TGF-β1、bFGF和PDGF在奶牛乳腺纤维化中作用的研究
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摘要
奶牛乳腺纤维化主要是由乳腺炎引起的一种常见的病理过程,而乳腺炎是奶牛的主要疾病之一,其发病率和感染率在国内外均较高,可引起奶牛乳腺不同程度的纤维化过程。纤维化的乳腺泌乳量降低,严重时可发展为乳腺硬化导致奶牛淘汰,给奶牛业造成严重的损失。
组织器官的纤维化过程主要取决于细胞外基质(ECM)的沉积、分解和相关细胞凋亡等方面,并与转化生长因子β(TGF-β)、碱性成纤维细胞生长因子(bFGF)和血小板源性生长因子(PDGF)等多种细胞因子密切相关。目前关于肝脏和肾脏等组织纤维化的研究较多,而有关乳腺纤维化的研究较少,在乳腺纤维化过程中除间质成纤维细胞产生ECM外,乳腺上皮细胞是否能转分化为肌成纤维细胞(MFB)而产生ECM仍不明确。α-平滑肌肌动蛋白(α-SMA),结缔组织生长因子(CTGF)和胶原I(COL I)是判断组织纤维化程度的主要指标,因此可通过检测此三项指标表达量的变化,以确定细胞因子在纤维化过程中的作用。
为在体外培养纯化出稳定生长的奶牛乳腺上皮细胞和成纤维细胞,通过外科手术的方法采取妊娠后期或泌乳期的荷斯坦奶牛乳腺组织,分离乳腺腺泡,用组织块培养法体外培养奶牛乳腺细胞,应用差时胰酶消化法和差速贴壁法将奶牛乳腺上皮细胞和成纤维细胞两种细胞分别纯化出来,并用免疫组化的方法对细胞的纯度进行鉴定。将不同浓度的TGF-β1(0,1,5,10ng/ml)、bFGF(0,5,10,20ng/ml)和PDGF-BB(0,5,10,20ng/ml)三种外源性细胞因子分别作用于体外培养的奶牛乳腺上皮细胞和成纤维细胞,于不同的时间点(12h,24h,48h,72h)提取细胞的总RNA和总蛋白,以β-actin作为内参基因,用Real-Time RT-PCR方法测定两种细胞中α-SMA. CTGF和COL I α1mRNA相对表达量的变化,其PCR产物进行测序分析；并用Western blot方法测定相应蛋白的表达。
研究结果表明：纯化的奶牛乳腺上皮细胞多为多角形,细胞核圆形或椭圆形,核仁清晰可见,多成鹅卵石样或铺路石样生长,并可分泌乳滴,角蛋白-18反应阳性,波形蛋白反应阴性；纯化的奶牛乳腺成纤维细胞多为长梭形,成旋涡状或放射状生长,角蛋白-18反应阴性,波形蛋白反应阳性。经纯化后两种细胞的纯度均可达95%以上,可满足后续试验的要求;外源性TGF-β1能够有效上调体外培养的奶牛乳腺上皮细胞和成纤维细胞中α-SMA、 CTGF和COL I α1mRNA及α-SMA蛋白的表达,并成一定的量效关系;外源性bFGF对体外培养奶牛乳腺上皮细胞和成纤维细胞CTGF mRNA的表达起促进作用,对成纤维细胞COL I α1mRNA的表达主要起促进作用,对奶牛乳腺上皮细胞COL I α1mRNA表达的作用不明显,高浓度的bFGF对奶牛乳腺上皮细胞和成纤维细胞a-SMA mRNA的表达均有抑制趋势,与a-SMA蛋白表达的结果不是很一致。外源性PDGF-BB对奶牛乳腺上皮细胞和成纤维细胞CTGF和COL I al mRNA的表达主要起促进作用；对奶牛乳腺成纤维细胞a-SMA蛋白的表达起促进作用,较低浓度时对奶牛乳腺成纤维细胞a-SMA mRNA的表达起促进作用；而高浓度时对奶牛乳腺上皮细胞a-SMA mRNA的表达有抑制趋势,与a-SMA蛋白表达的结果不是很一致。经测序分析,奶牛乳腺上皮细胞和成纤维细胞中目的基因CTGF、α-SMA和COL I α1的扩增产物序列一致,且通过比对分析得出其扩增产物均为牛的CTGF, a-SMA和COL I α1。
研究证实：组织块培养法结合应用差时胰酶消化法和差速贴壁法能够在体外培养并纯化出稳定生长的奶牛乳腺上皮细胞和成纤维细胞两种细胞。外源性TGF-β1对奶牛乳腺上皮细胞和成纤维细胞α-SMA、CTGF和COL I α1的mRNA及α-SMA蛋白的表达均具有促进作用,表明TGF-β1能够促进奶牛乳腺上皮细胞转分化和细胞外基质的产生。外源性bFGF对奶牛乳腺上皮细胞和成纤维细胞CTGF mRNA的表达起促进作用；对成纤维细胞COL I α1mRNA的表达主要起促进作用,对奶牛乳腺上皮细胞COL I α1mRNA表达的作用不明显；高浓度的bFGF对奶牛乳腺上皮细胞和成纤维细胞α-SMA mRNA的表达均有抑制趋势。外源性PDGF-BB对奶牛乳腺上皮细胞和成纤维细胞CTGF和COL I α1mRNA的表达主要起促进作用;对奶牛乳腺成纤维细胞α-SMA蛋白的表达起促进作用,较低浓度时对奶牛乳腺成纤维细胞表达α-SMA mRNA的表达起促进作用,高浓度时对奶牛乳腺上皮细胞α-SMA mRNA的表达有抑制趋势。因此,三种细胞因子对奶牛乳腺上皮细胞和成纤维细胞中转分化指标的表达均具有一定的作用,为进一步研究奶牛乳腺纤维化的机制和治疗奠定了基础。
Bovine mammary fibrosis were a common pathological process mainly caused by mastitis. As a major diseases of dairy cow, the incidence and infection rates of bovine mastitis were higher both at home and abroad, could leading to various degree of mammary fibrosis. During the process of mammary gland fibrosis, the milk yield were decreased, in seriously may resulting in the breast hardening, then lossing the ability of lactating milk, lead to serious losses of dairy industry.
The tissues and organs fibrosis were mainly depends on the deposition, decomposition of the extracellular matrix (ECM) and apoptosis of the related cells, which were closely related to cytokines such as transforming growth factor-P (TGF-β), basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). Currently, the research were mainly focus on the liver and kidney fibrosis, while rarely about the mammary fibrosis. In addition to the stromal fibroblasts producing ECM in fibrosis, whether the mammary epithelial cells could or not transdifferetiation into myofibroblasts then produce ECM remains unclear. It is reported that the a-smooth muscle actin (a-SMA), connective tissue growth factor (CTGF) and Collagen I (COL I) were the three main indicators during the epithelial-mesenchymal transition (EMT). Therefore, detected the changes of the three indicators could determine the role of the cytokines in the process of fibrosis.
To obtain stability purified bovine mammary epithelial cells and fibroblasts in vitro, the mammary tissue sample were collected from Holstein cows during late gestation or lactation by surgery. After isolated the mammary alveoli, the mammary cells were cultured by tissue explants method in vitro. Then bovine mammary epithelial cells and fibroblasts were purified and cultured separately by different time of trypsin-EDTA digestion and adherent method, and the purity of the cells were identified by immunocytochemistry method. To explore the effect of the_three_cytokine_of TGF-β1, bFGF and PDGF on the bovine mammary epithelial cells and fibroblasts, the two kind of cells were incubated with various concentrations of exogenous TGF-β1(0,1,5,10ng/ml), bFGF(0,5,10,20ng/ml) and PDGF-BB(0,5,10,20ng/ml) separately,12h,24h,48h,72h later, the total RNA and protein were extracted from the cells, then the changes of the mRNA relative expression of the three transdifferentiation indicators (CTGF, α-SMA and COLIα1) were determined by Real-Time quantitative RT-PCR with P-actin as an internal reference gene, the PCR product were analysis by sequencing., and the corresponding protein were determined by Western blot method.
The results showed that purified bovine mammary epithelial cells were mainly in polygonal, with round or oval nucleus, the nucleolus were visible and clear, which mainly in cobblestone or paving stone-like growth, and also could secret milk drop, with cytokeratin-18reaction positive, vimentin negative, while purified bovine mammary fibroblasts were mainly in spindle, in spiral or radial-shaped growth, with cytokeratin-18reaction negative, vimentin positive. After purification, the purity of both cells could exceed ninety-five percent, which could meet the requirement of following experiments. Exogenous TGF-β1could effetive increase the expression of a-SMA, CTGF, COLlα1mRNA and a-SMA protein both in the bovine mammary epithelial cells and fibroblasts, in a certain dose-effect way. Exogenous bFGF could increase the expression of CTGF mRNA both in the bovine mammary epithelial cells and fibroblasts, and mainly increase the expression of COL I al mRNA in the bovine mammary fibroblasts, while have no effect on the expression of COL I al mRNA in the bovine mammary epithelial cells, higher concentrations of bFGF have a inhibited tendency on the expression of a-SMA mRNA both in the bovine mammary epithelial cells and fibroblasts, which were inconsistent with the result of the protein expression. PDGF-BB mainly play a positive role on the expression of CTGF and COL I al both in the bovine mammary epithelial cells and fibroblasts, and could promote the expression of a-SMA protein in the bovine mammary fibroblasts, the expression of a-SMA mRNA were increased with lower concentration of PDGF-BB in the bovine mammary fibroblasts, while have a inhibited tendency with higher concentration of PDGF-BB on the expression of a-SMA mRNA in the bovine mammary epithelial cells, which were inconsistent with the results of the protein expression. The aim gene product of CTGF, a-SMA and COL I al amplified from the bovine mammary epithelial cells and fibroblasts were confirmed to be CTGF, a-SMA and COL I al gene from bovine by sequencing.
