TNF-α和IFN-γ及含有五种细胞因子的奶牛乳汁对奶牛乳腺纤维化影响的研究
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摘要
奶牛乳腺纤维化主要由奶牛乳腺炎引起，各种病因引起的奶牛乳腺炎均可导致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，严重时发展为乳腺硬化导致奶牛淘汰。研究细胞因子在奶牛乳腺纤维化中的作用，对奶牛乳腺纤维化的防治具有重要意义。
目前关于奶牛乳腺纤维化发生机制的研究报道很少，在奶牛乳腺纤维化过程中，除间质成纤维细胞（BMFB）能够产生细胞外基质（ECM）外，奶牛乳腺上皮细胞（BMEC）能否通过上皮-间质转化（EMT）形成肌纤维母细胞（MFB）并合成ECM仍不明确，与纤维化相关的一些细胞因子与BMEC的转分化及BMFB产生ECM的相互关系需要深入研究。本研究分别用不同浓度的TNF-α（1、5、10ng/mL）、IFN-γ (5、10、20ng/ml)及TNF-α/IFN-γ联合液（浓度比分别为1:1、1:2、1:5）作用于体外培养的BMEC和BMFB，于不同时刻（12h、24h、48h、72h）取细胞总RNA和总蛋白，分别用实时荧光定量RT-PCR和western-blot方法检测平滑肌肌动蛋白（α-SMA），结缔组织生长因子（CTGF）及胶原（ICOLIα1）mRNA及α-SMA蛋白表达水平。同时，根据细胞因子放免检测结果，用筛选出的含有五种细胞因子（TNF-α、IFN-γ、TGF-β1、bFGF、PDGF）的奶牛乳汁分别作用体外培养BMEC和BMFB，于不同的时刻(12h、24h、48h、72h)，用实时荧光定量RT-PCR的方法检测含有五种细胞因子的奶牛乳汁对两种细胞α-SMA、CTGF和COLIα1mRNA相对表达量的影响。
结果显示：外源性TNF-α对BMEC和BMFB α-SMA、CTGF和COLIα1三种基因mRNA表达基本起促进作用，对BMFB α-SMA的蛋白表达也起促进作用，但未检测到BMEC α-SMA蛋白的表达；外源性IFN-γ对BMEC和BMFB α-SMA、CTGF和COLIα1三种基因mRNA及α-SMA蛋白表达均呈抑制作用。不同比例的TNF-α/IFN-γ联合液均能明显抑制BMEC CTGF、α-SMA、COLIα1mRNA及α-SMA蛋白表达，且负时效、负量效关系明显；对BMFB CTGF、α-SMAmRNA及α-SMA蛋白表达也起明显抑制作用，但对COLIα1mRNA表达起促进作用。TNF-α和TGF-β高含量的乳汁作用BMEC和BMFB在各时刻（12h、24h、48h、72h）α-SMA、CTGF和COLIα1mRNA表达量均比低含量的乳汁作用高； IFN-γ高含量的乳汁对BMEC CTGF和COLIα1mRNA表达量的抑制作用较低含量的乳汁强，而对α-SMAmRNA表达量作用相反；对BMFB CTGF和COLIα1mRNA表达量的抑制作用，12h、24h含量高的乳汁较含量低的乳汁作用强，但48h、72h却相反，而对BMFB α-SMA的mRNA表达量的抑制作用，IFN-γ高含量的乳汁比低含量的乳汁强。bFGF高含量的乳汁作用BMEC和BMFB，CTGF和COLIα1mRNA表达量均比bFGF低含量的乳汁作用高，但对α-SMA mRNA表达的抑制作用却相反。PDGF-BB高含量的乳汁作用BMEC，CTGF和COLIα1mRNA表达量均比低含量的乳汁作用高，但对α-SMA mRNA表达的抑制作用却相反；PDGF-BB高含量的乳汁作用BMFB，α-SMA mRNA表达量均比低含量的乳汁作用高，而对CTGF和COLIα1mRNA表达的影响却相反。
研究结果表明，两种外源性细胞因子及含有细胞因子的乳汁对奶牛乳腺上皮细胞和成纤维细胞中纤维化指标的表达均产生一定的作用，为进一步探究乳腺纤维化的发生机制奠定了基础。
Bovine mammary fibrosis is an important pathological process which wasmainly caused by bovine mastitis that is a major disease in dairy cow. During theprocess of mammary gland fibrosis, the milk yield will decrease, the dairy cow will beeliminated as a result of mammary gland sclerosis in seriously cases. It’s significantthat study the role of cytokines in the bovine mammary gland fibrosis for preventionand control of bovine mammary gland fibrosis.
