronbaek H,et al.Increased number of myocardial voltage gated Ca2+ channels and unchanged total beta-receptor number in long-term STZ-diabetic rats[J].Eup J Endocrinol,1996,134(1):107-116.
[87]雅莉,田慧,潘长玉,等.血管紧张素Ⅱ对实验性糖尿病大鼠心肌病变的影响及卡托普利的保护作用[J].中国糖尿病杂志,2000,8(5)：298-300.
[88]李辉,李俭青,江时森,等.牛磺酸对糖尿病大鼠心肌组织肾素-血管紧张素系统的抑制作用[J].中国内分泌代谢杂志,1997,13(2)：108-110.
[89]Brown L,Wall D, Marchant C,et al.Tissue-specific changes in angiotensin Ⅱ receptors in streptozotocin-diabetic rats[J].J Endocinol,1997,154(2):355-362.
[90]Dostai DE,Rothbium KN,Chernin MI.Intracardiac detection of angiotensiongen and renin:a localized renin-angiotensin system in neonatal rat heart[J].Am J Physiol,1992,263(4 Pt 1):C838-C850.
[91]Zata R,Dunn BR,Meyer TW,et al.Prevention of diabetic glomerulopathy by harm acologicea melioration of glomerular capillary hypertension[J].J Clin Invest, 1986,77(6):1925-1930.
[92]Woo KT, Lau YK, Chan CM, et al. ATRA therapy restores normal renal functi-on and renal reserve and p revents renal failure [J].Ann Acad Med Singapore, 2005,34:52-59.
[93]杨福燕,邵凤杰.双重阻断肾素-血管紧张素系统对早期糖尿病肾病的影响[J].中国全科医学,2008,11(1B)：113-114.
[94]Han KH,Kang YS,Han SY,et al.Spironolactone ameliorates renal injury and connective tissue growth factor expression in type Ⅱ diabetic ratsl Kidney Int, 2006,70 (1):111-120.
[95]Takebayashi K,Matsumoto S,Aso Y,et al.Aldosterone blockade attenuates urina-ry monocyte chemoattractant protein-1 and oxidative stress in patients with type 2 diabetes complicated by diabetic nephropathy.J Clin Endecrinol Metab,2006,91 (6):2214-2217.
[96]Yamazaki H, Ohta K, Tsukiji H, et al.Corticosteroid enhances heme oxygenase-1 production by circulation monocytes by up-regulating hemoglobin scavenger rece-ptor and amplifying the receptor-mediated up take of hemoglobin-haptoglobin complex.Biochem Biophys Res Commun,2007,358(2):506-512.
[97]黄佳佳.肾素-血管紧张素-醛固酮系统与糖尿病微血管并发症的关系[J].国际内科学杂志,2008,35(9)：520-526.
[98]唐伟,吕国良,徐萍,等.RAAS阻断剂与糖尿病慢性并发症[J].实用临床医药杂志,2004,8(4)：25-29.
[99]林善锬.肾脏局部RAAS与糖尿病肾病[N].中国医学论坛报,2006-9-21-040.
[100]Robert AB,Flanders KC,Heine UI,et al.Transforming growth factor beta: multifunctional regulator of differentiation and developmen[J].Philos Trans R Soc Lond B Biol Sci,1990,327(1239):145-154.
[101]Blakytny R,Ludlow A,Martin GE,et al. Latent TGF-beta 1 activation by platele-ts[J]. J Cell Physiol,2004,199(1):67-76.
[102]Fukuda K,Kawata S,Tamura S, et al. Transforming growth factor beta1-induced degradation of activated Src tyrosine kinase in rat fibroblasts[J].Oncogene,1998, 16(26):3349-3356.
[103]Lee TC,Gold L I,Reibman J,et al.Immunohistochemical localization of transforming growth factor-beta and insulin-like growth factor-1 in asbestosis in the sheep model[J]. Int Arch Occup Environ Health,1997,69(3):157-164.
[104]Teicher BA.Malignant cells,directors of the malignant p rocess:role of transforming growth factor-beta[J].Cancer Metastasis Rev,2001,20(1-2):133-143.
[105]Sheppard D.Pulmonary fibrosis:a cellular overreaction or a failure of communication[J].J Clin Invest,2001,107(12):1501-1502.
[106]Jagirdar J,Begin R,Dufresne A,et al.Transforming growth factor-beta (TGF-beta) in silicosis[J]. Am J Resp ir Crit CareMed,1996,154(4 Pt 1): 1076-1081.
[107]Sime PJ,Zhou X,Graham FL,et al.Adenovector-mediated gene transfer of active transforming growth factor-β1 induces p rolonged severe fibrosis in rat lung[J].J Clin Invest,1997,100(4):768-776.
[108]陈刚,余民浙.转化生长因子-β1 (TGF-β1)与肺纤维化研究的进展[J].中 国疗养医学,2007,16(1)：3-5.
[109]Linnala A,Kinnula V,Laitinen LA, et al.Transforming growth factor-beta regulates the expression of fibronectin and tenascin in BEAS 2B human bronchial epithelial cells[J]. Am J Resp ir CellMol Biol,1995,13(5):578-585.
[110]Coker RK,Laurent GJ.Pulmonary fibrosis:cytokines in banlance[J].Eur Respir J,1998,11(6):1218-1221.
[111]Coker RK,Laurent GJ,Shahzeidi S,et al.Transforming growth factors-beta 1,-beta 2,-beta 3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis[J].Am J Pathol, 1997,150(3):981-991.
[112]Liu JY,Brody AR.Increased TGF-beta 1 in lungs of asbestos-exposed rats and mice:reduced expression in TNF-alpha receptor knockout mice[J].J Environ Pathol Toxicol Oncol,2001,20(2):97-108.
[113]YoshidaM,Hayashi S.Role of TGF-beta and PDGF on the pathogenesis of pulmonary fibrosis-analysis by vivo gene transfer[J].Nippon Rinsho,1996,54(2): 418-422.
[114]Ludwicka A,Ohba T,Trojanowska M,et al.Elevated level of platelet derived growth factor and transforming growth factor-beta 1 in bronchoalveolar lavage fluid from patients with scleroderma[J].J Rheumatol,1995,22(10):1876-1883.
[115]Denis M.Neutralization of transforming growth factor-beta 1 in a mouse model of immune-induced lung fibrosis[J].Immunology,1994,82(4):584-590.
[116]Kapanci Y,Desmouliere A, Pache JC,et al. Cytoskeletal protein modulation in pulmonary alveolarmyofibroblasts during idiopathic pulmonary fibosis.Possible role of transforming growth factor beta and tumor necrosis factor alpha[J].Am JResp ir Crit Care Med,1995,152(6 Pt 1):2163-2169.
[117]Bienkowski RS,Gotkin MG.Control of collagen deposition in mammalian lung[J].Proc Soc Exp BiolMed,1995,209(2):118-140.
[118]Gharaee-KermaniM,Denholm EM,Phan SH.Costimulation of fibroblast collagen and transforming growth factor β1 gene expression by monocyte chemoattractant protein-1 via specific receptors[J].J Biol Chem,1996,271(30): 17779-17784.
[119]Eickelberg O,Pansky A,Kochler E,et al.Molecular mechanisms of TGF-β antag-onism by interferon(gamma) and cyclosporine A in lung fibroblasts[J].Faseb J,2001,15(3):797-806.
[120]Venkatesan N,Roughley PJ,Ludwig MS,et al.Proteoglycan expression in bleomycin lung fibroblasts:role of transforming growth factor-β1 and interferon-γ[J]. Am J Physiol Lung CellMol Physiol,2002,283(4):806-814.
[121]Vaillant P,Menard O,Vignaud JM,et al.The role of cytokines in human lung fibrosis[J].Monaldi Arch Chest Dis,1996,51(2):145-152.
[122]Lee CG,Cho SJ Kang MJ,et al.Eavly growth response gene-1 mediated apop-tosis is essential for transforming growth factor beta 1-induced pulmonary fibrosis[J].Exp Med,2004,200(3):377-389.
[123]Arkwright PD,Laurie S,Super M,et al.TGF-(31 genotype and accelerated decline in lung function of patients with cystic fibrosis.Thorax,2000,55(6):459-462.