The study confirmed that the two stably growth cell lines of bovine mammary epithelial cells and fibroblasts could be cultured and purified in vitro by the block tissue explants method combined with the different time of trypsin-EDTA digestion and the adherent method. TGF-β1could promote the expression of a-SMA, CTGF mRNA and COLlal mRNA and a-SMA protein both in the bovine mammary epithelial cells and fibroblasts, indicated that TGF-β1could promote transdifferentiation of the bovine mammary epithelial cell and generation of the ECM. Exogenous bFGF could increase the expression of CTGF mRNA both in the bovine mammary epithelial cells and fibroblasts, and mainly promote the expression of COL I α1mRNA in the bovine mammary fibroblasts, while have no effect on the bovine mammary epithelial cells, higher concentrations of bFGF have an inhibited tendency on the expression of a-SMA mRNA both in the bovine mammary epithelial cells and fibroblasts. Exogenous PDGF-BB mainly promote the expression of CTGF and COL I al mRNA both in the bovine mammary epithelial cells and fibroblasts, and promote the expression of a-SMA protein in the bovine mammary fibroblasts, the expression of a-SMA mRNA were increased with lower concentration of PDGF-BB in the bovine mammary fibroblasts, while were inhibited with higher concentration of PDGF-BB in the bovine mammary epithelial cells. Thus all the three cytokines have some certain effect on the expression of the transdifferentiation indicators both in the bovine mammary epithelial cells and fibroblasts, laid a foundation for the further study of the mechanisms and the treatment of bovine mammary fibrosis.
组织器官的纤维化过程主要取决于细胞外基质(ECM)的沉积、分解和相关细胞凋亡等方面,并与转化生长因子β(TGF-β)、碱性成纤维细胞生长因子(bFGF)和血小板源性生长因子(PDGF)等多种细胞因子密切相关。目前关于肝脏和肾脏等组织纤维化的研究较多,而有关乳腺纤维化的研究较少,在乳腺纤维化过程中除间质成纤维细胞产生ECM外,乳腺上皮细胞是否能转分化为肌成纤维细胞(MFB)而产生ECM仍不明确。α-平滑肌肌动蛋白(α-SMA),结缔组织生长因子(CTGF)和胶原I(COL I)是判断组织纤维化程度的主要指标,因此可通过检测此三项指标表达量的变化,以确定细胞因子在纤维化过程中的作用。
为在体外培养纯化出稳定生长的奶牛乳腺上皮细胞和成纤维细胞,通过外科手术的方法采取妊娠后期或泌乳期的荷斯坦奶牛乳腺组织,分离乳腺腺泡,用组织块培养法体外培养奶牛乳腺细胞,应用差时胰酶消化法和差速贴壁法将奶牛乳腺上皮细胞和成纤维细胞两种细胞分别纯化出来,并用免疫组化的方法对细胞的纯度进行鉴定。将不同浓度的TGF-β1(0,1,5,10ng/ml)、bFGF(0,5,10,20ng/ml)和PDGF-BB(0,5,10,20ng/ml)三种外源性细胞因子分别作用于体外培养的奶牛乳腺上皮细胞和成纤维细胞,于不同的时间点(12h,24h,48h,72h)提取细胞的总RNA和总蛋白,以β-actin作为内参基因,用Real-Time RT-PCR方法测定两种细胞中α-SMA. CTGF和COL I α1mRNA相对表达量的变化,其PCR产物进行测序分析；并用Western blot方法测定相应蛋白的表达。
研究结果表明：纯化的奶牛乳腺上皮细胞多为多角形,细胞核圆形或椭圆形,核仁清晰可见,多成鹅卵石样或铺路石样生长,并可分泌乳滴,角蛋白-18反应阳性,波形蛋白反应阴性；纯化的奶牛乳腺成纤维细胞多为长梭形,成旋涡状或放射状生长,角蛋白-18反应阴性,波形蛋白反应阳性。经纯化后两种细胞的纯度均可达95%以上,可满足后续试验的要求;外源性TGF-β1能够有效上调体外培养的奶牛乳腺上皮细胞和成纤维细胞中α-SMA、 CTGF和COL I α1mRNA及α-SMA蛋白的表达,并成一定的量效关系;外源性bFGF对体外培养奶牛乳腺上皮细胞和成纤维细胞CTGF mRNA的表达起促进作用,对成纤维细胞COL I α1mRNA的表达主要起促进作用,对奶牛乳腺上皮细胞COL I α1mRNA表达的作用不明显,高浓度的bFGF对奶牛乳腺上皮细胞和成纤维细胞a-SMA mRNA的表达均有抑制趋势,与a-SMA蛋白表达的结果不是很一致。外源性PDGF-BB对奶牛乳腺上皮细胞和成纤维细胞CTGF和COL I al mRNA的表达主要起促进作用；对奶牛乳腺成纤维细胞a-SMA蛋白的表达起促进作用,较低浓度时对奶牛乳腺成纤维细胞a-SMA mRNA的表达起促进作用；而高浓度时对奶牛乳腺上皮细胞a-SMA mRNA的表达有抑制趋势,与a-SMA蛋白表达的结果不是很一致。经测序分析,奶牛乳腺上皮细胞和成纤维细胞中目的基因CTGF、α-SMA和COL I α1的扩增产物序列一致,且通过比对分析得出其扩增产物均为牛的CTGF, a-SMA和COL I α1。
研究证实：组织块培养法结合应用差时胰酶消化法和差速贴壁法能够在体外培养并纯化出稳定生长的奶牛乳腺上皮细胞和成纤维细胞两种细胞。外源性TGF-β1对奶牛乳腺上皮细胞和成纤维细胞α-SMA、CTGF和COL I α1的mRNA及α-SMA蛋白的表达均具有促进作用,表明TGF-β1能够促进奶牛乳腺上皮细胞转分化和细胞外基质的产生。外源性bFGF对奶牛乳腺上皮细胞和成纤维细胞CTGF mRNA的表达起促进作用；对成纤维细胞COL I α1mRNA的表达主要起促进作用,对奶牛乳腺上皮细胞COL I α1mRNA表达的作用不明显；高浓度的bFGF对奶牛乳腺上皮细胞和成纤维细胞α-SMA mRNA的表达均有抑制趋势。外源性PDGF-BB对奶牛乳腺上皮细胞和成纤维细胞CTGF和COL I α1mRNA的表达主要起促进作用;对奶牛乳腺成纤维细胞α-SMA蛋白的表达起促进作用,较低浓度时对奶牛乳腺成纤维细胞表达α-SMA mRNA的表达起促进作用,高浓度时对奶牛乳腺上皮细胞α-SMA mRNA的表达有抑制趋势。因此,三种细胞因子对奶牛乳腺上皮细胞和成纤维细胞中转分化指标的表达均具有一定的作用,为进一步研究奶牛乳腺纤维化的机制和治疗奠定了基础。
Bovine mammary fibrosis were a common pathological process mainly caused by mastitis. As a major diseases of dairy cow, the incidence and infection rates of bovine mastitis were higher both at home and abroad, could leading to various degree of mammary fibrosis. During the process of mammary gland fibrosis, the milk yield were decreased, in seriously may resulting in the breast hardening, then lossing the ability of lactating milk, lead to serious losses of dairy industry.
The tissues and organs fibrosis were mainly depends on the deposition, decomposition of the extracellular matrix (ECM) and apoptosis of the related cells, which were closely related to cytokines such as transforming growth factor-P (TGF-β), basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). Currently, the research were mainly focus on the liver and kidney fibrosis, while rarely about the mammary fibrosis. In addition to the stromal fibroblasts producing ECM in fibrosis, whether the mammary epithelial cells could or not transdifferetiation into myofibroblasts then produce ECM remains unclear. It is reported that the a-smooth muscle actin (a-SMA), connective tissue growth factor (CTGF) and Collagen I (COL I) were the three main indicators during the epithelial-mesenchymal transition (EMT). Therefore, detected the changes of the three indicators could determine the role of the cytokines in the process of fibrosis.
To obtain stability purified bovine mammary epithelial cells and fibroblasts in vitro, the mammary tissue sample were collected from Holstein cows during late gestation or lactation by surgery. After isolated the mammary alveoli, the mammary cells were cultured by tissue explants method in vitro. Then bovine mammary epithelial cells and fibroblasts were purified and cultured separately by different time of trypsin-EDTA digestion and adherent method, and the purity of the cells were identified by immunocytochemistry method. To explore the effect of the_three_cytokine_of TGF-β1, bFGF and PDGF on the bovine mammary epithelial cells and fibroblasts, the two kind of cells were incubated with various concentrations of exogenous TGF-β1(0,1,5,10ng/ml), bFGF(0,5,10,20ng/ml) and PDGF-BB(0,5,10,20ng/ml) separately,12h,24h,48h,72h later, the total RNA and protein were extracted from the cells, then the changes of the mRNA relative expression of the three transdifferentiation indicators (CTGF, α-SMA and COLIα1) were determined by Real-Time quantitative RT-PCR with P-actin as an internal reference gene, the PCR product were analysis by sequencing., and the corresponding protein were determined by Western blot method.