There were few reports on mechanism of bovine mammary fibrosis. In this study,the bovine mammary epithelial cells and fibroblast were plated in six-well plates andafter overnight incubation at37℃the cells were treated withTNF-α（1,5,10ng/mL）and IFN-γ(5,10,20ng/ml) and incubate the two kinds of cells with cow milkcontaining TNF-α, IFN-γ, TGF-β1, bFGF, PDGF selected by Cytokine immunedetection for12h,24h,48h and72h. Total RNA from each sample was extractedusing Trizol reagent following the manufacturer’s instructions. we detected the effectof TNF-α，IFN-γ and cow milk containing five cytokines to the mRNA expression ofthe three transdifferentiation indicators (CTGF, α-SMA and COL Ⅰα1) in the twokinds of cells by Real-Time quantitative PCR with β-actin as an internal referencegene. We extracted protein in12h，24h，48h and72h, then detected the effect ofdifferent concentrations of TNF-α（1,5,10ng/mL），IFN-γ(5,10,20ng/ml) to the proteinexpression lever of α-SMA by Western blot method. Meanwhile, we incubated thetwo kinds of cells cultured with associated cell supernatant of TNF-α, IFN-γ (1:1,1:2,1:5) in vitro. Then detected the expression of mRNA of CTGF, α-SMA and COL Ⅰα1by Real-Time quantitative PCR, and detected the protein expression of α-SMA byWestern blot in12h,24h,48h and72h.
The study indicated that exogenous TNF-α increased the expression of α-SMA, CTGF, COLⅠ α1mRNA in the bovine mammary epithelial cells and fibroblasts, andthe protein expression of α-SMA in bovine mammary fibroblasts, while the proteinexpression of α-SMA wasn’t detected in the bovine mammary epithelial cells.Exogenous IFN-γ inhibited the expression of α-SMA, CTGF and COLⅠ α1mRNA inthe bovine mammary epithelial cells and fibroblasts. Exogenous IFN-γ inhibited theexpression of α-SMA, CTGF and COL Ⅰα1mRNA and the protein expression ofα-SMA in the bovine mammary epithelial cells and fibroblasts. The cow milk selectedcontaining higher levels of TNF-α promoted the expression of α-SMA, CTGF,COL Ⅰα1mRNA in the BMEC and BMFB than the cow milk of low TNF-α. Thecow milk selected containing higher concentration of IFN-γ promoted the expressionof CTGF, COLⅠ α1mRNA in the BMEC than the cow milk of lower IFN-γ. Butα-SMA mRNA expressed lower by cow milk with IFN-γ of higher concentration thanlow in the BMEC. The cow milk selected containing higher concentration of IFN-γdecreased the expression of CTGF, COL Ⅰα1mRNA in earlier stage (12h,24h) andincreased in later stage(48h,72h) in the fibroblasts, but the higher concentrations ofIFN-γ have a inhibited tendency on the expression of α-SMA mRNA in thefibroblasts. The cow milk selected containing higher concentration of TGF-β1promoted the expression of α-SMA, CTGF, COL Ⅰ α1mRNA in the BMEC andBMFB than the cow milk of low TGF-β1. The cow milk selected containing higherconcentration of bFGF promoted the expression of CTGF, COLⅠ α1mRNA in theBMEC and BMFB than the cow milk of low bFGF, but the higher concentrations ofbFGF have a inhibited tendency on the expression of α-SMA mRNA. The cow milkselected containing higher concentration of PDGF-BB mainly plays a positive role onthe expression of CTGF and COL Ⅰα1mRNA in the bovine mammary epithelial cells,but the mRNA expression of α-SMA was increased with lower concentration ofPDGF-BB. The cow milk selected containing higher concentration of PDGF-BBmainly played a positive role on the expression of α-SMA mRNA in the bovinemammary fibroblasts, but the expression of CTGF and COL Ⅰα1mRNA wereincreased with lower concentration of PDGF-BB. The associated cell supernatant ofdifferent concentrations of TNF-α, IFN-γ inhibited the expression of α-SMA, CTGF and COL Ⅰα1mRNA and the protein expression of α-SMA in the bovine mammaryepithelial cells, and showed typical dose and time effect relationship.The associatedcell supernatant of different concentrations of TNF-α, IFN-γ inhibited the expressionof α-SMA, CTGF mRNA and the protein expression of α-SMA in the bovinemammary fibroblasts, but promote the expression of COL Ⅰα1mRNA in the bovinemammary fibroblasts.