[124]Lasky JA,Brody AR. Interstitial fibrosis and growth factors [J]. Environ Health Perspect,2000,108(suppl 4):751-762.
[125]Zhu Y,Farrehi PM,Fay WP.Plasminogen activator inhibitor-I enhances neointima formation after oxidative vascular injury in atherosclerosis-prone mice[J]. Circulation,2001,103(25):3105-3110.
[126]Hashimoto S,Gon Y,Takeshita I,et al.Transforming growth factor-(31 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway[J].Am J Resp ir Crit Care Med, 2001,163(1):152-157.
[127]Platten M,Wick W,Wild BC,et al.Transforming growth factors beta (1) (TGF-beta (1)) and TGF-beta (2) promote glioma cell migration via up-regulation of alpha (V) beta (3) integrin expression[J].Biochem Biophys Res Co,2000,268(2): 607-611.
[128]Zuniga J E,Groppe J C,Cui Y,et al.Assembly of TbetaRI:TbetaRII:TGFbeta ternary complex in vitro with receptor extracellular domains is cooperative and isoform-dependent[J].J Mol Biol,2005,354(5):1052-1068.
[129]Massague J,Chen YG.Controlling TGF-β signaling[J].Genes Dev,2000,14(6): 627-644.
[130]Koibuchi Y,Lee WS,Gibbons GH,Pratt RE.Role of transforming growth factor-beta 1 in the cellular growth response to angiotensin Ⅱ [J].Hypertension, 1993,21(6 Pt 2):1046-1050.
[131]Marshall RP,Gohlke P,Chambers RC,Howell DC,Bottoms SE,Unger T, et al. Angiotensin Ⅱ and the fibroproliferative response to acute lung injury[J].Am J Physiol Lung Cell Mol Physiol,2004,286(1):L156-L164.
[132]Otsuka M,Takabashi H,Shiratori M,Chiba H,Abe S.Reduction of bleomycin induced lung fibrosis by candesartan cilexetil,an angiotensin Ⅱ type 1 receptor antagonist[J].Thorax.2004,59(1):31-38.
[133]Otsuka M,Takahashi H,Shiratori M,et al.Reduction of bleomycin induced lung fibrosis by candesartan cilexetil,an angiotensin Ⅱ type 1 receptor antagonist[J]. Thorax,2004,59(1):31.
[134]徐治波,冯玉麟,高蜀生.氯沙坦对大鼠肺纤维化的干预作用及机制探讨[J].中国呼吸与危重监护杂志,2006,5(6)：452-455.
[135]Sarkar S,Vellaichamy E,Young D,et al.Influence of cytokines and growth factors in ANG Ⅱ-mediated collagen upregulation by fibroblasts in rats:role of myocytes[J].Am J Physiol Heart Circ Physiol,2004,287(1):107.
[136]李勇,彭素岚,汤俊起,等.替米沙坦对博来霉素诱导的大鼠肺纤维化模型的干预作用[J].西部医学,2008,20(1)：26-28.
[137]Liang X,Zhang H,Zhou A,et al.Screening and identification of the up-regulated genes in human mesangial cells exposed to angiotensin Ⅱ [J].Hypertens-Res,2003, 26(3):225-235.
[138]林善琰主编.当代肾脏病学[M].上海：上海科技教育出版社,2001：194
[139]Ford CM,Li S,Pickering JG.Angiotensin Ⅱ stimulates collagen synthesis in human vascular smooth muscle cells. Involvement of the AT(1) receptor, transforming growth factor-beta,and tyrosine phosphorylation[J].Arterioscler Thromb Vasc Biol.1999,19(8):1843-1851.
[1]Batlle M,Roig E,Perez-Villa F,et al.Increased expression of the renin- angiotensin system and mast cell density but not of angiotensin-converting enzyme Ⅱ in late stages of human heart failure[J].J- Heart-Lung-Transplant,2006,25(9):1117-1125.
[2]Nabeshima Y,Tazuma S,Kanno K,et al.Anti-fibrogenic function of angiotensin II type 2 receptor in CC14-induced liver fibrosis[J].Biochem-Biophys-Res-Commun,2006,346(3):658-664.
[3]Mahmood J,Khan F,Okada S,et al.Local delivery of angiotensin receptor blocker into the kidney ameliorates progression of experimental glomerulonephritis[J]. Kidney-Int,2006,70 (9):1591-1598.
[4]Yao HW,Zhu JP,Zhao MH,et al.Losartan attenuates bleomycin-induced pulmonary fibrosis in rats[J].Respiration,2006,73 (2):236-242.
[5]Morihara K,Takai S,Takenaka H,et al.Cutaneous tissue agiotensin-converting enzyme may participate in pathologic scar formation in human skin[J].J Am Acad Dermatol,2006,54(2):251-257.
[6]Sayeski pp,Showkat Ali.M,Semeniuk DJ,et al.Angiotensin Ⅱ signal transduction pathways[J].Regulation Peptide,1998,78(1):19-29.
[7]Volpe M,Musumeci B,Paolis PD,et al.Angiotensin Ⅱ AT2 receptor subtype:an uprising frontier in cardiovascular disease? [J]. Journal of Hypertension,2003,21 (8):1429-1443.
[8]Donoghue M,Hsieh,Baronas E et al.A novel angiotensin-converting enzyme-related carboxypeptidase(ACE2) converts angiotensin I to angiotensin 1-9 [J]. Circ Res.2000,87(7):523-525.
[9]Tipnis SR,Hooper NM,Hyde R et al.A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase[J].J Biol Chem.2000,275(43):33238-33243.
[10]Crackower MA,Sarao R,Oudit GY.Angiotensin-converting enzyme 2 is an essential regulator of heart function[J].Nature.2002,417(6891):822-828.
[11]Saris JJ,Derkx FH,De Bruin RJ et al.High-affinity prorenin binding to cardiac man-6-P/IGF-Ⅱ receptors precedes proteolytic activation to rennin[J].Am J Physiol Heart Circ Physiol.2001,280(4):H1706-H1715.
[12]Sadoshima J.Cytokine actions of angiotensin Ⅱ [J].Circ Res,2000,86(12):1187-1189.
[13]谭强,刘新民,曾惠惠,等.TGF-β与肺纤维化中华临床医师杂志(电子版)[J].2007,1(1)：50-55.
[14]陈刚,余民浙.转化生长因子-β1与肺纤维化研究的进展[J].2007,16(1)：3-5.
[15]王建平,申玉瑶,杨燕.大鼠肺纤维化过程中TGF-β1和PDGF在不同肺组织中的表达变化及意义[J].山东医药,2008,48(23)：26-28.
[16]甘红英,刘学军.肺纤维化大鼠肺组织转化生长因子-β1和前胶原基因的表达[J].中国药物与临床,2006,6(8)：612-613.
[17]Bartram U,Speer CP.The role of transforming growth factor beta in lung development and disease[J].Chest,2004,125(2):754-765.
[18]Bonniaud P,Kolb M,Galt T,et al.Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis[J].J Immunol,2004, 173(3):2099-2102.
[19]李相辉,赵宗江.基质金属蛋白酶-9及组织抑制剂-1与肾间质纤维化[J].中国中西医结合肾病杂志,2007,8(3)：179-181.
[20]Motogima M,Kakuchi J,Yoshioka A,et al.Effect of simultaneous blockade of AT1 and AT2 receptors on the NF-KB pathway and renal inflammatory response [J].Biochim Biophys Acta,2005,1449(3):217-226.
[21]Marpa Ruiz Ortega,Carracedo J,Ramirez R,et al.Estimation of podocyte number :a comparison of methods[J].Kidney Int,2006,54(2):1497-1510.
[22]聂凌,王江,宋熔等.血管紧张素Ⅱ对心脏成纤维细胞PTEN基因表达及增殖的影响[J].心脏杂志,2007,19(4)：377-379.
[23]焦东东,蔡辉.血管紧张素Ⅱ与心脏胶原沉积[J].中国微循环,2009,13(5)：435-437.
[24]Otsuka M,Takahashi H,Shiratori M,et al.Reduction of bleomycin induced lung fibrosis by candesartan cilexetil,an angiotensin Ⅱ type 1 receptor antagonist[J]. Thorax,2004,59(1):31-38.