The results showed that purified bovine mammary epithelial cells were mainly in polygonal, with round or oval nucleus, the nucleolus were visible and clear, which mainly in cobblestone or paving stone-like growth, and also could secret milk drop, with cytokeratin-18reaction positive, vimentin negative, while purified bovine mammary fibroblasts were mainly in spindle, in spiral or radial-shaped growth, with cytokeratin-18reaction negative, vimentin positive. After purification, the purity of both cells could exceed ninety-five percent, which could meet the requirement of following experiments. Exogenous TGF-β1could effetive increase the expression of a-SMA, CTGF, COLlα1mRNA and a-SMA protein both in the bovine mammary epithelial cells and fibroblasts, in a certain dose-effect way. Exogenous bFGF could increase the expression of CTGF mRNA both in the bovine mammary epithelial cells and fibroblasts, and mainly increase the expression of COL I al mRNA in the bovine mammary fibroblasts, while have no effect on the expression of COL I al mRNA in the bovine mammary epithelial cells, higher concentrations of bFGF have a inhibited tendency on the expression of a-SMA mRNA both in the bovine mammary epithelial cells and fibroblasts, which were inconsistent with the result of the protein expression. PDGF-BB mainly play a positive role on the expression of CTGF and COL I al both in the bovine mammary epithelial cells and fibroblasts, and could promote the expression of a-SMA protein in the bovine mammary fibroblasts, the expression of a-SMA mRNA were increased with lower concentration of PDGF-BB in the bovine mammary fibroblasts, while have a inhibited tendency with higher concentration of PDGF-BB on the expression of a-SMA mRNA in the bovine mammary epithelial cells, which were inconsistent with the results of the protein expression. The aim gene product of CTGF, a-SMA and COL I al amplified from the bovine mammary epithelial cells and fibroblasts were confirmed to be CTGF, a-SMA and COL I al gene from bovine by sequencing.
The study confirmed that the two stably growth cell lines of bovine mammary epithelial cells and fibroblasts could be cultured and purified in vitro by the block tissue explants method combined with the different time of trypsin-EDTA digestion and the adherent method. TGF-β1could promote the expression of a-SMA, CTGF mRNA and COLlal mRNA and a-SMA protein both in the bovine mammary epithelial cells and fibroblasts, indicated that TGF-β1could promote transdifferentiation of the bovine mammary epithelial cell and generation of the ECM. Exogenous bFGF could increase the expression of CTGF mRNA both in the bovine mammary epithelial cells and fibroblasts, and mainly promote the expression of COL I α1mRNA in the bovine mammary fibroblasts, while have no effect on the bovine mammary epithelial cells, higher concentrations of bFGF have an inhibited tendency on the expression of a-SMA mRNA both in the bovine mammary epithelial cells and fibroblasts. Exogenous PDGF-BB mainly promote the expression of CTGF and COL I al mRNA both in the bovine mammary epithelial cells and fibroblasts, and promote the expression of a-SMA protein in the bovine mammary fibroblasts, the expression of a-SMA mRNA were increased with lower concentration of PDGF-BB in the bovine mammary fibroblasts, while were inhibited with higher concentration of PDGF-BB in the bovine mammary epithelial cells. Thus all the three cytokines have some certain effect on the expression of the transdifferentiation indicators both in the bovine mammary epithelial cells and fibroblasts, laid a foundation for the further study of the mechanisms and the treatment of bovine mammary fibrosis.
引文
1 齐长明.奶牛疾病学(上、下)[M].北京：中国农业科学技术出版社,2006：438-443
2倪洪权,孙胜利,殷宪达.奶牛乳房炎的辩证论治[J].吉林畜牧兽医,2007,(1)：54-55
3韩炎森.奶山羊乳房炎病原菌调查及其细胞因子的变化检测[D].西北农林科技大学,2011
4 Zeisberg EM, Potenta SE, Sugimoto H, et al. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition[J]. J Am Soc Nephrol,2008,19(12): 2282-2287
5 Zeisberg M, Yang C, Martino M, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition[J]. J Biol Chem,2007,282(32): 23337-23347
6 Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis:the myofibroblast in focus[J]. Chest,2007,132(4):1311-1321
7王华,魏伟.肝纤维化与细胞因子的关系[J].中国药理学通报,2002,18(2)：132-136
8 王颖航,潘志,南红梅等.肾纤维化的分子病理机制探讨[J].中国中西医结合肾病杂志,2006,7(1)：34-37
9 韦小瑜,何云,程明亮.细胞因子与肺纤维化[J].中国西南军医杂志,2006,8(2)：54-57
1 0孙蕴伟,袁耀宗.细胞因子与胰腺星状细胞在慢性胰腺炎胰腺纤维化中的作用[J].国外医学.消化系疾病分册,2001,21(4)：239-242
11 陈博,曹阳,笪邦红等TGF-β2对体外培养牛晶状体上皮细胞CTGF蛋白及mRNA表达的影响[J].国际眼科杂志,2008,8(4)：701-704
12 Parapuram SK, Chang B, Li L, et al. Differential effects of TGFbeta and vitreous on the transformation of retinal pigment epithelial cells [J]. Invest Ophthalmol Vis Sci,2009,50(12):5965-5974
13 Eickelberg 0, Kohler E, Reichenberger F, et al. Extracellular matrixdeposition by primary human lung fibroblasts in response to TGF-β3 and TGF-β3 [J]. AmJ Physiol, 1999,276(5 Pt 1):L814-824
14 Flisiak R, Maxwell P. Plasma tissue inhibitor of metalloproteinase-1 and transforming growth factor beta-1-possible noninvasive biomakers of hepatic fibrosis in patients with chronic B and C hepatitis[J]. Hepato gastroenterology, 2002,49(47):1369-1372
15 Zhang BB, Cai WM, Weng HL, et al. Diagnostic value of platelet derived growth factor-BB, transforming growth factor-betal, matrix metalloproteinase-1, and tissue inhibitor of matrix metalloproteinase-1 in serum and peripheral blood mononuclear cells for hepatic fibrosis[J]. World J Gastroenterol,2003,9(11): 2490-2496
16 陈建晖,高学军,李庆章.奶牛乳腺上皮细胞体外培养技术研究进展[J].东北农业大学学报,2009,40(7)：132-135
17 Wheeler TT, Callaghan MR, Davis SR, et al. Milk protein synthesis, gene expression, and hormonal responsiveness in primary cultures of mammary cells from lactating sheep [J]. Exp Cell Res,1995,217(2):346-354
18徐曼妮,厉曙光,赵建阳等.乳腺生物反应器表达载体的检测方法[J].生物技术通报,2003(5)：23-26
19 宋亚男,陈志伟,刘东武.牛乳腺上皮细胞体外培养体系研究进展[J].生命科学仪器,2008,6(9)：3-8
20 张骞,顾小卫.乳腺上皮细胞的研究及应用[J].中国牧业通讯,2008,(21)：9-11
21 马仲华.家畜解剖学与组织胚胎学(第三版)[M].北京：中国农业出版社,2002：69-246
22 陈杰.家畜生理学(第四版)[M].北京：中国农业出版社,2003：425-441
23 Flanders KC, Wakefield LM. Transforming growth factor-βs and mammary gland involution; functional roles and implications for cancer progression [J]. J Mammary Gland Biol Neoplasia,2009, (14):131-144
24 LASFARGUES EY. Cultivation and behavior in vitro of the normal mammary epithelium of the adult mouse[J]. Anat Rec,1957,127(1):117-129
25 Medina D, Oborn CJ. Growth of preneoplastic mammary epithelial cells in serum-free medium[J]. Cancer Res,1980,40(11):3982-3987
26 Danielson KG, Oborn CJ, Durban EM, et al. Epithelial mouse mammary cell line exhibiting normal morphogenesis in vivo and functional differentiation in vitro [J]. Proc Natl Acad Sci U S A,1984,81(12):3756-3760.