The results suggested that the two kind of exogenous cytokines and the cow milkcontaining cytokines have some certain effect on the expression of the fibrosisindexes both the bovine mammary epithelial cells and fibroblasts, and laid afoundation for the further study of the mechanisms of bovine mammary fibrosis.
目前关于奶牛乳腺纤维化发生机制的研究报道很少，在奶牛乳腺纤维化过程中，除间质成纤维细胞（BMFB）能够产生细胞外基质（ECM）外，奶牛乳腺上皮细胞（BMEC）能否通过上皮-间质转化（EMT）形成肌纤维母细胞（MFB）并合成ECM仍不明确，与纤维化相关的一些细胞因子与BMEC的转分化及BMFB产生ECM的相互关系需要深入研究。本研究分别用不同浓度的TNF-α（1、5、10ng/mL）、IFN-γ (5、10、20ng/ml)及TNF-α/IFN-γ联合液（浓度比分别为1:1、1:2、1:5）作用于体外培养的BMEC和BMFB，于不同时刻（12h、24h、48h、72h）取细胞总RNA和总蛋白，分别用实时荧光定量RT-PCR和western-blot方法检测平滑肌肌动蛋白（α-SMA），结缔组织生长因子（CTGF）及胶原（ICOLIα1）mRNA及α-SMA蛋白表达水平。同时，根据细胞因子放免检测结果，用筛选出的含有五种细胞因子（TNF-α、IFN-γ、TGF-β1、bFGF、PDGF）的奶牛乳汁分别作用体外培养BMEC和BMFB，于不同的时刻(12h、24h、48h、72h)，用实时荧光定量RT-PCR的方法检测含有五种细胞因子的奶牛乳汁对两种细胞α-SMA、CTGF和COLIα1mRNA相对表达量的影响。
结果显示：外源性TNF-α对BMEC和BMFB α-SMA、CTGF和COLIα1三种基因mRNA表达基本起促进作用，对BMFB α-SMA的蛋白表达也起促进作用，但未检测到BMEC α-SMA蛋白的表达；外源性IFN-γ对BMEC和BMFB α-SMA、CTGF和COLIα1三种基因mRNA及α-SMA蛋白表达均呈抑制作用。不同比例的TNF-α/IFN-γ联合液均能明显抑制BMEC CTGF、α-SMA、COLIα1mRNA及α-SMA蛋白表达，且负时效、负量效关系明显；对BMFB CTGF、α-SMAmRNA及α-SMA蛋白表达也起明显抑制作用，但对COLIα1mRNA表达起促进作用。TNF-α和TGF-β高含量的乳汁作用BMEC和BMFB在各时刻（12h、24h、48h、72h）α-SMA、CTGF和COLIα1mRNA表达量均比低含量的乳汁作用高； IFN-γ高含量的乳汁对BMEC CTGF和COLIα1mRNA表达量的抑制作用较低含量的乳汁强，而对α-SMAmRNA表达量作用相反；对BMFB CTGF和COLIα1mRNA表达量的抑制作用，12h、24h含量高的乳汁较含量低的乳汁作用强，但48h、72h却相反，而对BMFB α-SMA的mRNA表达量的抑制作用，IFN-γ高含量的乳汁比低含量的乳汁强。bFGF高含量的乳汁作用BMEC和BMFB，CTGF和COLIα1mRNA表达量均比bFGF低含量的乳汁作用高，但对α-SMA mRNA表达的抑制作用却相反。PDGF-BB高含量的乳汁作用BMEC，CTGF和COLIα1mRNA表达量均比低含量的乳汁作用高，但对α-SMA mRNA表达的抑制作用却相反；PDGF-BB高含量的乳汁作用BMFB，α-SMA mRNA表达量均比低含量的乳汁作用高，而对CTGF和COLIα1mRNA表达的影响却相反。
研究结果表明，两种外源性细胞因子及含有细胞因子的乳汁对奶牛乳腺上皮细胞和成纤维细胞中纤维化指标的表达均产生一定的作用，为进一步探究乳腺纤维化的发生机制奠定了基础。