[25]徐治波,冯玉麟,高蜀生.氯沙坦对大鼠肺纤维化的干预作用及机制探讨[J].中国呼吸与危重监护杂志,2006,5(6)：452-455.
[26]Sarkar S,Vellaichamy E,Young D,et al.Influence of cytokines and growth factors in ANGⅡ-mediated collagen upregulation by fibroblasts in rats:role of myocytes[J].Am J Physiol Heart Circ Physiol,2004,287(1):H107-H117.
[27]李勇,彭素岚,汤俊起,等.替米沙坦对博来霉素诱导的大鼠肺纤维化模型的干预作用[J].西部医学,2008,20(1)：26-28.
[28]Bullock GR,Steyaert I,Bilbe GDistribution of type-1 and type-2 angiotensin rece-ptors in the normal human lung and in lungs from patients with chronic obstructi-ve pulmonary disease[J].Histochem Cell Biol,2001,115(2):117-124.
[29]Marshall RP,Gohlke P, Chambers RC.Angiotensin Ⅱ and the fibroproliferative response to acute lung injury[J].Am J Physiol Lung Cell Mol Physiol,2004,286(1) :L156-L164.
[30]Molteni A,Ward WF,Ts'ao CH,et al.Cytostatic properties of some angiotensin I converting enzyme inhibitors and of angiotensin Ⅱ type 1 receptor antagonists[J]. Curr Pharm Des,2003,9(9):751-761.
[31]Song L,Wang D,Cui X,et al.Kinetic alterations of angiotensin-Ⅱ and nitric oxide in radiation pulmonary fibrosis[J].J Environ Pathol Toxicol Oncol,1998, 17(2):141-150.
[32]Song JS, Kang CM, Rhee CK,et al. Effects of elastase inhibitor on the epithelial cell apoptosis in bleomycin-induced pulmonary fibrosis[J].Exp Lung Res.2009, 35(10):817-829.
[33]Drakopanagiotakis F,Xifteri A,Polychronopoulos V,et al.Apoptosis in lung injury and fibrosis[J].Eur Respir J.2008,32(6):1631-1638.
[34]Crestani B,Marchand-Adam S,Fabre A,et al.Mechanisms in pulmonary fibrosis [J].Rev Prat.2007,57(20):2222-2226.
[35]Kuwano K.Involvement of epithelial cell apoptosis in interstitial lung diseases[J].Intern Med.2008,47(5):345-353.
[36]Kuwano K.Epithelial cell apoptosis and lung remodeling[J].Cell Mol Immunol. 2007,4(6):419-429.
[37]Wang R,Ramos C,Joshi I,et al.Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides[J].Am J Physiol,1999,277(6 Pt 1):1158-1164.
[38]Wang R,Ibarra-Sunga O,Verlinski I,et al.Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captoprilor by a caspase inhibitor[J].Am J Physiol Lung Cell Mol Physiol,2000,279(1):143-151.
[39]He M,He X,Xie Q,et al. Angiotensin Ⅱ induces the expression of tissue factor and its mechanism in human monocytes[J].Thromb Res,2006,117(5):579-590.
[40]Mahrouf M,Ouslimani N,Peynet J,et al.Metformin reduces angiotensin-mediated intracellular production of reactive oxygen species in endothelial cells through the inhibition of protein kinase c[J].Biochem Pharmacol,2006,72(2):176-183.
[41]Martin T,Hagimoto N,Nakamura M. Apoptosis and epithelial Injury in the lungs [J].Proceedings of the American Thoracic Society,2005,2(3):214-220.
[42]Wang R,Zagariya A,Ibarra-Sunga O,et al.Angiotensin Ⅱinduces apoptosis in human and rat alveolar epithelial cells [J].Am J Physiol Lung Cell Mol Physiol,1999,276(5 Pt 1):885-889.
[43]Li X,Rayford H,Uhal BD.Essential roles for angiotensin receptor AT1a in bleomycin-induced apoptosis and lung fibrosis in mice[J].Am J Pathol,2003, 163(6):2523-2530.
[44]Mastruzzo C,Crimi N,Vancheri C.Role of oxidative stress in pulmonary fibrosis[J].Monaldi Arch Chest Dis,2002,57(3-4):173-176.
[45]Papp M,Li X,Zhuang J,et al.Angiotensin receptor subtype AT(1) mediates alveolar epithelial cell apoptosis in response to ANG Ⅱ[J].Am J Physiol Lung Cell Mol Physiol,2002,282(4):L713-L718.
[46]Lukkarinen HP,Laine J,Aho H,et al.Angiotensin Ⅱ receptor inhibtion prevents pneumocyte apoptosis in surfactant-depleted rat lungs[J].Pediatr Pulmonol,2005, 39(4):349-358.
[47]Wang R,Alam G,Zagariya A.Apoptosis of lung epithelial cells in response to TNF-alpha requires angiotensin Ⅱ generation de novo[J].J Cell Physiol,2000, 185(2):253-259.
[48]Le Cras TD,Spitzmiller RE,Albertine KH,et al.VEGF causes pulmonary hemorrhage,hemosiderosis,and air space enlargement in neonatal mice[J].Am J Physiol Lung Cell Mol Physiol,2004,287(1):L134-L142.
[49]李春晖,谭茗月,张新超.激活过氧化物酶增殖物激活受体对血管紧张素II诱导内皮细胞中单核细胞趋化因子-1表达的影响[J].中华老年医学杂志,2006,25(9)：664-667.
[50]Inoshima I,Kuwano K,Hamada N,et al.Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary fibrosis in mice[J].Am J Physiol Lung Cell Mol Physiol,2004,286(5):L1038-L1044.
[51]方向群,朱元珏,胡晓玲,等.氯沙坦对大鼠肺纤维化模型的干预作用及对MCP-1和bFGF表达的影响[J].中华结核和呼吸杂志,2002,25(5)：268-272.
[52]何平平,李杰平,张书杰,等.阻断肾素-血管紧张素-醛固酮系统对大鼠肺维化的干预作用及对MCP-1表达的影响[J].南华大学学报·医学版,2007,35(2)： 186-191.
[53]Streiter RM.Inflammatory mechanisms are not a minor component of the pathogenesis of idiopathic pulmonary fibrosis[J].Am J Respir Crit Care Med,2002,165(4):1206-1208.
[54]Xu Y,Hua J,Mui A,et al.Release of biologically active TGF-beta1 by alveolar epithelial cells results in pulmonary fibrosis[J].Am J Physiol Lung Cell Mol Physiol,2003,285(3):L527-L539.
[55]Nguyen L,Wald WF, Ts'ao CH,et al.Captopril inhibits proliferation of human lung fibroblasts in culture:a potential antifiborotic mechanism[J].Proc Soc Exp Biol Med,1994,205(1):80-84.
[56]Slight SH,Joseph J,Fanjam VK,et al.Extra-adrenal mineralocorticoids and cardiovascular tissule[J]J Mol Cell Cardiol,1999,31(6):1175-1184.
[57]Winter DC,Schneider MF,Osullivan GC,et al.Rapid effects of aldosterone on sodium hydrogen exchange in isolated colonic crypts[J].J Member Biol,1999,170 (1):17-26.
[58]赵力,赵鸣武,方秋红,等.螺内酯减轻博莱霉素A5引起的大鼠肺纤维化[J].中华结核和呼吸杂志,1998,21(5)：300-302.
[59]赵力,赵呜武,方秋红,等.醛固酮促进大鼠肺组织胶原的合成[J].基础医学与临床,2001,21(5)：460-464.
[60]Brown NJ,Nakamura S,Ma LJ,et al.Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo[J].Kidney Int,2000,58(3): 1219-1227.
[61]Fiebelar A,Schmidt F,Muller DN,et al.Mineralocorticoid receptor affects AP-1 and nuclear factor-kappaB activation in angiotensin Ⅱ-induced cardiac injury[J].Hypertension,2001,37(2 Pt 2):787-793.
[2]Enomoto T,Usuki J,Azuma A,et al. Diabetes mellitus may increase risk for idiopathic pulmonary fibrosis[J].Chest,2003,123(6):2007-2011.
[3]刘松平,张宏.糖尿病肺损害[J].国际内分泌代谢杂志,2004,24(5)：341-343.