27 Haslam SZ, Counterman LJ. Mammary stroma modulates hormonal responsiveness of mammary epithelium in vitro in the mouse[J]. Endocrinology,1991,129:2017-2023
28 于婷,陈志伟,刘东武.牛乳腺上皮细胞体外培养研究进展[J].生命科学仪器,2009,7(3)： 10-15
29 李震,王英,刘惠莉等.牛乳腺上皮细胞的分离培养[J].上海农业学报,2000,16(3)：25-28
30 彭新荣,郑月茂,张涌.体外培养的牛乳腺上皮细胞形态学研究[J].西北农林科技大学学报(自然科学版),2005,33(1)：13-17
31 崔立莉.奶牛乳腺上皮细胞体外培养体系的建立及其应用[D].乌鲁木齐：新疆农业大学,2006：13-33
32 丁月云,张莉莉,陈莎莎等.组织块种植法体外培养奶牛乳腺上皮细胞[J].南京农业大学学报,2008,31(4)：91-96
33吴娟,王凤龙,王申元.奶牛乳腺上皮细胞的原代培养[J].安徽农业科学,2009,37(6)：2497-2499,2513
34 王亨,吴培福,邱昌伟等.荷斯坦奶牛乳腺上皮细胞的体外培养[J].畜牧与兽医,2007,39(4)：41-43
35 王治国,王传蓉,王加启.不同方法分离奶牛乳腺上皮细胞体外培养的研究[J].乳业科学与技术,2009,(1)：35-38
36 林桂娟,王恬,陈才勇.机械破碎法分离奶牛乳腺上皮细胞的体外培养研究[J].畜牧与兽医,2004,36(7)：4-7
37 Boutinaud M, Ben Chedly MH, Delamaire E, et al. Milking and feed restriction regulate transcripts of mammary epithelial cells purified from milk[J]. J Dairy Sci,2008,91(3):988-998
38 Schmid B, Schiller DL, Grund C. Tissue type-specific expression of intermediate filament protein in a cultured epithelial cell line from bovine mammary gland[J]. Cell Biol,1983,96(1):37-50
39 Gibson CA, Vega JR, Baumrucker CR, et al. Establishment and characterization of bovine manunary epithelial cell lines[J]. In Vitro Cell Dev Biol,1991,27A(7): 2585-2594
40 Huynh, Robitaille G, Turner J. Establishment of bovine mammary epithelial cell line (MAC-T) An in vitro model for bovine lactation[J]. Exp Cell Res,1991,197:191-199
41 Zavizion B, van Duffelen M, Schaeffer W, et al. Establishment and charaeterization of a bovine mammary epithelial cell line with unique properties [J]. In Vitro Cell Dev Biol Anim,1996,32(3):138-148
42 Guzzman RC, Osborn RC, Richards JE, et al. Effects of phorbol esters on normal and tumorous mouse mammary epithelial cells epithelial in collagen gels[J]. J.Natl Cancer Inst,1983,71:69-72
43 Vernon RB, Angello JC, Iruela-Aeispe ML, et al. Re organization of basement membrane matrices by cellular traetion promotes the formation of cellular networks in vitro[J]. Lab. Invest,1992,66:536-547
44 Tania Geman, Itamar Barash. Characterization of an epithelial cell line from bovine mammary gland[J]. In Vitro Cell Dev Biol,2002,38:282-292
45 Kong DS, Zheng SZ, Lu Y, Wang AY. Research progress on myof ibroblasts: their sources and roles in liver fibrogensis[J]. Chin PharmaCOL Bull,2011,27(3):297-300
46 Timpl R. Macromolecular organization of basement membranes [J]. Curr opin Cell bio, 1996,8:618
47 Safadi R, Friedman ST. Hepatic fibrosis-role of hepatic stellate cell activation[J]. Med GenMed,2002,4:27
48 Takanori Tsuji, Soichiro Ibaragi, Guo-fu Hu. Epithelial-Mesenchymal Transition and Cell Cooperativity in Metastasis[J]. Cancer Res,2009,69(18):7135-7139
49 Kalluri R, Neilson EC. Epithelia-mesenchymal transition and its implications for fibrosis[J]. J Clin Invest,2003,112(12):1776-1784
50 KalluriR, Weinberg RA. The basics of epithelial-mesenchymal transit ion[J]. J Clin Invest,2009,119(6):1420
51 Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transit ions [J]. J Clin Invest,2009,119 (6):1429
52 Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells [J]. J Clin Invest,2009,119(6):1417
53 Ayano Kabashima, Hajime Higuchi, Hiromasa Takaishi, et al. Side population of pancreatic cancer cells predominates in TGF-β-mediated epithelial to mesenchymal transition and invasion[J]. Int. J. Cancer,2009,124(12):2771-2779
54 Petersen OW. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma[J]. Am J Pathol,2003,162:391-402
55赵欣,王允山,吉爱国.基质金属蛋白酶在乳腺癌上皮间质转化中的作用[J].生命的化学,2011,31(5)：702-706
56 Henderson NC, Forbes SJ. Hepatic fibrogenesis:From within and outwith[J]. Toxocology,2008,254:130-135
57 贾继东,李海.肝脏纤维化基础与临床研究进展[J].中华肝脏病杂志,2009,17(1)：5-6
58 Abou-Shady M, Friess H, Zimmerhamm A, et al. Connectivetissue growth factor inhuman liver cirrhosis[J]. Liver,2000,20(2):296-304
59 王亚利,赵玉庸,陈志强,等.肾络通对大鼠系膜细胞外基质分泌及转化生长因子β1表达的影响[J].中国中药杂志,2005,30(3)：201-203
60 Verrecchia F, Mauviel A. Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expressionand regulation[J]. J Invest Dermatol,2002,118(2):211-215
61 Shek FW, Benyon RC. How can transforming growth factor beta be targeted usefully to combat liver fibrosis[J]. Eur J GastroenterolHepato,2004,16(2):123-126
62 陈晓红,何有成,姚集鲁.细胞因子对肝纤维化形成的影响[J].国外医学内科学分册,2001,28(1)：21-24
63 王彩生,赵志清.肝纤维化发病机制研究进展[J].内蒙古医学杂志,2010,42(3)：331-334
64张愚,屈文东,黄华等.bFGF及TGF-β1在实验性肝硬化中的免疫组化研究[J].胃肠病学和肝病学杂志,2005,14(1)：40-44
65 Eddy A A. Molecular basis renal fibrosis[J]. Pediatr Nephrol,2000,15(34):290-301
66 Yang JW, Liu YH. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis[J]. American Journal of Pathology,2001,159(4):1465-1475
67 Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation[J]. KidneyInt,2002,61(5):1714-1728
68 Fan JM, Huang XR, Ng YY, et al. Interleukin-1 induces tubular epithelial-myo-fibroblast transdifferentiation through a transforming growth factor-betal-dependent mechanism in vitro1[J].Am J Kidney Dis,2001,37(4):820-831
69 Cheng S, Lovett DH. Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation[J]. Am J Pathol,2003,162(6): 1937-1949
70 PardaliK, MoustakasA. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer[J]. Biochmi Biophys Acta,2007,1775(1):21-62
71 Lee YH, Albig AR, Regner M, et al. Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism[J]. Carcinogenesis,2008,29(12):2243-2251
72 Miettinen PJ, Ebner R, Lopez AR, et al. TGF-β induced transdifferentiation of mammary epithelial cells to mesenchymal cells:involvement of type I receptors[J]. J Cell Biol,1994,127(6 Pt 2):2021-2036
73 Taylor MA, Parvani JG, Schiemann WP. The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-beta in normal and malignant mammary epithelial cells [J]. J Mammary Gland Biol Neoplasia,2010,15(2):169-190
74 Kim K K, Kugler M C, Wolters P J, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix[J]. Proc Natl Acad Sci USA,2006,103(35):13180-13185
75 Willis B C, Liebler J M, Luby-Phelps K, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-betal: potential role in idiopathic pulmonary fibrosis[J]. Am J Pathol,2005,166(5): 1321-1332
76章晓联.医学免疫学[M].武昌：武汉大学出版社,2008：61-81
77 Barnard, JA, Bascom. CC. Lyons, RM, et al. Transforming growth factor β in the control of epidermal prol iferation [J]. Am. J. Med. Sci.,1988,296:159-163
78 芮炜玮,易祥华.转化生长因子β1及相关细胞因子在肺纤维化发生中的作用[J].同济大学学报(医学版),2010,31(3)：133-136
79 Feng XH, Derynck R. Specificity and versatility in TGF-beta signaling through Smads[J]. Annu Rev Cell Dev Biol,2005,21:659-693
80 Massague J, Gomis RR. The logic of TGFbeta signaling[J]. FEBS Lett,2006,580: 2811-2820
81 Roberts AB, Sporn MB. The transforming growth factor-betas[J]. In: Roberts AB, Sporn MB, editors. Handbook of experimental pharmacology. New York:Springer-Verlag,1990,95:419-472
82 Derynck R, Jarrett J A, Chen E Y, et al. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells [J]. Nature,1985,316 (6030):701-705
83 Purchio A F, Cooper J A, Brunner A M, et al. Identif ication of mannose 6-phosphate in two asparagine-linked sugar chains of recombinant transforming growth factor-beta 1 precursor [J]. J Biol Chem,1988,263(28):14211-14215
84 王燕艳.转化生长因子-p与肝纤维化[J].实用医技杂志,2010,17(5)：436-437
85 Inuzuka S, Ueno T, Torimura Tet al.The significance of colocalization of plasminogen activator inhibitor-1 and vitronectin in hepatic fibrosis[J]. Scand J Gastroenterol,1997,32(10):1052-1060
86 Cheng J, Grande J P. Transforming growth factor-β signal transduction and progressive renal disease[J]. Experimental Biology Medicine,2002,227(11): 943-956.