Bovine mammary fibrosis is an important pathological process which wasmainly caused by bovine mastitis that is a major disease in dairy cow. During theprocess of mammary gland fibrosis, the milk yield will decrease, the dairy cow will beeliminated as a result of mammary gland sclerosis in seriously cases. It’s significantthat study the role of cytokines in the bovine mammary gland fibrosis for preventionand control of bovine mammary gland fibrosis.
There were few reports on mechanism of bovine mammary fibrosis. In this study,the bovine mammary epithelial cells and fibroblast were plated in six-well plates andafter overnight incubation at37℃the cells were treated withTNF-α（1,5,10ng/mL）and IFN-γ(5,10,20ng/ml) and incubate the two kinds of cells with cow milkcontaining TNF-α, IFN-γ, TGF-β1, bFGF, PDGF selected by Cytokine immunedetection for12h,24h,48h and72h. Total RNA from each sample was extractedusing Trizol reagent following the manufacturer’s instructions. we detected the effectof TNF-α，IFN-γ and cow milk containing five cytokines to the mRNA expression ofthe three transdifferentiation indicators (CTGF, α-SMA and COL Ⅰα1) in the twokinds of cells by Real-Time quantitative PCR with β-actin as an internal referencegene. We extracted protein in12h，24h，48h and72h, then detected the effect ofdifferent concentrations of TNF-α（1,5,10ng/mL），IFN-γ(5,10,20ng/ml) to the proteinexpression lever of α-SMA by Western blot method. Meanwhile, we incubated thetwo kinds of cells cultured with associated cell supernatant of TNF-α, IFN-γ (1:1,1:2,1:5) in vitro. Then detected the expression of mRNA of CTGF, α-SMA and COL Ⅰα1by Real-Time quantitative PCR, and detected the protein expression of α-SMA byWestern blot in12h,24h,48h and72h.