[4]张宏,白景文,于振涛,等.2型糖尿病患者慢性肺损伤的超微病理改变及临床意义[J].解剖学报,2005,36(6)：656-659.
[5]赵伟,张宏,谢云,等.2型糖尿病患者支气管黏膜超微结构的病理变化[J].解剖学报,2006,37(6)：685-688.
[6]张宏,白景文,曹泽伟,等.糖尿病家兔早期肺组织超微结构的改变及中药干预治疗的影响[J].中国中西医结合急救杂志,2005,12(3)：170-172.
[7]Wang R,Ibarra-Sunga O,Verlinski I,et al.Abrogation of bleomycin-induced Epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor[J].Am J Physiol Lung Cell Mol Physiol,2000,279(1):L143-L151.
[8]Marshall RP.The pulmonary rennin-angiotensin system[J]. Current Pharmaceutical Design,2003,9(9):715-722.
[9]Otsuka M,Takahashi H,Shiratori M,et al.Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist[J]. Thorax.2004,59(1):31-38.
[10]Bullock GR,Steyaert I,Bilbe GDistribution of type-1 and type-2 angiotensin rece-ptors in the normal human lung and in lungs from patients with chronic obstructi-ve pulmonary disease[J].Histochem Cell Biol,2001,115(2):117-124.
[11]Sarkar S,Vellaichamy E,Young D,et al.Influence of cytokines and growth factors in ANG II-mediated collagen upregulation by fibroblasts in rats:role of myocytes[J].Am J Physiol Heart Circ Physiol,2004,287(1):H107-H117.
[12]Davis TM,KnuimanM,Kendall P,et al.Reduced pulmonary function and its associations in type 2 diabetes:the Fremantle Diabetes Study[J].Diabetes Res Clin Pract,2000,50(2):153-159.
[13]Goldman MD.Lung dysfunction in diabetes[J].Diabetes Care,2003,26(6): 1915-1918.
[14]沈轶,尹福在,姚立新,等.2型糖尿病患者的肺功能研究[J].中国糖尿病杂志,2000,8(6)：370-379.
[15]孙玉桂,张秀玲,张继安.糖尿病肺功能改变的临床价值[J].辽宁实用糖尿病杂志,2001,(1)：23-24.
[16]江山平,黄莉文,李依群,等.2型糖尿病患者的肺功能改变[J].中华结核和呼吸杂志,2005,28(1)：65-66.
[17]Popov D,Simioneseu M.Alterations of lung structure in experimental diabetes,and diabetes associated with hyperlipidaemia in hamsters[J].Eur Respir,1997,10(8):1850-1858.
[18]Weyrand B Jonchneere A,Fraus A, et al. Diabetes mellitus induees a thickning of the pulmonary basal lamina[J].Respiration,1999,66(1):14-19.
[19]Ofulue F,Kida K,Thurllbeck WM.Experimental diabetes and the iung [J].Am Rev Respir Dis,1988,137(1):162-166.
[20]Sahebjami H,Denhnolm D.Lung mechanies and conneelive tissue proteins in diabetic Bio-Breeding/Woreester Wistar rats[J].J Appi Physiol,1987,62(4): 1430-1435.
[21]Plopper CG,Morishige WK.Alterations in granular (type II) pneumoreyte ultrastructure by streptozotocin induced dibetes in the rals [J]. Lab Invest,1987, 38(2):143-148.
[22]沈兴平,舒昌达,张佐才,等.实验性糖尿病肺形态学及氧自由基研究[J].中国病理生理杂志,2000,16(6)：552-556.
[23]Kawano K,Hirashima T,Mori S,et al.Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty(OLETF) strain[J].Diabetes,1992,41(11):1422-1428.
[24]Kawano K.OLETF(Otsuka Long-Evans Tokushima Fatty) rat:a new NIDDM rat strain[J].Diabetes Res Clin Pract,1994,24(suppl):S317-S320.
[25]Funakoshi A.Little or noexpression of the cholecystokin A receptor gene in the pancreas of diabetic rats(Otsuka Long-Evans Tokushima Fatty=OLETF Rats) [J].Biochem Biophys Res Commun,1994(2),199:482-488.
[26]Hirashima G.A diabetogenic gene(ODB-1)assigned to the X chromosome in OLETF rats[J].Diabtes Res Clin Pract,1995,27(2):91-96.
[27]Hirashima T,Kawano K Mori S, et al.A diabetogenic gene,ODB2, identified on chromosome 14 of the OLETF rat and its synergistic action with ODBl[J].Biochem Biophys Res Commun,1996,224(2):420-425.
[28]Bumpus FM,Schwarts H and Page IH.Synthesis and pharmacology of the octapeptide angiotonin[J].Science,1957,125(3253):886-887.
[29]Rittel W,Iselin B,Kappeler H,et al.Synthesis of a highly effective Angiotensin Ⅱ amide(L-asparagynyl-L-arginyl-L-valyl-L4yrosyl-L-isoleucyl-L-hi stidyl-L-prolyl-L-phenylalanine) [J].Helv Chim Acta,1957,40(4):614-624.
[30]Mento PF,Wiikes BM.Plasma angiotensins and blood pressure during converting enzyme inhibition[J].Hypertension,1987,9(6 Pt 2):Ⅲ42-Ⅲ48.
[31]Urata H,et al.Wide spread tissue distribution of human chymase[J].J Hyperten.1994,12(9):S17-S22.
[32]Rosendorff C.The rennin angiotensin system and vascular hypertrophy[J].J Am Coll Cardial.1996,28(4):803-812.
[33]Timmermans PB,Duncia JV,Carini DJ,et al.Discovery of losartan,the first angiotensin II receptor antagonist[J].Hum Hypertens,1995,9(suppl 5):S3-S18.
[34]Michael E,Knauss TC,Pierce GF,et al.The importance of tyrosine phosphorylation in angiotensin Ⅱ type 1 receptor signaling[J].Hypertension, 1996,27(3 Pt 2):476-480.
[35]Khosla MC,Smeby RR,Bumpus FM.Structure activity relationship in angiotensin Ⅱ analogs,in Handbook of Experimental Pharmacology[J].Springer-Verlag,1974: 126-156.
[36]Martin MM,Victor X,Zhao X,et al.Identification and characterization of functional angiotensin II type 1 receptors on immortalized human fetal aortic vascular smooth muscle cells[J].Molecular and Cellular Endocrinology, 2001,183(1-2):81-91.
[37]Moore SA,Patel AS,Huang N,et al.Effects of mutations in the highly concerved DRY motif on binding affinity,expression,and Gprotein recruitment of the human angiotensin Ⅱ type-2 receptor[J].Molecular Brain Res.2002,109(1-2):161-167.
[38]Sasaki K,Yamano Y,Bardhan S,et al.Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin Ⅱ type-1 receptor[J].Nature. 1991,351 (6323):230-233.
[39]Murphy TJ,Alexander RW,Griendling KK,et al.Isolation of a cDNA encoding the vascular type-1 angiotensin Ⅱ receptor[J].Nature.1991,351(6323):233-236.
[40]Bergsma DJ,Ellis C,Kumar C,et al.Cloning and characterization of a human angiotensin Ⅱ type 1 receptor[J].Biochem Biophys Res Commun,1992,183(3): 989-995.
[41]Guo DF,Furuta H,Mizukoshi M,et al.The genomic organization of human angiotensin Ⅱ type 1 receptor[J]. Biochem Biophys Res Commun,1994, 200(1):313-319.
[42]Curnow KM,Pasoe L,Davies E,et al.Alternatively spliced human type 1 angiotensin Ⅱ receptor mRNAs are translated at different efficiencies and encode two receptor isoforms[J].Mol Endocrinol,1995,9(9):1250-1262.
[43]Jayadev S,Smith RD,Jagadeesh G,et al.N-linked glycosylation is required for optimal AT1a angiotensin receptor expression in COS-7 cells[J].Endocrinology, 1999,140(5):2010-2017.
[44]Ohyama K,Yamano Y,Sano T,et al.Disulfide bridges in extracellular domains of angiotensin Ⅱ receptor type Ⅰ A[J].Regul Pept,1995,57(2):141-147.
[45]Sadoshima J.Cytokine actions of angiotensin Ⅱ [J].Circ Res,2000,86(12):1187-1189.