87 Derynck R, Gelbart W M, Harland R M, et al. Nomenclature:vertebrate mediators of TGFbeta family signals[J]. Cell,1996,87(2):173
88 Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease [J]. Biochim Biophys Acta,2008,1782:197-228
89 Keski-Oja, J., Moses, H. L. Growth inhibitory polypeptides in the regulation of cell proliferation[J]. Med. Biol,1987,65:13-20
90 Reiss M. TGF-beta and cancer[J]. Microbes Infect,1999,1:1327-1347
91 Kingsley DM. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms [J]. Genes Dev,1994,8133-8146
92 Flanders KC. Smad3 as a mediator of the fibrotic response [J]. Int J Exp Pathol. 2004,85:47-64
93牛晓华,任来成.TGF-β/Smads信号转导通路与肾间质纤维化的关系[J].山西中医学院学报,2006,7(6)：51-53
94 Massague J. TGF-beta signal transduction[J]. Annu Rev Biochem,1998,67:753-791.
95 Heldin C H, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins[J]. Nature,1997,390 (6659):465-471
96 Massague J, Seoane J, Wotton D. Smad transcription factors [J]. Genes Dev.2005, 19:2783-2810
97 Schmierer B, Hill CS. TGFbeta-SMAD signal transduction:molecular specificity and functional flexibility[J]. Nat Rev Mol Cell Biol,2007, (8):970-982
98 Daly AC, Randall RA, Hill CS. Transforming growth factor beta-induced Smad1/5 phosphorylation in epithelial cells is mediatedby novel receptor complexes and is essential for anchorage-independent growth[J]. Mol Cell Biol,2008, (28): 6889-6902
99 Goumans MJ, Valdimarsdottir G, Itoh S, et al. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors [J]. EMBO J,2002, (21): 1743-1753
100 Wakefield LM, Roberts AB. TGF-beta signaling:positive and negative effects on tumorigenesis[J]. Curr Opin Genet Dev,2002,12:22-29
101 Wrighton KH, Feng XH. To (TGF) beta or not to (TGF) beta: fine-tuning of Smad signaling via post-translational modifications [J]. Cell Signal,2008, 20:1579-1591
102 Zhang YE. Non-Smad pathways in TGF-beta signal ing [J]. Cell Res,2009,19:128-139.
103 Eivers E, Fuentealba LC, De Robertis EM. Integrating positional information at the level of Smadl/5/8[J]. Curr Opin Genet Dev,2008,18:304-310
104陈惠,杨耀防bFGF的生物作用分子机制研究进展[J].九江医学,2009,24(1)：73-75
105 Gospodarowicz D, Jones KL, Sato G. Purification of a growth factor for ovarian cells from bovine pituitary glands[J]. Proc Nat1 Acad Sci USA,1974,71(6):2295
1 06 伊海英,孙晓艳,付小兵,等.碱性成纤维细胞生长因子的研究进展[J].解放军医学杂志,2008,33(6)：776-778
107 Malkowski A, Sobolewski K, Jaworski S, et al. FGF binding by extracellular matrix components of Wharton's jelly. Acta Biochim Pol,2007,54(2):357
108 Eriksson AE, Cousens LS, Weaver LH, et al. Three-dimensional structure of human basic fibroblast growth factor [J]. Proc Natl Acad Sci USA,1991,88:3441
109屈晓辉,周建华bFGF/FGFR信号转导途径与肿瘤[J].国际病理科学与临床杂志,2006,27(2)：125-129
110 Itoh N. The Fgf families in humans, mice, and zebrafish:their evolutional processes and roles in development, metabolism, and disease [J]. Biol Pharm Bull, 2007,30(10):1819
111 Zhang X, Ibrahimi OA, Olsen SK, et al. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family[J]. J Biol Chem,2006, 281 (23):15694
112 Schlessinger J. Common and distinct elements in cellular signaling via EGF and FGF receptors[J]. Science,2004,306(5701):1506
113 Coumoul X, Deng CX. Roles of FGF receptors in mammalian development and congenital diseases [J]. Birth Defects Res C Embryo Today,2003,69(4):286
114 Schlessinger J. Cell signaling by receptor tyrosine kinases[J]. Cell,2000, 103(2):211
115 Xu C, Rosler E, Jiang J, et al. Basic fibroblast growth factor supports undifferentiated human embryonic stem cell growth without conditioned medium[J]. Stem Cells,2005,23(3):315
116 Ben-Zvi T, Yayon A, Gertler A, et al. Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling[J]. J Cell Sci,2006,119 (pt2):380
117 Lamothe B, Yamada M, Schaeper U, et al. The docking protein Gabl is an essential component of an indirect mechanism for fibroblast growth factor stimulation of the phosphatidylinositol 3-kinase/Akt antiapoptotic pathway[J]. Mol Cell Biol, 2004,24(13):5657
118 Heldin CH, Eriksson U, Ostman A. New members of the platelet-derived growth factor family of mitogens[J]. Arch Bioeheml Biophys,2002,398(2):284-290
119 Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms[J]. Cytokine Growth Factor Rev,2004,15(4):197-204
120 Bonner JC. Regulation of PDGF and its recptors in fibrotic diseases [J]. Cytokine Growth Factor Rev,2004,15(4):255-273
121 Marra F, Gentilini A, Pinzani M, etal. PhosPhatidylinositol 3-kinase is required for Platelet-derived growth factor's actions on hepatic stellate cells [J]. Gastroenterology,1997,112(4):1297-1306
122 吴晓玲,曾维政,蒋明德,等.肝纤维化的信号转导通路.世界华人消化杂志14(22)：2223-2228
123 张峰,雷娜,张晓平等.血小板衍生生长因子体外对大鼠肝星状细胞表达细胞外基质的影响[J].中国药理学通报,2012,28(1)：48-53
124 Hazzalin C A, Mahadevan L C. MAPK-regulated transcription:a continuously variable gene switch[J]. Nat Rev Mol Cell Biol,2002,3(1):30-40
125 周剑虹,邢新,任常群,等.血小板源生长因子受体α和β在瘢痕疙瘩成纤维细胞中表达的差异性研究[J].中国美容医学,2009,18(6)：814
126 Matitashvili E, Bauman DE. Culture of primary bovine mammary epithelial cells[J]. In Vitro Cell Dev Biol Anim,1999,35 (8):431-434
127 杜娟,狄和双,王根林.奶牛乳腺上皮细胞系的建立及高温对细胞超微结构的影响[J].生物工程学报,2007,23：471-476
128 Jose'L. Anaya-Lo'pez, Oscar E, et al.Invasive potential of bacterial isolates associated with subclinical bovine mastitis[J].J. Research in Veterinary Science, 2006,81:358-361
129 Livak K J, Schmittgen T D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method [J]. Methods,2001, 25 (4):402-408
130 Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis[J]. J Mol Med,2004,82(3):175-181.
131 Gressner AM, Weiskirchen R, Breitkop K, et al. Roles of TGF-beta in hepatic fibrosis[J]. Front Biosci,2002, (7):d793-807
132 刘维田,王吉耀,朱无难等.转化生长因子β1对纤维母细胞ⅠⅢ、型前胶原酶mRNA的影响[J].中华肝脏病杂志,1996,4(2)：97-100
133 Mejlvang J, Kriajevska M, Berditchevdki F, et al. Characterization of E-cadherin dependent and independent event sin a new model of c-Fos-mediated epithelial-mesenchymal transition[J]. Exp Cell Res,2007,313(2):380-393
134 Kaimori A, Potter J, Kaimori JY, et al. Transforming growth factor-betal induces an epithelial-mesenchymal transition state in mouse hepatocytes in vitro[J]. J Biol Chem,2007,282(30):22089-22101
135 Wang P, Liu T, Cong M, et al. Expression of extracellular matrix genes in cultured hepatic oval cells:an origin of hepatic stellate cells through transforming growth factor beta? [J]. Liver Int,2009,29(4):575-584.
136 肖永陶,葛文松,徐雷鸣等.转化生长因子β1对肠道上皮-间质转分化影响的体外研究[J].临床儿科杂志,2012,30(2)：160-16
137 Leask A, Holmes A, Black C M, Abraham D J. Connective tissuegrowth factor gene regulation. Requirements for its induction by transforming growth factor-beta 2 in fibroblasts [J]. J Biol Chem,2003,278 (15):13008-13015.