The study indicated that exogenous TNF-α increased the expression of α-SMA, CTGF, COLⅠ α1mRNA in the bovine mammary epithelial cells and fibroblasts, andthe protein expression of α-SMA in bovine mammary fibroblasts, while the proteinexpression of α-SMA wasn’t detected in the bovine mammary epithelial cells.Exogenous IFN-γ inhibited the expression of α-SMA, CTGF and COLⅠ α1mRNA inthe bovine mammary epithelial cells and fibroblasts. Exogenous IFN-γ inhibited theexpression of α-SMA, CTGF and COL Ⅰα1mRNA and the protein expression ofα-SMA in the bovine mammary epithelial cells and fibroblasts. The cow milk selectedcontaining higher levels of TNF-α promoted the expression of α-SMA, CTGF,COL Ⅰα1mRNA in the BMEC and BMFB than the cow milk of low TNF-α. Thecow milk selected containing higher concentration of IFN-γ promoted the expressionof CTGF, COLⅠ α1mRNA in the BMEC than the cow milk of lower IFN-γ. Butα-SMA mRNA expressed lower by cow milk with IFN-γ of higher concentration thanlow in the BMEC. The cow milk selected containing higher concentration of IFN-γdecreased the expression of CTGF, COL Ⅰα1mRNA in earlier stage (12h,24h) andincreased in later stage(48h,72h) in the fibroblasts, but the higher concentrations ofIFN-γ have a inhibited tendency on the expression of α-SMA mRNA in thefibroblasts. The cow milk selected containing higher concentration of TGF-β1promoted the expression of α-SMA, CTGF, COL Ⅰ α1mRNA in the BMEC andBMFB than the cow milk of low TGF-β1. The cow milk selected containing higherconcentration of bFGF promoted the expression of CTGF, COLⅠ α1mRNA in theBMEC and BMFB than the cow milk of low bFGF, but the higher concentrations ofbFGF have a inhibited tendency on the expression of α-SMA mRNA. The cow milkselected containing higher concentration of PDGF-BB mainly plays a positive role onthe expression of CTGF and COL Ⅰα1mRNA in the bovine mammary epithelial cells,but the mRNA expression of α-SMA was increased with lower concentration ofPDGF-BB. The cow milk selected containing higher concentration of PDGF-BBmainly played a positive role on the expression of α-SMA mRNA in the bovinemammary fibroblasts, but the expression of CTGF and COL Ⅰα1mRNA wereincreased with lower concentration of PDGF-BB. The associated cell supernatant ofdifferent concentrations of TNF-α, IFN-γ inhibited the expression of α-SMA, CTGF and COL Ⅰα1mRNA and the protein expression of α-SMA in the bovine mammaryepithelial cells, and showed typical dose and time effect relationship.The associatedcell supernatant of different concentrations of TNF-α, IFN-γ inhibited the expressionof α-SMA, CTGF mRNA and the protein expression of α-SMA in the bovinemammary fibroblasts, but promote the expression of COL Ⅰα1mRNA in the bovinemammary fibroblasts.
The results suggested that the two kind of exogenous cytokines and the cow milkcontaining cytokines have some certain effect on the expression of the fibrosisindexes both the bovine mammary epithelial cells and fibroblasts, and laid afoundation for the further study of the mechanisms of bovine mammary fibrosis.
引文
1误义行,黄利权.奶牛乳腺炎防治的免疫学和药理学机制[J].中国兽医杂志,2003,39（3）:40-44.
2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.
3陈健琦.奶牛乳房炎综合防治初探[J].中国畜禽传染病,1990,(6):38-39.
4林曦.家畜病理学[M].第三版.北京:中国农业出版社，1999.
5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.
6马学恩.家畜病理学[M].第四版.呼和浩特:中国农业出版社,2007.
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卫张蕊,周国锋.炎症细胞和细胞因子在肺纤维化中作用的研究进展[J].细胞与分子免疫学杂志,2005,21(1):85-87.
10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.
12Parapuram SK, Chang B, Li L, et al. Differential effects of TGF beta and vitreouson the transformation of retinal pigment epithelial cells[J]. Invest Ophthalmol VisSci,2009,50(12):5965-5974.
13Wen FQ, Kohyama T, Skold CM, et al. Glucocorticoids molecular TGF beta productionby human fetal lung fibroblasts. In flam at ion,2003,27(9):19.
14赵国仁,朱凌冬,安纲.乳腺癌中转化生长因子TGFβ1mRNA及蛋白表达及意义[J].中国实用医药，2008,3（13）：15-17.
15MARLEEN ROELOFS, LUIGI FAGGIAN, FRANCESCA PAMPINELLA, et al. Transforming growthfactor β1involvement in the conversion of fibroblasts to smooth muscle cells inthe rabbit bladder serosa[J]. Histochemical Journal,1998,30(5):393-404.