[46]Parsons KK,Coffman TM,The rennin-angiotensin system:it's all in your head[J].J Clin Invest.2007,117(4):873-876.
[47]Po Sing Leung.The physiology of a local rennin-angiotensin system in the pancreas[J].Physiol.2007,580(Pt1):31-37.
[48]Rodgers KE,Abiko M,Girgis W,et al.Acceleration of dermis tissue repair by angiotensin Ⅱ [J].Wound Rep Reg,1997,5(4):175-183.
[49]Phillips MI,Speakman EA,Kimura B.Levels of angiotensin and molecular biology of the tissue rennin angiotensin systems[J].Regul Pept,1993,43(1-2): 1-20.
[50]Peters Jand Clausmeyer S. Intracellular sorting of renin:cell type specific differences and their consequences[J].J-Mol-Cell-Cardiol,2002,34(12):1561-1568.
[51]MacKenzie SM,Fraser R,Connell JM,et al.Local renin-angiotensin systems and their interactions with extra-adrenal corticosteroid production[J].J-Renin-Angiotensin-Aldosterone-Syst,2002,3 (4):214-221.
[52]Zhou J, Pavel J,Macova MA,et al.ATl receptor blockade regulates the local angiotensin Ⅱ system in cerebral microvessels from spontaneously hypertensive rats[J].Stroke,2006,37(5):1271-1276.
[53]Garcia MJ,Martinez-Martos JM,Mayas MD,et al.Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of male mice[J].Life-Sci,2003, 73 (5):525-538.
[54]马骥,林善淡,朱依纯.当代肾脏病学[M].上海：上海教育出版社,2001,第1版,63-74.
[55]Schauser KH,Nielsen AH,Winther H,et al.Localization of the renin-angiotensin System in the bovine ovary:Cyclic variation of the angiotensin Ⅱ receptor expression[J].Biol Reprod,2001,65(6):1672-1680.
[56]Mitsube K,Mikuni M,Matousek M,et al.Role of the angiotensin Ⅱ system in regulation of ovulation and blood flow in the rat ovary[J].Repreduction,2003, 125(3):425-435.
[57]Shutttleworth G,Pipkin FB,Hunter MG.In vitro development of pig preantral follieieles cultured in a serum-free medium and the effect of angiotensin Ⅱ[J]. Reproduction,2002,123(6):807-818.
[58]Leung PS,Sernia C.The renin-angiotensin system and male reproduction:new functions for old hormones[J].J Mol Endocrinol,2003,30(3):263-270.
[59]Franke FE,Pauls K,Metzger R,et al.Agiotensin I-converting enzyme and potential substrates in human testis and testicular tumours[J].APMIS,2003, 111(1):234-244.
[60]Dinh DT,Frauman AG,Johnston CI,et al.Agiotensin receptors:distribution, signaling and function[J].Clinical Science,2001,100(5):481-492.
[61]Stegbauer J,Vonend O,Oberhauser V,et al.Effects of angiotensin-(1-7) and other bioactive components of the renin-angiotensin system on vascular resistance and noradrenaline release in rat kidney[J].Journal of Hypertension,2003,21(7):1391- 1399.
[62]Rodgers K,Xiong S,Felix J,et al.Development of angiotensin(1-7) as an agent to accelerate dermal repair[J].Wound Repair Regen,2001,9(3):238-247.
[63]Batlle M,Roig E,Perez-Villa F,et al.Increased expression of the renin-angiotensin system and mast cell density but not of angiotensin-converting enzyme Ⅱ in late stages of human heart failure[J].J-Heart-Lung-Transplant,2006, 25(9):1117-1125.
[64]Nabeshima Y,Tazuma S,Kanno K,et al.Anti-fibrogenic function of angiotensin II type 2 receptor in CC14-induced liver fibrosis[J].Biochem-Biophys-Res-Commun,2006,346(3):658-664.
[65]Bataller R,Sancho-Bru P,Gines P,et al.Liver fibrogenesis:a new role for the renin-angiotensin system[J].Antioxid-Redox-Signal,2005,7(9-10):1346-1355.
[66]Yang L,Bataller R,Dulyx J,et al.Attenuated hepatic inflammation and fibrosis in Angiotensin type 1a receptor deficient mice[J].J- Hepatol,2005,43(2):317-323.
[67]Mahmood J,Khan F,Okada S,et al.Local delivery of angiotensin receptor blocker into the kidney ameliorates progression of experimental glomerulonephritis[J].Kidney-Int,2006,70(9):1591-1598.
[68]Yao HW,Zhu JP,Zhao MH,et al.Losartan attenuates bleomycin-induced pulmonary fibrosis in rats[J].Respiration,2006,73 (2):236-242.
[69]Chen CM,Chou HC,Hsu H,et al.Transforming growth factor-betal upregulation is independent of angiotensin in paraquat-induced lung fibrosis[J].Toxicology, 2005,216(2-3):181-187.
[70]Morihara K,Takai S,Takenaka H,et al.Cutaneous tissue agiotensin-converting enzyme may participate in pathologic scar formation in human skin[J].J Am Acad Dermatol,2006,54(2):251-257.
[71]Hitoshi Y,Shigeki K,Ryuichi N,et al.A ngiotensin-Ⅱ and vascular endothelial growth factor interaction plays an important role in rat liver fibrosis development[J].Hepatology Research,2006,36(2):124-129.
[72]De Gasparo M,Catt KJ.International Union of Pharmacology.ⅩⅩⅢ.The Angiotensin II Receptor[J].Pharmacol.Rev,2000,52(3):415-472.
[73]Le Cras TD,Spitzmiller RE,Albertine KH,et al.VEGF causes pulmonary hemorrhage,hemosiderosis,and air space enlargement in neonatal mice[J].Am J Physiol Lung Cell Mol Physiol,2004,287(1):L134-L142.
[74]李春晖,谭茗月,张新超.激活过氧化物酶增殖物激活受体对血管紧张素1I诱导内皮细胞中单核细胞趋化因子-1表达的影响[J].中华老年医学杂志,2006,25(9)：664-667.
[75]Inoshima I,Kuwano K,Hamada N,et al.Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary fibrosis in mice[J].Am J Physiol Lung Cell Mol Physiol,2004,286(5):L1038-L1044.
[76]方向群,朱元珏,胡晓玲,等.氯沙坦对大鼠肺纤维化模型的干预作用及对MCP-1和bFGF表达的影响[J].中华结核和呼吸杂志,2002,25(5)：268-272.
[77]何平平,李杰平,张书杰,等.阻断肾素-血管紧张素-醛固酮系统对大鼠肺维化的干预作用及对MCP-1表达的影响[J].南华大学学报·医学版,2007,35(2)：186-191.
[78]Page EL,Robitaille GA,Pouyssegur,Richard DE:Induction of Hypoxia-Inducible Factor 1-α by Transcriptional and Translation Mechanisms[J]JBC,2002,277(50): 48403-48409.
[79]He M,He X,Xie Q,et al. Angiotensin II induces the expression of tissue factor and its mechanism in human monocytes[J].Thromb Res,2006,117(5):579-590.
[80]Mahrouf M,Ouslimani N,Peynet J,et al.Metformin reduces angiotensin-mediated intracellular production of reactive oxygen species in endothelial cells through the inhibition of protein kinase c[J].Biochem Pharmacol,2006,72(2):176-183.
[81]FeenerEP,Nurthrup JM,Aiello LP,et al.Angiotensin II induces plasminogen activator inhibitor-1 and-2 expression in vascular endothelial and smooth Muscle cells[J].J Clin Invest,1995,95(3):1353-1362.
[82]王利,罗义,杨阳.缬沙坦对血管紧张素II诱导人脐静脉内皮细胞分泌tPA、PA I-1抗原的影响[J].广州医学院学报,2007,35(3)：1-5.
[83]王大志,张书瑜,杨晓璐.缬沙坦和依那普利对自发性高血压大鼠血浆sICAM-1和PAI-1的影响[J].山东医药,2005,45(34)：：23-24.
[84]鹿育萨,王萍芝,王瑞英,等.血管紧张素Ⅱ和卡托普利、缬沙坦对人脐静脉内皮细胞PAI-1、tPA蛋白表达的影响[J].高血压杂志,2005,13(10)：637-641.