138 刘霞,许朝霞,曹秀荣,等.银杏叶提取物对肺纤维化模型大鼠肺组织结缔组织生长因子表达的影响[J].时真国医国药,2009,(07)
139 Mehra A, Wrana JI. TGF-beta and the Smad signal transduction pathway[J]. Biochem Cell Biol,2002,80 (5):605-622
140 Grotendoral GR, Rahmanie H, Duncan MR. Combinatorial aignaling pathways delermine fibroblast proliferation and myofibroblast differential ion[J]. FASEB J,2004, 18(3):469-479
141 Shi Y, Massage J. Mechanisms of TGF-beta signaling from cell membrane to thenucleus[J]. Cell,2003,113(6):685-700
142 Kavsak P, Rasmussen RK, Causing CG, et al. Smad7 binds to Smurf2 from an E3 ubiquitin ligase that targets TGF-beta receptor for degradation[J]. Mol Cell,2000, 6(6):1365-1375
143 Korchynskyi 0, Landstrom M, Stoika R, et al. Expression of Smad proteins in human colorectal cancer [J]. Int J Cancer,1999,82 (2):197-202
144 Frazier KS, Paredes A, Dube P, et al. Connective tissue growth factor expression in the rat remnant kidney model and association with tubular epithelial cells undergoing transdifferentiation [J]. Vet Pathol,2000,37(4):328-335
145 Harlow CR, Davidson L, Burns KH, et al. FSH and TGF-beta superfamily members regulate granulosa cell connective tissue growth factor gene expression in vitro and in vivo[J]. Endocrinology,2002,143(9):3316-3325
146 Parapuram SK, Chang B, Li L, et al. Differential effects of TGFβ and Vitreous on the transformation of retinal pigment epithelial cells [J]. Invest Ophthalmol Vis Sci,2009,50(12):5965-5974
147 Frazier KS, Grotendorst GR. Expression of connective tissue growth factor mRNA in the fibrous stroma of mammary tumors [J]. Int J Biochem Cell Biol,1997, 29(1):153-161
148 Phillips AO, Topley N, Morrisey K, et al. Basic fibroblast growth factor stim ulates the release of preformed transforming growth factor betal from human proximal tub ular cells in the absence of De Novo gene transcription or mRNA translation[J]. Laboratory Investigation,1997,76(4):591
149 Jones SG, Morrisey K, Williams JD, et al. TGF-betal stimulates the release of pre-formed bFGF from renal proximal tubular cells[J]. Kidney Int,1999,56(5):83
150 Gressner A M, Weiskirchen R. Modern pathogenetic concepts of liver f ibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets [J]. J Cell Mol Med,2006,10(1):76-99
151 Bonner J C. Regulation of PDGF and its receptors in f ibrotic diseases [J]. Cytokine Growth Factor Rev,2004,15(4):255-273
152 Leask A, Abraham DJ. The role of connective tissue growth factor, multifunctional matricellu-lar protein, in fibroblast biology[J]. Biochem Cell Biol,2003, 81 (6):355
153 张丽萍,孙玉敏,陈晓玲.结缔组织生长因子在纤维增生性疾病形成中的作用.医学综述,2007, 13(20)：1546
154 Liu Y, Wen X M, Lui E L, et al. Therapeutic targeting of the PDGF and TGF-beta-signaling pat hways in hepatic stellate cells by PTK787/ZK22258[J]. Lab Invest,2009,89(10):1152-1160
2倪洪权,孙胜利,殷宪达.奶牛乳房炎的辩证论治[J].吉林畜牧兽医,2007,(1)：54-55
3韩炎森.奶山羊乳房炎病原菌调查及其细胞因子的变化检测[D].西北农林科技大学,2011
4 Zeisberg EM, Potenta SE, Sugimoto H, et al. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition[J]. J Am Soc Nephrol,2008,19(12): 2282-2287
5 Zeisberg M, Yang C, Martino M, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition[J]. J Biol Chem,2007,282(32): 23337-23347
6 Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis:the myofibroblast in focus[J]. Chest,2007,132(4):1311-1321
7王华,魏伟.肝纤维化与细胞因子的关系[J].中国药理学通报,2002,18(2)：132-136
8 王颖航,潘志,南红梅等.肾纤维化的分子病理机制探讨[J].中国中西医结合肾病杂志,2006,7(1)：34-37
9 韦小瑜,何云,程明亮.细胞因子与肺纤维化[J].中国西南军医杂志,2006,8(2)：54-57
1 0孙蕴伟,袁耀宗.细胞因子与胰腺星状细胞在慢性胰腺炎胰腺纤维化中的作用[J].国外医学.消化系疾病分册,2001,21(4)：239-242
11 陈博,曹阳,笪邦红等TGF-β2对体外培养牛晶状体上皮细胞CTGF蛋白及mRNA表达的影响[J].国际眼科杂志,2008,8(4)：701-704
12 Parapuram SK, Chang B, Li L, et al. Differential effects of TGFbeta and vitreous on the transformation of retinal pigment epithelial cells [J]. Invest Ophthalmol Vis Sci,2009,50(12):5965-5974
13 Eickelberg 0, Kohler E, Reichenberger F, et al. Extracellular matrixdeposition by primary human lung fibroblasts in response to TGF-β3 and TGF-β3 [J]. AmJ Physiol, 1999,276(5 Pt 1):L814-824
14 Flisiak R, Maxwell P. Plasma tissue inhibitor of metalloproteinase-1 and transforming growth factor beta-1-possible noninvasive biomakers of hepatic fibrosis in patients with chronic B and C hepatitis[J]. Hepato gastroenterology, 2002,49(47):1369-1372
15 Zhang BB, Cai WM, Weng HL, et al. Diagnostic value of platelet derived growth factor-BB, transforming growth factor-betal, matrix metalloproteinase-1, and tissue inhibitor of matrix metalloproteinase-1 in serum and peripheral blood mononuclear cells for hepatic fibrosis[J]. World J Gastroenterol,2003,9(11): 2490-2496
16 陈建晖,高学军,李庆章.奶牛乳腺上皮细胞体外培养技术研究进展[J].东北农业大学学报,2009,40(7)：132-135
17 Wheeler TT, Callaghan MR, Davis SR, et al. Milk protein synthesis, gene expression, and hormonal responsiveness in primary cultures of mammary cells from lactating sheep [J]. Exp Cell Res,1995,217(2):346-354
18徐曼妮,厉曙光,赵建阳等.乳腺生物反应器表达载体的检测方法[J].生物技术通报,2003(5)：23-26
19 宋亚男,陈志伟,刘东武.牛乳腺上皮细胞体外培养体系研究进展[J].生命科学仪器,2008,6(9)：3-8
20 张骞,顾小卫.乳腺上皮细胞的研究及应用[J].中国牧业通讯,2008,(21)：9-11
21 马仲华.家畜解剖学与组织胚胎学(第三版)[M].北京：中国农业出版社,2002：69-246
22 陈杰.家畜生理学(第四版)[M].北京：中国农业出版社,2003：425-441
23 Flanders KC, Wakefield LM. Transforming growth factor-βs and mammary gland involution; functional roles and implications for cancer progression [J]. J Mammary Gland Biol Neoplasia,2009, (14):131-144
24 LASFARGUES EY. Cultivation and behavior in vitro of the normal mammary epithelium of the adult mouse[J]. Anat Rec,1957,127(1):117-129
25 Medina D, Oborn CJ. Growth of preneoplastic mammary epithelial cells in serum-free medium[J]. Cancer Res,1980,40(11):3982-3987
26 Danielson KG, Oborn CJ, Durban EM, et al. Epithelial mouse mammary cell line exhibiting normal morphogenesis in vivo and functional differentiation in vitro [J]. Proc Natl Acad Sci U S A,1984,81(12):3756-3760.
27 Haslam SZ, Counterman LJ. Mammary stroma modulates hormonal responsiveness of mammary epithelium in vitro in the mouse[J]. Endocrinology,1991,129:2017-2023
28 于婷,陈志伟,刘东武.牛乳腺上皮细胞体外培养研究进展[J].生命科学仪器,2009,7(3)： 10-15
29 李震,王英,刘惠莉等.牛乳腺上皮细胞的分离培养[J].上海农业学报,2000,16(3)：25-28
30 彭新荣,郑月茂,张涌.体外培养的牛乳腺上皮细胞形态学研究[J].西北农林科技大学学报(自然科学版),2005,33(1)：13-17
31 崔立莉.奶牛乳腺上皮细胞体外培养体系的建立及其应用[D].乌鲁木齐：新疆农业大学,2006：13-33
32 丁月云,张莉莉,陈莎莎等.组织块种植法体外培养奶牛乳腺上皮细胞[J].南京农业大学学报,2008,31(4)：91-96
33吴娟,王凤龙,王申元.奶牛乳腺上皮细胞的原代培养[J].安徽农业科学,2009,37(6)：2497-2499,2513
34 王亨,吴培福,邱昌伟等.荷斯坦奶牛乳腺上皮细胞的体外培养[J].畜牧与兽医,2007,39(4)：41-43
35 王治国,王传蓉,王加启.不同方法分离奶牛乳腺上皮细胞体外培养的研究[J].乳业科学与技术,2009,(1)：35-38
36 林桂娟,王恬,陈才勇.机械破碎法分离奶牛乳腺上皮细胞的体外培养研究[J].畜牧与兽医,2004,36(7)：4-7
37 Boutinaud M, Ben Chedly MH, Delamaire E, et al. Milking and feed restriction regulate transcripts of mammary epithelial cells purified from milk[J]. J Dairy Sci,2008,91(3):988-998
38 Schmid B, Schiller DL, Grund C. Tissue type-specific expression of intermediate filament protein in a cultured epithelial cell line from bovine mammary gland[J]. Cell Biol,1983,96(1):37-50
39 Gibson CA, Vega JR, Baumrucker CR, et al. Establishment and characterization of bovine manunary epithelial cell lines[J]. In Vitro Cell Dev Biol,1991,27A(7): 2585-2594
40 Huynh, Robitaille G, Turner J. Establishment of bovine mammary epithelial cell line (MAC-T) An in vitro model for bovine lactation[J]. Exp Cell Res,1991,197:191-199
41 Zavizion B, van Duffelen M, Schaeffer W, et al. Establishment and charaeterization of a bovine mammary epithelial cell line with unique properties [J]. In Vitro Cell Dev Biol Anim,1996,32(3):138-148
42 Guzzman RC, Osborn RC, Richards JE, et al. Effects of phorbol esters on normal and tumorous mouse mammary epithelial cells epithelial in collagen gels[J]. J.Natl Cancer Inst,1983,71:69-72