16Luttenberger T，Schmlid一Kotsas A，Menke A，et al. Platelet-derived growth factorsstimulate Prolierfation and extacellular matrix synthesis of Pancreatic Stellatecells: implications in pathogenesis of pancreas fibrosis[J].Lab Invest，2000，80(l):47-55.
17Sbrucker KA, Peterson TC[J].Toxicol ApplPharmacol,1998,149(1):120-126.
18Schlessinger J. Common and distinct elements in cellular signaling via EGF and FGFreceptors[J]. Science,2004,306(5701):1506.
19Duncan MR, Berman B. Differencial regulation of collagen, glycosaminoglycan,fibronection and collagenase activity production in cultured human adult dermalfibroblasts by interleukin1-α and β and TNF-α and β [J].J InestDermatol,1989,92(5):699-706.
20Bachem MG, Sell KM, Melchior B, et al. Tumor necrosis factor alpha (TNF alpha) andtransforming growth factor beta1(TGF beta1) stimulate fibronectin synthesis andthe transdifferentiation of fat-storing cells in the rat liver into myofibroblasts[J]. Virchows Arch B Cell Pathol Incl Mol Pathol，1993,63(2):123-130.
21杨永平.γ-干扰素对肝星状细胞表达al(Ⅰ) mRNA信号传递途径的影响[J].中华肝脏病杂志,2000,8:123-124.
22Ziesche R,Hofbauer E,Wittmann K, et al. A preliminary study of long-term treatmentwith interferon gamma-1β and low-dose prednisolone in patients with idiopathicpulmonary fibrosis[J]. N Engl J Med,1999，341:1264-1269.
23魏林,王海燕.细胞外基质在人系膜细胞增生性肾小球肾炎中的变化[J].中华病理杂志,1994,23:7.
24Ayo SH, Radnik RA, Graoni J. High glucose causes an in crease in extracellular matrixproteins in cultured mesangial cells[J].Am J Pathol,1990,136:1339.
25Wakisaka M, Spiro M J, Spiro RG. Synthesis of type Ⅵ collagen by cultured glomerularcells and comprison of its regulation by glucose and other factors with that of typeⅣ collagen [J]. Diabetes,1994,43:95.
26Kitagawa T, Masumi A, Akamatsu Y. Transforming growth factor-β1stimulates glucoseuptake and the expression of glucose transporter mRNA in quiescent Swiss mouse3T3cell [J]. J Biol Chem,1991,266:18066.
27Fu XD, Maniatis T. Isolation of a complementary DNA that encodes the mammalian splicingfactor SC35[J]. Science.1992,256(5056):535-538.
28金伯泉.细胞与分子免疫学.[M]北京:世界图书出版公司,2001:64-88.
29Eisenberg LM, Eisenberg CA. Stem cell plasticity, cell fusion, and transdifferen-tiation[J]. Birth Defects Res C Embryo Today,2003,69(3):209-218.
30Krause DS, Theise ND, Collector MI, et al. Multi-organ, multi-lineage engraftmentby a single bone marrow-derived stem cell[J]. Cell,2001,105(3):369-377.
31Horb ME, Shen CN, Tosh D, et al. Experimental conversion of liver to pancreas[J].CurrBiol,2003,13(2):105-115.
32Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions indevelopment and disease[J].Cell,2009,139(5):871-890.
33张彦洁，王俊青，任建敏等.上皮细胞转分化及其表观遗传学调控[J].生命科学，2012,24（2）：191-197.
34Kornelia Polyak, Robert A, Weinberg. Transitions between epithelial and mesenchymalstates: acquisition of malignant and stem cell traits[J].Focus Migration andMetastasis,2009,4(9):265-273.
35Dumont, N. et al. Sustained induction of epithelial to mesenchymal transitionactivates DNA methylation of genes silenced in basal like breast cancers[J]. Proc.Natl Acad. Sci.2008，105:14867-14872.
36Ozdamar, B. et al. Regulation of the polarity protein Par6by TGFβ receptors controlsepithelial cell plasticity[J]. Science2005,307:1603-1609.