[85]施志明,钱晓明,许瑞吉,等.实验性糖尿病大鼠心肌ATⅡ和心肌超微结构的研究[J].中国糖尿病杂志,1996,4(1)：28-30.
[86]Gotzsche LB,Rosenqvist N, Gronbaek H,et al.Increased number of myocardial voltage gated Ca2+ channels and unchanged total beta-receptor number in long-term STZ-diabetic rats[J].Eup J Endocrinol,1996,134(1):107-116.
[87]雅莉,田慧,潘长玉,等.血管紧张素Ⅱ对实验性糖尿病大鼠心肌病变的影响及卡托普利的保护作用[J].中国糖尿病杂志,2000,8(5)：298-300.
[88]李辉,李俭青,江时森,等.牛磺酸对糖尿病大鼠心肌组织肾素-血管紧张素系统的抑制作用[J].中国内分泌代谢杂志,1997,13(2)：108-110.
[89]Brown L,Wall D, Marchant C,et al.Tissue-specific changes in angiotensin Ⅱ receptors in streptozotocin-diabetic rats[J].J Endocinol,1997,154(2):355-362.
[90]Dostai DE,Rothbium KN,Chernin MI.Intracardiac detection of angiotensiongen and renin:a localized renin-angiotensin system in neonatal rat heart[J].Am J Physiol,1992,263(4 Pt 1):C838-C850.
[91]Zata R,Dunn BR,Meyer TW,et al.Prevention of diabetic glomerulopathy by harm acologicea melioration of glomerular capillary hypertension[J].J Clin Invest, 1986,77(6):1925-1930.
[92]Woo KT, Lau YK, Chan CM, et al. ATRA therapy restores normal renal functi-on and renal reserve and p revents renal failure [J].Ann Acad Med Singapore, 2005,34:52-59.
[93]杨福燕,邵凤杰.双重阻断肾素-血管紧张素系统对早期糖尿病肾病的影响[J].中国全科医学,2008,11(1B)：113-114.
[94]Han KH,Kang YS,Han SY,et al.Spironolactone ameliorates renal injury and connective tissue growth factor expression in type Ⅱ diabetic ratsl Kidney Int, 2006,70 (1):111-120.
[95]Takebayashi K,Matsumoto S,Aso Y,et al.Aldosterone blockade attenuates urina-ry monocyte chemoattractant protein-1 and oxidative stress in patients with type 2 diabetes complicated by diabetic nephropathy.J Clin Endecrinol Metab,2006,91 (6):2214-2217.
[96]Yamazaki H, Ohta K, Tsukiji H, et al.Corticosteroid enhances heme oxygenase-1 production by circulation monocytes by up-regulating hemoglobin scavenger rece-ptor and amplifying the receptor-mediated up take of hemoglobin-haptoglobin complex.Biochem Biophys Res Commun,2007,358(2):506-512.
[97]黄佳佳.肾素-血管紧张素-醛固酮系统与糖尿病微血管并发症的关系[J].国际内科学杂志,2008,35(9)：520-526.
[98]唐伟,吕国良,徐萍,等.RAAS阻断剂与糖尿病慢性并发症[J].实用临床医药杂志,2004,8(4)：25-29.
[99]林善锬.肾脏局部RAAS与糖尿病肾病[N].中国医学论坛报,2006-9-21-040.
[100]Robert AB,Flanders KC,Heine UI,et al.Transforming growth factor beta: multifunctional regulator of differentiation and developmen[J].Philos Trans R Soc Lond B Biol Sci,1990,327(1239):145-154.
[101]Blakytny R,Ludlow A,Martin GE,et al. Latent TGF-beta 1 activation by platele-ts[J]. J Cell Physiol,2004,199(1):67-76.
[102]Fukuda K,Kawata S,Tamura S, et al. Transforming growth factor beta1-induced degradation of activated Src tyrosine kinase in rat fibroblasts[J].Oncogene,1998, 16(26):3349-3356.
[103]Lee TC,Gold L I,Reibman J,et al.Immunohistochemical localization of transforming growth factor-beta and insulin-like growth factor-1 in asbestosis in the sheep model[J]. Int Arch Occup Environ Health,1997,69(3):157-164.
[104]Teicher BA.Malignant cells,directors of the malignant p rocess:role of transforming growth factor-beta[J].Cancer Metastasis Rev,2001,20(1-2):133-143.
[105]Sheppard D.Pulmonary fibrosis:a cellular overreaction or a failure of communication[J].J Clin Invest,2001,107(12):1501-1502.
[106]Jagirdar J,Begin R,Dufresne A,et al.Transforming growth factor-beta (TGF-beta) in silicosis[J]. Am J Resp ir Crit CareMed,1996,154(4 Pt 1): 1076-1081.
[107]Sime PJ,Zhou X,Graham FL,et al.Adenovector-mediated gene transfer of active transforming growth factor-β1 induces p rolonged severe fibrosis in rat lung[J].J Clin Invest,1997,100(4):768-776.
[108]陈刚,余民浙.转化生长因子-β1 (TGF-β1)与肺纤维化研究的进展[J].中 国疗养医学,2007,16(1)：3-5.
[109]Linnala A,Kinnula V,Laitinen LA, et al.Transforming growth factor-beta regulates the expression of fibronectin and tenascin in BEAS 2B human bronchial epithelial cells[J]. Am J Resp ir CellMol Biol,1995,13(5):578-585.
[110]Coker RK,Laurent GJ.Pulmonary fibrosis:cytokines in banlance[J].Eur Respir J,1998,11(6):1218-1221.
[111]Coker RK,Laurent GJ,Shahzeidi S,et al.Transforming growth factors-beta 1,-beta 2,-beta 3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis[J].Am J Pathol, 1997,150(3):981-991.
[112]Liu JY,Brody AR.Increased TGF-beta 1 in lungs of asbestos-exposed rats and mice:reduced expression in TNF-alpha receptor knockout mice[J].J Environ Pathol Toxicol Oncol,2001,20(2):97-108.
[113]YoshidaM,Hayashi S.Role of TGF-beta and PDGF on the pathogenesis of pulmonary fibrosis-analysis by vivo gene transfer[J].Nippon Rinsho,1996,54(2): 418-422.
[114]Ludwicka A,Ohba T,Trojanowska M,et al.Elevated level of platelet derived growth factor and transforming growth factor-beta 1 in bronchoalveolar lavage fluid from patients with scleroderma[J].J Rheumatol,1995,22(10):1876-1883.
[115]Denis M.Neutralization of transforming growth factor-beta 1 in a mouse model of immune-induced lung fibrosis[J].Immunology,1994,82(4):584-590.
[116]Kapanci Y,Desmouliere A, Pache JC,et al. Cytoskeletal protein modulation in pulmonary alveolarmyofibroblasts during idiopathic pulmonary fibosis.Possible role of transforming growth factor beta and tumor necrosis factor alpha[J].Am JResp ir Crit Care Med,1995,152(6 Pt 1):2163-2169.
[117]Bienkowski RS,Gotkin MG.Control of collagen deposition in mammalian lung[J].Proc Soc Exp BiolMed,1995,209(2):118-140.
[118]Gharaee-KermaniM,Denholm EM,Phan SH.Costimulation of fibroblast collagen and transforming growth factor β1 gene expression by monocyte chemoattractant protein-1 via specific receptors[J].J Biol Chem,1996,271(30): 17779-17784.
[119]Eickelberg O,Pansky A,Kochler E,et al.Molecular mechanisms of TGF-β antag-onism by interferon(gamma) and cyclosporine A in lung fibroblasts[J].Faseb J,2001,15(3):797-806.
[120]Venkatesan N,Roughley PJ,Ludwig MS,et al.Proteoglycan expression in bleomycin lung fibroblasts:role of transforming growth factor-β1 and interferon-γ[J]. Am J Physiol Lung CellMol Physiol,2002,283(4):806-814.
[121]Vaillant P,Menard O,Vignaud JM,et al.The role of cytokines in human lung fibrosis[J].Monaldi Arch Chest Dis,1996,51(2):145-152.