43 Vernon RB, Angello JC, Iruela-Aeispe ML, et al. Re organization of basement membrane matrices by cellular traetion promotes the formation of cellular networks in vitro[J]. Lab. Invest,1992,66:536-547
44 Tania Geman, Itamar Barash. Characterization of an epithelial cell line from bovine mammary gland[J]. In Vitro Cell Dev Biol,2002,38:282-292
45 Kong DS, Zheng SZ, Lu Y, Wang AY. Research progress on myof ibroblasts: their sources and roles in liver fibrogensis[J]. Chin PharmaCOL Bull,2011,27(3):297-300
46 Timpl R. Macromolecular organization of basement membranes [J]. Curr opin Cell bio, 1996,8:618
47 Safadi R, Friedman ST. Hepatic fibrosis-role of hepatic stellate cell activation[J]. Med GenMed,2002,4:27
48 Takanori Tsuji, Soichiro Ibaragi, Guo-fu Hu. Epithelial-Mesenchymal Transition and Cell Cooperativity in Metastasis[J]. Cancer Res,2009,69(18):7135-7139
49 Kalluri R, Neilson EC. Epithelia-mesenchymal transition and its implications for fibrosis[J]. J Clin Invest,2003,112(12):1776-1784
50 KalluriR, Weinberg RA. The basics of epithelial-mesenchymal transit ion[J]. J Clin Invest,2009,119(6):1420
51 Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transit ions [J]. J Clin Invest,2009,119 (6):1429
52 Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells [J]. J Clin Invest,2009,119(6):1417
53 Ayano Kabashima, Hajime Higuchi, Hiromasa Takaishi, et al. Side population of pancreatic cancer cells predominates in TGF-β-mediated epithelial to mesenchymal transition and invasion[J]. Int. J. Cancer,2009,124(12):2771-2779
54 Petersen OW. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma[J]. Am J Pathol,2003,162:391-402
55赵欣,王允山,吉爱国.基质金属蛋白酶在乳腺癌上皮间质转化中的作用[J].生命的化学,2011,31(5)：702-706
56 Henderson NC, Forbes SJ. Hepatic fibrogenesis:From within and outwith[J]. Toxocology,2008,254:130-135
57 贾继东,李海.肝脏纤维化基础与临床研究进展[J].中华肝脏病杂志,2009,17(1)：5-6
58 Abou-Shady M, Friess H, Zimmerhamm A, et al. Connectivetissue growth factor inhuman liver cirrhosis[J]. Liver,2000,20(2):296-304
59 王亚利,赵玉庸,陈志强,等.肾络通对大鼠系膜细胞外基质分泌及转化生长因子β1表达的影响[J].中国中药杂志,2005,30(3)：201-203
60 Verrecchia F, Mauviel A. Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expressionand regulation[J]. J Invest Dermatol,2002,118(2):211-215
61 Shek FW, Benyon RC. How can transforming growth factor beta be targeted usefully to combat liver fibrosis[J]. Eur J GastroenterolHepato,2004,16(2):123-126
62 陈晓红,何有成,姚集鲁.细胞因子对肝纤维化形成的影响[J].国外医学内科学分册,2001,28(1)：21-24
63 王彩生,赵志清.肝纤维化发病机制研究进展[J].内蒙古医学杂志,2010,42(3)：331-334
64张愚,屈文东,黄华等.bFGF及TGF-β1在实验性肝硬化中的免疫组化研究[J].胃肠病学和肝病学杂志,2005,14(1)：40-44
65 Eddy A A. Molecular basis renal fibrosis[J]. Pediatr Nephrol,2000,15(34):290-301
66 Yang JW, Liu YH. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis[J]. American Journal of Pathology,2001,159(4):1465-1475
67 Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation[J]. KidneyInt,2002,61(5):1714-1728
68 Fan JM, Huang XR, Ng YY, et al. Interleukin-1 induces tubular epithelial-myo-fibroblast transdifferentiation through a transforming growth factor-betal-dependent mechanism in vitro1[J].Am J Kidney Dis,2001,37(4):820-831
69 Cheng S, Lovett DH. Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation[J]. Am J Pathol,2003,162(6): 1937-1949
70 PardaliK, MoustakasA. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer[J]. Biochmi Biophys Acta,2007,1775(1):21-62
71 Lee YH, Albig AR, Regner M, et al. Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism[J]. Carcinogenesis,2008,29(12):2243-2251
72 Miettinen PJ, Ebner R, Lopez AR, et al. TGF-β induced transdifferentiation of mammary epithelial cells to mesenchymal cells:involvement of type I receptors[J]. J Cell Biol,1994,127(6 Pt 2):2021-2036
73 Taylor MA, Parvani JG, Schiemann WP. The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-beta in normal and malignant mammary epithelial cells [J]. J Mammary Gland Biol Neoplasia,2010,15(2):169-190
74 Kim K K, Kugler M C, Wolters P J, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix[J]. Proc Natl Acad Sci USA,2006,103(35):13180-13185
75 Willis B C, Liebler J M, Luby-Phelps K, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-betal: potential role in idiopathic pulmonary fibrosis[J]. Am J Pathol,2005,166(5): 1321-1332
76章晓联.医学免疫学[M].武昌：武汉大学出版社,2008：61-81
77 Barnard, JA, Bascom. CC. Lyons, RM, et al. Transforming growth factor β in the control of epidermal prol iferation [J]. Am. J. Med. Sci.,1988,296:159-163
78 芮炜玮,易祥华.转化生长因子β1及相关细胞因子在肺纤维化发生中的作用[J].同济大学学报(医学版),2010,31(3)：133-136
79 Feng XH, Derynck R. Specificity and versatility in TGF-beta signaling through Smads[J]. Annu Rev Cell Dev Biol,2005,21:659-693
80 Massague J, Gomis RR. The logic of TGFbeta signaling[J]. FEBS Lett,2006,580: 2811-2820
81 Roberts AB, Sporn MB. The transforming growth factor-betas[J]. In: Roberts AB, Sporn MB, editors. Handbook of experimental pharmacology. New York:Springer-Verlag,1990,95:419-472
82 Derynck R, Jarrett J A, Chen E Y, et al. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells [J]. Nature,1985,316 (6030):701-705
83 Purchio A F, Cooper J A, Brunner A M, et al. Identif ication of mannose 6-phosphate in two asparagine-linked sugar chains of recombinant transforming growth factor-beta 1 precursor [J]. J Biol Chem,1988,263(28):14211-14215
84 王燕艳.转化生长因子-p与肝纤维化[J].实用医技杂志,2010,17(5)：436-437
85 Inuzuka S, Ueno T, Torimura Tet al.The significance of colocalization of plasminogen activator inhibitor-1 and vitronectin in hepatic fibrosis[J]. Scand J Gastroenterol,1997,32(10):1052-1060
86 Cheng J, Grande J P. Transforming growth factor-β signal transduction and progressive renal disease[J]. Experimental Biology Medicine,2002,227(11): 943-956.
87 Derynck R, Gelbart W M, Harland R M, et al. Nomenclature:vertebrate mediators of TGFbeta family signals[J]. Cell,1996,87(2):173
88 Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease [J]. Biochim Biophys Acta,2008,1782:197-228
89 Keski-Oja, J., Moses, H. L. Growth inhibitory polypeptides in the regulation of cell proliferation[J]. Med. Biol,1987,65:13-20
90 Reiss M. TGF-beta and cancer[J]. Microbes Infect,1999,1:1327-1347
91 Kingsley DM. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms [J]. Genes Dev,1994,8133-8146
92 Flanders KC. Smad3 as a mediator of the fibrotic response [J]. Int J Exp Pathol. 2004,85:47-64
93牛晓华,任来成.TGF-β/Smads信号转导通路与肾间质纤维化的关系[J].山西中医学院学报,2006,7(6)：51-53
94 Massague J. TGF-beta signal transduction[J]. Annu Rev Biochem,1998,67:753-791.
95 Heldin C H, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins[J]. Nature,1997,390 (6659):465-471
96 Massague J, Seoane J, Wotton D. Smad transcription factors [J]. Genes Dev.2005, 19:2783-2810
97 Schmierer B, Hill CS. TGFbeta-SMAD signal transduction:molecular specificity and functional flexibility[J]. Nat Rev Mol Cell Biol,2007, (8):970-982
98 Daly AC, Randall RA, Hill CS. Transforming growth factor beta-induced Smad1/5 phosphorylation in epithelial cells is mediatedby novel receptor complexes and is essential for anchorage-independent growth[J]. Mol Cell Biol,2008, (28): 6889-6902
99 Goumans MJ, Valdimarsdottir G, Itoh S, et al. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors [J]. EMBO J,2002, (21): 1743-1753
100 Wakefield LM, Roberts AB. TGF-beta signaling:positive and negative effects on tumorigenesis[J]. Curr Opin Genet Dev,2002,12:22-29
101 Wrighton KH, Feng XH. To (TGF) beta or not to (TGF) beta: fine-tuning of Smad signaling via post-translational modifications [J]. Cell Signal,2008, 20:1579-1591