37Come, C. et al. Snail and slug play distinct roles during breast carcinomaprogression[J].Clin Cancer Res.2006,12:5395-5402.
38Yang, J.&Weinberg, R. A. Epithelial mesenchymal transition: at the crossroads ofdevelopment and tumor metastasis[J]. Dev. Cell,2008,14:818-829.
39Mani, S. A. et al. The epithelial mesenchymal transition generates cells withproperties of stem cells[J]. Cell,2008,133:704-715.
40James D, Levine A.J, Besser D. Hemmati Brivanlou, A. TGFβ/activin/nodal signalingis necessary for the maintenance of pluripotency in human embryonic stem cells[J].Development,2005,132:1273-1282.
41Ozdamar, B. et al. Regulation of the polarity protein Par6by TGFβ receptors controlsepithelial cellplasticity[J]. Science,2005,307:1603-1609.
42Bissell DM， Hepat olo gy， et al.Expression of variant fibronectins in wound healing:cellular source and biological activity of the EIIIA segment in rat hepaticfibrogenesis[J].Semin Liver Dis,1990,11(3):488-498.
43Carswell E, Old L, Kassel R, et al. An Endotoxin-Induced Serum Factor that CausesNecrosis of Tumors[J]. Proceedings of the National Academy of Science,1975,72(9):3666-3670.
44Shalaby AS,Ramadan AA,Osman SE, et al. Studies of the accessory genital glands(colleterial glands) of the female Spodoptera littoralis (Boisd.)(Lepidoptera,Noctuidae).I.An anatomical and histological study[J]. Folia morphologica,1985,33(3):266-270.
45张东波,张喜丰,张秀英.临床型乳腺炎奶牛乳清和血清中IL-6、TNF-α水平测定.[J]贵州畜牧兽医,2009,33(2):8-9.
46Saile B, Nlatthes N, Knittel T, et al.Transforming growth factor beta and tumornecrosis factor alpha inhibit both apoptosis and proliferation of activated rathepatic stellate cells[J]. Hepatology,1999,30:196-202.
47Bachem MG, Meyer D, Melchior R, et al. Activation of rat liver perisinusoidal lipocytesby transforming growth factors derived from myofibroblast-like cells[J]. J ClinInvest1992;8919-27.
48Verrecchia F, Wagner EF, Mauviel A. Distinct involvement of the Jun-N-terminal kinaseand NF-kappaB pathways in the repression of the human COL1A2gene by TNF-alpha[J].EMBO Rep,2002,3:1069-1074.
49Zhang F, Laiho M.On and off: proteasome and TGF-beta signaling[J]. ExpCell Res,2003,291:275-281
50Mytien T. Goldberg, Yuan-Ping Han, Chunli Yan, et al. TNF-a Suppresses a-Smooth MuscleActin Expression in Human Dermal Fibroblasts: An Implication for Abnormal WoundHealing[J] Journal of Investigative Dermatology,2007,127:2645-2655.
51Zhang HG,Huang N,Liu D,et al.Gene therapy that inhibits nuclear thranslocation ofnuclear factor KB results in tumor necrosis factor-induced apoptosis of human synovialfibroblasts[J].Arithritis Rheum,2000,43(5),1094-105.
52Ryffel B,Brockhaus M,Greiner B,et al.TNF receptor distribution in human lymphoidtissues[J].Immunol,1991,74(3):446-452.
53Lepidi H,Ciubotariu R,Bongrand P,et al.Protein tyrosine kinases and TNF-alphasecretion in human monocyte[J].Int J Immunopharmacol,1994,16(5-6):407-12.
54Lee JC,Prabhakar U,Griswold DE,et al.Low molecular-weight TNF biosynthesisinhibors:strategies and prospectives[J].Circ Shock,1994,44(3):97-103.
55Strassmann BG,patil-Koota V,Finkelman F,et al.Evidence for the involvement ofinterleukine10in the differential deactivation of murine peritoneal macrophagesbyprostaglandin E2[J] J Exp Med,1994,180(6):2365-2370.