[122]Lee CG,Cho SJ Kang MJ,et al.Eavly growth response gene-1 mediated apop-tosis is essential for transforming growth factor beta 1-induced pulmonary fibrosis[J].Exp Med,2004,200(3):377-389.
[123]Arkwright PD,Laurie S,Super M,et al.TGF-(31 genotype and accelerated decline in lung function of patients with cystic fibrosis.Thorax,2000,55(6):459-462.
[124]Lasky JA,Brody AR. Interstitial fibrosis and growth factors [J]. Environ Health Perspect,2000,108(suppl 4):751-762.
[125]Zhu Y,Farrehi PM,Fay WP.Plasminogen activator inhibitor-I enhances neointima formation after oxidative vascular injury in atherosclerosis-prone mice[J]. Circulation,2001,103(25):3105-3110.
[126]Hashimoto S,Gon Y,Takeshita I,et al.Transforming growth factor-(31 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway[J].Am J Resp ir Crit Care Med, 2001,163(1):152-157.
[127]Platten M,Wick W,Wild BC,et al.Transforming growth factors beta (1) (TGF-beta (1)) and TGF-beta (2) promote glioma cell migration via up-regulation of alpha (V) beta (3) integrin expression[J].Biochem Biophys Res Co,2000,268(2): 607-611.
[128]Zuniga J E,Groppe J C,Cui Y,et al.Assembly of TbetaRI:TbetaRII:TGFbeta ternary complex in vitro with receptor extracellular domains is cooperative and isoform-dependent[J].J Mol Biol,2005,354(5):1052-1068.
[129]Massague J,Chen YG.Controlling TGF-β signaling[J].Genes Dev,2000,14(6): 627-644.
[130]Koibuchi Y,Lee WS,Gibbons GH,Pratt RE.Role of transforming growth factor-beta 1 in the cellular growth response to angiotensin Ⅱ [J].Hypertension, 1993,21(6 Pt 2):1046-1050.
[131]Marshall RP,Gohlke P,Chambers RC,Howell DC,Bottoms SE,Unger T, et al. Angiotensin Ⅱ and the fibroproliferative response to acute lung injury[J].Am J Physiol Lung Cell Mol Physiol,2004,286(1):L156-L164.
[132]Otsuka M,Takabashi H,Shiratori M,Chiba H,Abe S.Reduction of bleomycin induced lung fibrosis by candesartan cilexetil,an angiotensin Ⅱ type 1 receptor antagonist[J].Thorax.2004,59(1):31-38.
[133]Otsuka M,Takahashi H,Shiratori M,et al.Reduction of bleomycin induced lung fibrosis by candesartan cilexetil,an angiotensin Ⅱ type 1 receptor antagonist[J]. Thorax,2004,59(1):31.
[134]徐治波,冯玉麟,高蜀生.氯沙坦对大鼠肺纤维化的干预作用及机制探讨[J].中国呼吸与危重监护杂志,2006,5(6)：452-455.
[135]Sarkar S,Vellaichamy E,Young D,et al.Influence of cytokines and growth factors in ANG Ⅱ-mediated collagen upregulation by fibroblasts in rats:role of myocytes[J].Am J Physiol Heart Circ Physiol,2004,287(1):107.
[136]李勇,彭素岚,汤俊起,等.替米沙坦对博来霉素诱导的大鼠肺纤维化模型的干预作用[J].西部医学,2008,20(1)：26-28.
[137]Liang X,Zhang H,Zhou A,et al.Screening and identification of the up-regulated genes in human mesangial cells exposed to angiotensin Ⅱ [J].Hypertens-Res,2003, 26(3):225-235.
[138]林善琰主编.当代肾脏病学[M].上海：上海科技教育出版社,2001：194
[139]Ford CM,Li S,Pickering JG.Angiotensin Ⅱ stimulates collagen synthesis in human vascular smooth muscle cells. Involvement of the AT(1) receptor, transforming growth factor-beta,and tyrosine phosphorylation[J].Arterioscler Thromb Vasc Biol.1999,19(8):1843-1851.
[1]Batlle M,Roig E,Perez-Villa F,et al.Increased expression of the renin- angiotensin system and mast cell density but not of angiotensin-converting enzyme Ⅱ in late stages of human heart failure[J].J- Heart-Lung-Transplant,2006,25(9):1117-1125.
[2]Nabeshima Y,Tazuma S,Kanno K,et al.Anti-fibrogenic function of angiotensin II type 2 receptor in CC14-induced liver fibrosis[J].Biochem-Biophys-Res-Commun,2006,346(3):658-664.
[3]Mahmood J,Khan F,Okada S,et al.Local delivery of angiotensin receptor blocker into the kidney ameliorates progression of experimental glomerulonephritis[J]. Kidney-Int,2006,70 (9):1591-1598.
[4]Yao HW,Zhu JP,Zhao MH,et al.Losartan attenuates bleomycin-induced pulmonary fibrosis in rats[J].Respiration,2006,73 (2):236-242.
[5]Morihara K,Takai S,Takenaka H,et al.Cutaneous tissue agiotensin-converting enzyme may participate in pathologic scar formation in human skin[J].J Am Acad Dermatol,2006,54(2):251-257.
[6]Sayeski pp,Showkat Ali.M,Semeniuk DJ,et al.Angiotensin Ⅱ signal transduction pathways[J].Regulation Peptide,1998,78(1):19-29.
[7]Volpe M,Musumeci B,Paolis PD,et al.Angiotensin Ⅱ AT2 receptor subtype:an uprising frontier in cardiovascular disease? [J]. Journal of Hypertension,2003,21 (8):1429-1443.
[8]Donoghue M,Hsieh,Baronas E et al.A novel angiotensin-converting enzyme-related carboxypeptidase(ACE2) converts angiotensin I to angiotensin 1-9 [J]. Circ Res.2000,87(7):523-525.
[9]Tipnis SR,Hooper NM,Hyde R et al.A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase[J].J Biol Chem.2000,275(43):33238-33243.
[10]Crackower MA,Sarao R,Oudit GY.Angiotensin-converting enzyme 2 is an essential regulator of heart function[J].Nature.2002,417(6891):822-828.
[11]Saris JJ,Derkx FH,De Bruin RJ et al.High-affinity prorenin binding to cardiac man-6-P/IGF-Ⅱ receptors precedes proteolytic activation to rennin[J].Am J Physiol Heart Circ Physiol.2001,280(4):H1706-H1715.
[12]Sadoshima J.Cytokine actions of angiotensin Ⅱ [J].Circ Res,2000,86(12):1187-1189.
[13]谭强,刘新民,曾惠惠,等.TGF-β与肺纤维化中华临床医师杂志(电子版)[J].2007,1(1)：50-55.
[14]陈刚,余民浙.转化生长因子-β1与肺纤维化研究的进展[J].2007,16(1)：3-5.
[15]王建平,申玉瑶,杨燕.大鼠肺纤维化过程中TGF-β1和PDGF在不同肺组织中的表达变化及意义[J].山东医药,2008,48(23)：26-28.
[16]甘红英,刘学军.肺纤维化大鼠肺组织转化生长因子-β1和前胶原基因的表达[J].中国药物与临床,2006,6(8)：612-613.
[17]Bartram U,Speer CP.The role of transforming growth factor beta in lung development and disease[J].Chest,2004,125(2):754-765.
[18]Bonniaud P,Kolb M,Galt T,et al.Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis[J].J Immunol,2004, 173(3):2099-2102.
[19]李相辉,赵宗江.基质金属蛋白酶-9及组织抑制剂-1与肾间质纤维化[J].中国中西医结合肾病杂志,2007,8(3)：179-181.
[20]Motogima M,Kakuchi J,Yoshioka A,et al.Effect of simultaneous blockade of AT1 and AT2 receptors on the NF-KB pathway and renal inflammatory response [J].Biochim Biophys Acta,2005,1449(3):217-226.
[21]Marpa Ruiz Ortega,Carracedo J,Ramirez R,et al.Estimation of podocyte number :a comparison of methods[J].Kidney Int,2006,54(2):1497-1510.
[22]聂凌,王江,宋熔等.血管紧张素Ⅱ对心脏成纤维细胞PTEN基因表达及增殖的影响[J].心脏杂志,2007,19(4)：377-379.
[23]焦东东,蔡辉.血管紧张素Ⅱ与心脏胶原沉积[J].中国微循环,2009,13(5)：435-437.