102 Zhang YE. Non-Smad pathways in TGF-beta signal ing [J]. Cell Res,2009,19:128-139.
103 Eivers E, Fuentealba LC, De Robertis EM. Integrating positional information at the level of Smadl/5/8[J]. Curr Opin Genet Dev,2008,18:304-310
104陈惠,杨耀防bFGF的生物作用分子机制研究进展[J].九江医学,2009,24(1)：73-75
105 Gospodarowicz D, Jones KL, Sato G. Purification of a growth factor for ovarian cells from bovine pituitary glands[J]. Proc Nat1 Acad Sci USA,1974,71(6):2295
1 06 伊海英,孙晓艳,付小兵,等.碱性成纤维细胞生长因子的研究进展[J].解放军医学杂志,2008,33(6)：776-778
107 Malkowski A, Sobolewski K, Jaworski S, et al. FGF binding by extracellular matrix components of Wharton's jelly. Acta Biochim Pol,2007,54(2):357
108 Eriksson AE, Cousens LS, Weaver LH, et al. Three-dimensional structure of human basic fibroblast growth factor [J]. Proc Natl Acad Sci USA,1991,88:3441
109屈晓辉,周建华bFGF/FGFR信号转导途径与肿瘤[J].国际病理科学与临床杂志,2006,27(2)：125-129
110 Itoh N. The Fgf families in humans, mice, and zebrafish:their evolutional processes and roles in development, metabolism, and disease [J]. Biol Pharm Bull, 2007,30(10):1819
111 Zhang X, Ibrahimi OA, Olsen SK, et al. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family[J]. J Biol Chem,2006, 281 (23):15694
112 Schlessinger J. Common and distinct elements in cellular signaling via EGF and FGF receptors[J]. Science,2004,306(5701):1506
113 Coumoul X, Deng CX. Roles of FGF receptors in mammalian development and congenital diseases [J]. Birth Defects Res C Embryo Today,2003,69(4):286
114 Schlessinger J. Cell signaling by receptor tyrosine kinases[J]. Cell,2000, 103(2):211
115 Xu C, Rosler E, Jiang J, et al. Basic fibroblast growth factor supports undifferentiated human embryonic stem cell growth without conditioned medium[J]. Stem Cells,2005,23(3):315
116 Ben-Zvi T, Yayon A, Gertler A, et al. Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling[J]. J Cell Sci,2006,119 (pt2):380
117 Lamothe B, Yamada M, Schaeper U, et al. The docking protein Gabl is an essential component of an indirect mechanism for fibroblast growth factor stimulation of the phosphatidylinositol 3-kinase/Akt antiapoptotic pathway[J]. Mol Cell Biol, 2004,24(13):5657
118 Heldin CH, Eriksson U, Ostman A. New members of the platelet-derived growth factor family of mitogens[J]. Arch Bioeheml Biophys,2002,398(2):284-290
119 Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms[J]. Cytokine Growth Factor Rev,2004,15(4):197-204
120 Bonner JC. Regulation of PDGF and its recptors in fibrotic diseases [J]. Cytokine Growth Factor Rev,2004,15(4):255-273
121 Marra F, Gentilini A, Pinzani M, etal. PhosPhatidylinositol 3-kinase is required for Platelet-derived growth factor's actions on hepatic stellate cells [J]. Gastroenterology,1997,112(4):1297-1306
122 吴晓玲,曾维政,蒋明德,等.肝纤维化的信号转导通路.世界华人消化杂志14(22)：2223-2228
123 张峰,雷娜,张晓平等.血小板衍生生长因子体外对大鼠肝星状细胞表达细胞外基质的影响[J].中国药理学通报,2012,28(1)：48-53
124 Hazzalin C A, Mahadevan L C. MAPK-regulated transcription:a continuously variable gene switch[J]. Nat Rev Mol Cell Biol,2002,3(1):30-40
125 周剑虹,邢新,任常群,等.血小板源生长因子受体α和β在瘢痕疙瘩成纤维细胞中表达的差异性研究[J].中国美容医学,2009,18(6)：814
126 Matitashvili E, Bauman DE. Culture of primary bovine mammary epithelial cells[J]. In Vitro Cell Dev Biol Anim,1999,35 (8):431-434
127 杜娟,狄和双,王根林.奶牛乳腺上皮细胞系的建立及高温对细胞超微结构的影响[J].生物工程学报,2007,23：471-476
128 Jose'L. Anaya-Lo'pez, Oscar E, et al.Invasive potential of bacterial isolates associated with subclinical bovine mastitis[J].J. Research in Veterinary Science, 2006,81:358-361
129 Livak K J, Schmittgen T D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method [J]. Methods,2001, 25 (4):402-408
130 Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis[J]. J Mol Med,2004,82(3):175-181.
131 Gressner AM, Weiskirchen R, Breitkop K, et al. Roles of TGF-beta in hepatic fibrosis[J]. Front Biosci,2002, (7):d793-807
132 刘维田,王吉耀,朱无难等.转化生长因子β1对纤维母细胞ⅠⅢ、型前胶原酶mRNA的影响[J].中华肝脏病杂志,1996,4(2)：97-100
133 Mejlvang J, Kriajevska M, Berditchevdki F, et al. Characterization of E-cadherin dependent and independent event sin a new model of c-Fos-mediated epithelial-mesenchymal transition[J]. Exp Cell Res,2007,313(2):380-393
134 Kaimori A, Potter J, Kaimori JY, et al. Transforming growth factor-betal induces an epithelial-mesenchymal transition state in mouse hepatocytes in vitro[J]. J Biol Chem,2007,282(30):22089-22101
135 Wang P, Liu T, Cong M, et al. Expression of extracellular matrix genes in cultured hepatic oval cells:an origin of hepatic stellate cells through transforming growth factor beta? [J]. Liver Int,2009,29(4):575-584.
136 肖永陶,葛文松,徐雷鸣等.转化生长因子β1对肠道上皮-间质转分化影响的体外研究[J].临床儿科杂志,2012,30(2)：160-16
137 Leask A, Holmes A, Black C M, Abraham D J. Connective tissuegrowth factor gene regulation. Requirements for its induction by transforming growth factor-beta 2 in fibroblasts [J]. J Biol Chem,2003,278 (15):13008-13015.
138 刘霞,许朝霞,曹秀荣,等.银杏叶提取物对肺纤维化模型大鼠肺组织结缔组织生长因子表达的影响[J].时真国医国药,2009,(07)
139 Mehra A, Wrana JI. TGF-beta and the Smad signal transduction pathway[J]. Biochem Cell Biol,2002,80 (5):605-622
140 Grotendoral GR, Rahmanie H, Duncan MR. Combinatorial aignaling pathways delermine fibroblast proliferation and myofibroblast differential ion[J]. FASEB J,2004, 18(3):469-479
141 Shi Y, Massage J. Mechanisms of TGF-beta signaling from cell membrane to thenucleus[J]. Cell,2003,113(6):685-700
142 Kavsak P, Rasmussen RK, Causing CG, et al. Smad7 binds to Smurf2 from an E3 ubiquitin ligase that targets TGF-beta receptor for degradation[J]. Mol Cell,2000, 6(6):1365-1375
143 Korchynskyi 0, Landstrom M, Stoika R, et al. Expression of Smad proteins in human colorectal cancer [J]. Int J Cancer,1999,82 (2):197-202
144 Frazier KS, Paredes A, Dube P, et al. Connective tissue growth factor expression in the rat remnant kidney model and association with tubular epithelial cells undergoing transdifferentiation [J]. Vet Pathol,2000,37(4):328-335
145 Harlow CR, Davidson L, Burns KH, et al. FSH and TGF-beta superfamily members regulate granulosa cell connective tissue growth factor gene expression in vitro and in vivo[J]. Endocrinology,2002,143(9):3316-3325
146 Parapuram SK, Chang B, Li L, et al. Differential effects of TGFβ and Vitreous on the transformation of retinal pigment epithelial cells [J]. Invest Ophthalmol Vis Sci,2009,50(12):5965-5974
147 Frazier KS, Grotendorst GR. Expression of connective tissue growth factor mRNA in the fibrous stroma of mammary tumors [J]. Int J Biochem Cell Biol,1997, 29(1):153-161
148 Phillips AO, Topley N, Morrisey K, et al. Basic fibroblast growth factor stim ulates the release of preformed transforming growth factor betal from human proximal tub ular cells in the absence of De Novo gene transcription or mRNA translation[J]. Laboratory Investigation,1997,76(4):591
149 Jones SG, Morrisey K, Williams JD, et al. TGF-betal stimulates the release of pre-formed bFGF from renal proximal tubular cells[J]. Kidney Int,1999,56(5):83
150 Gressner A M, Weiskirchen R. Modern pathogenetic concepts of liver f ibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets [J]. J Cell Mol Med,2006,10(1):76-99
151 Bonner J C. Regulation of PDGF and its receptors in f ibrotic diseases [J]. Cytokine Growth Factor Rev,2004,15(4):255-273
152 Leask A, Abraham DJ. The role of connective tissue growth factor, multifunctional matricellu-lar protein, in fibroblast biology[J]. Biochem Cell Biol,2003, 81 (6):355
153 张丽萍,孙玉敏,陈晓玲.结缔组织生长因子在纤维增生性疾病形成中的作用.医学综述,2007, 13(20)：1546
154 Liu Y, Wen X M, Lui E L, et al. Therapeutic targeting of the PDGF and TGF-beta-signaling pat hways in hepatic stellate cells by PTK787/ZK22258[J]. Lab Invest,2009,89(10):1152-1160