[24]Otsuka M,Takahashi H,Shiratori M,et al.Reduction of bleomycin induced lung fibrosis by candesartan cilexetil,an angiotensin Ⅱ type 1 receptor antagonist[J]. Thorax,2004,59(1):31-38.
[25]徐治波,冯玉麟,高蜀生.氯沙坦对大鼠肺纤维化的干预作用及机制探讨[J].中国呼吸与危重监护杂志,2006,5(6)：452-455.
[26]Sarkar S,Vellaichamy E,Young D,et al.Influence of cytokines and growth factors in ANGⅡ-mediated collagen upregulation by fibroblasts in rats:role of myocytes[J].Am J Physiol Heart Circ Physiol,2004,287(1):H107-H117.
[27]李勇,彭素岚,汤俊起,等.替米沙坦对博来霉素诱导的大鼠肺纤维化模型的干预作用[J].西部医学,2008,20(1)：26-28.
[28]Bullock GR,Steyaert I,Bilbe GDistribution of type-1 and type-2 angiotensin rece-ptors in the normal human lung and in lungs from patients with chronic obstructi-ve pulmonary disease[J].Histochem Cell Biol,2001,115(2):117-124.
[29]Marshall RP,Gohlke P, Chambers RC.Angiotensin Ⅱ and the fibroproliferative response to acute lung injury[J].Am J Physiol Lung Cell Mol Physiol,2004,286(1) :L156-L164.
[30]Molteni A,Ward WF,Ts'ao CH,et al.Cytostatic properties of some angiotensin I converting enzyme inhibitors and of angiotensin Ⅱ type 1 receptor antagonists[J]. Curr Pharm Des,2003,9(9):751-761.
[31]Song L,Wang D,Cui X,et al.Kinetic alterations of angiotensin-Ⅱ and nitric oxide in radiation pulmonary fibrosis[J].J Environ Pathol Toxicol Oncol,1998, 17(2):141-150.
[32]Song JS, Kang CM, Rhee CK,et al. Effects of elastase inhibitor on the epithelial cell apoptosis in bleomycin-induced pulmonary fibrosis[J].Exp Lung Res.2009, 35(10):817-829.
[33]Drakopanagiotakis F,Xifteri A,Polychronopoulos V,et al.Apoptosis in lung injury and fibrosis[J].Eur Respir J.2008,32(6):1631-1638.
[34]Crestani B,Marchand-Adam S,Fabre A,et al.Mechanisms in pulmonary fibrosis [J].Rev Prat.2007,57(20):2222-2226.
[35]Kuwano K.Involvement of epithelial cell apoptosis in interstitial lung diseases[J].Intern Med.2008,47(5):345-353.
[36]Kuwano K.Epithelial cell apoptosis and lung remodeling[J].Cell Mol Immunol. 2007,4(6):419-429.
[37]Wang R,Ramos C,Joshi I,et al.Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides[J].Am J Physiol,1999,277(6 Pt 1):1158-1164.
[38]Wang R,Ibarra-Sunga O,Verlinski I,et al.Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captoprilor by a caspase inhibitor[J].Am J Physiol Lung Cell Mol Physiol,2000,279(1):143-151.
[39]He M,He X,Xie Q,et al. Angiotensin Ⅱ induces the expression of tissue factor and its mechanism in human monocytes[J].Thromb Res,2006,117(5):579-590.
[40]Mahrouf M,Ouslimani N,Peynet J,et al.Metformin reduces angiotensin-mediated intracellular production of reactive oxygen species in endothelial cells through the inhibition of protein kinase c[J].Biochem Pharmacol,2006,72(2):176-183.
[41]Martin T,Hagimoto N,Nakamura M. Apoptosis and epithelial Injury in the lungs [J].Proceedings of the American Thoracic Society,2005,2(3):214-220.
[42]Wang R,Zagariya A,Ibarra-Sunga O,et al.Angiotensin Ⅱinduces apoptosis in human and rat alveolar epithelial cells [J].Am J Physiol Lung Cell Mol Physiol,1999,276(5 Pt 1):885-889.
[43]Li X,Rayford H,Uhal BD.Essential roles for angiotensin receptor AT1a in bleomycin-induced apoptosis and lung fibrosis in mice[J].Am J Pathol,2003, 163(6):2523-2530.
[44]Mastruzzo C,Crimi N,Vancheri C.Role of oxidative stress in pulmonary fibrosis[J].Monaldi Arch Chest Dis,2002,57(3-4):173-176.
[45]Papp M,Li X,Zhuang J,et al.Angiotensin receptor subtype AT(1) mediates alveolar epithelial cell apoptosis in response to ANG Ⅱ[J].Am J Physiol Lung Cell Mol Physiol,2002,282(4):L713-L718.
[46]Lukkarinen HP,Laine J,Aho H,et al.Angiotensin Ⅱ receptor inhibtion prevents pneumocyte apoptosis in surfactant-depleted rat lungs[J].Pediatr Pulmonol,2005, 39(4):349-358.
[47]Wang R,Alam G,Zagariya A.Apoptosis of lung epithelial cells in response to TNF-alpha requires angiotensin Ⅱ generation de novo[J].J Cell Physiol,2000, 185(2):253-259.
[48]Le Cras TD,Spitzmiller RE,Albertine KH,et al.VEGF causes pulmonary hemorrhage,hemosiderosis,and air space enlargement in neonatal mice[J].Am J Physiol Lung Cell Mol Physiol,2004,287(1):L134-L142.
[49]李春晖,谭茗月,张新超.激活过氧化物酶增殖物激活受体对血管紧张素II诱导内皮细胞中单核细胞趋化因子-1表达的影响[J].中华老年医学杂志,2006,25(9)：664-667.
[50]Inoshima I,Kuwano K,Hamada N,et al.Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary fibrosis in mice[J].Am J Physiol Lung Cell Mol Physiol,2004,286(5):L1038-L1044.
[51]方向群,朱元珏,胡晓玲,等.氯沙坦对大鼠肺纤维化模型的干预作用及对MCP-1和bFGF表达的影响[J].中华结核和呼吸杂志,2002,25(5)：268-272.
[52]何平平,李杰平,张书杰,等.阻断肾素-血管紧张素-醛固酮系统对大鼠肺维化的干预作用及对MCP-1表达的影响[J].南华大学学报·医学版,2007,35(2)： 186-191.
[53]Streiter RM.Inflammatory mechanisms are not a minor component of the pathogenesis of idiopathic pulmonary fibrosis[J].Am J Respir Crit Care Med,2002,165(4):1206-1208.
[54]Xu Y,Hua J,Mui A,et al.Release of biologically active TGF-beta1 by alveolar epithelial cells results in pulmonary fibrosis[J].Am J Physiol Lung Cell Mol Physiol,2003,285(3):L527-L539.
[55]Nguyen L,Wald WF, Ts'ao CH,et al.Captopril inhibits proliferation of human lung fibroblasts in culture:a potential antifiborotic mechanism[J].Proc Soc Exp Biol Med,1994,205(1):80-84.
[56]Slight SH,Joseph J,Fanjam VK,et al.Extra-adrenal mineralocorticoids and cardiovascular tissule[J]J Mol Cell Cardiol,1999,31(6):1175-1184.
[57]Winter DC,Schneider MF,Osullivan GC,et al.Rapid effects of aldosterone on sodium hydrogen exchange in isolated colonic crypts[J].J Member Biol,1999,170 (1):17-26.
[58]赵力,赵鸣武,方秋红,等.螺内酯减轻博莱霉素A5引起的大鼠肺纤维化[J].中华结核和呼吸杂志,1998,21(5)：300-302.
[59]赵力,赵呜武,方秋红,等.醛固酮促进大鼠肺组织胶原的合成[J].基础医学与临床,2001,21(5)：460-464.
[60]Brown NJ,Nakamura S,Ma LJ,et al.Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo[J].Kidney Int,2000,58(3): 1219-1227.
[61]Fiebelar A,Schmidt F,Muller DN,et al.Mineralocorticoid receptor affects AP-1 and nuclear factor-kappaB activation in angiotensin Ⅱ-induced cardiac injury[J].Hypertension,2001,37(2 Pt 2):787-793.