56Rothe J,Gehr G,Loerscher H.TNF receptor-structure and function [J]. ImmunolRes,1992,11(2):81-90.
57Hohmann HP, Remy R, Brockhaus M, et al. Two different cell types have differentmajor receptors for human tumor necrosis factor (TNFalpha)[J].JBiolChem,1989,264(25):14927-14934.
58Erickson SL, de-Sauvage FL, Kikly K, et al. Decreased sensitivity to tumor necrosisfactor but normal T-cell development in TNF receptor-2-deficient mice[J].Nature,1994,372(6506):560-563.
59王辉.肿瘤坏死因子相关调亡诱导配体与肝病.[J]实用医院临床杂志,2008,5(3):109-111.
60Iredale JP,Benyon RC,Pickering J,et al.Mechanisms of spontaneous resolusion of ratliver fibrosis.Hepatic stellate cell apoptosis and resuced hepatic expression ofmetalloproteinase inhibitors[J].J Clin Invest,1998,102:538.
61Baroni GS,Ambrosio AD,Curto P,et al.Interferon gamma decreases hepatic stellate cellactivation and extracellular matric deposition in rat liver fibrosis [J].Hepatology,1996,23:1189-1199.
62Rockey DC,Maher JJ,Jarnagin WR,et al.Inhibition of rat hepatic lipocyte activationin culture by interferon-gamma[J].Hepatology,1992,16,776-784.
63陈燕清，张复春，等。干扰素-γ与干扰素-α治疗肝纤维化的对比研究[J]。实用医学杂志，2003，19：366-367.
64Eddy A A. Molecular basis renal fibrosis[J]. Pediatr Nephrol,2000,15(34):290-301.
65Yang JW, Liu YH. Dissection of key events in tubular epithelial to myofibroblasttransition and its implications in renal interstitial fibrosis[J]. AmericanJournal of Pathology,2001,159(4):1465-1475.
66Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2in epithelial-mesenchymal transformation[J]. KidneyInt,2002,61(5):1714-1728.
67Fan JM, Huang XR, Ng YY, et al. Interleukin-1induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta1dependent mechanism in vitro[J]. Am J Kidney Dis,2001,37(4):820-831.
68Cheng S, Lovett DH. Gelatinase A (MMP-2) is necessary and sufficient for renal tubularcell epithelial-mesenchymal transformation[J]. Am J Pathol,2003,162(6):1937-1949.
69Taal MW，Zandi-Nejad K，Weening B，et al.Proinflammatory gene expression andmacrophage recruitment in the rat remnant kidney[J]. Kidney Int，2000，58:1664-1676.
70Valles PG，Pascual L，Manucha W，et al.Role of endogenous nitric oxide in unilateralureteropelvic junction obstruction in children[J]. Kidney Int，2003，63:1104-1115.
71Guo G，Morrissey J，McCracken R，et al.Role of TNFR1and TNFR2receptors intubulointerstitial fibrosis of obstructive nephropathy[J].Am J Physiol，1999，277：766-772.
72Ruiz-Ortega M，Ruperez M，Lorenzo O，et al.Angiotensin II regulates the synthesisof proinflammatory cytokines and chemokines in the kidney[J].Kidney Int Suppl，2002，82:12-22.
73Fan-Chi Chang, Yu-Hsiang Chou, Yi-Ting Chen. Novel insights into pericyte-myofibroblast transition and therapeutic targets in renal fibrosis[J]. Journal ofthe Formosan Medical Association,2012,111:589-598.
74Derynck R, Jarrett J A, Chen E Y, et al. Human transforming growth factor-betacomplementary DNA sequence and expression in normal and transformed cells[J]. Nature,1985,316(6030):701-705.
75Purchio A F, Cooper J A, Brunner A M, et al. Identification of mannose6-phosphatein two asparagine-linked sugar chains of recombinant transforming growth factor-beta1precursor[J]. J Biol Chem,1988,263(28):14211-14215.
76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.
77Bonner JC. Regulation of PDGF and its recptors in fibrotic diseases[J]. Cytokine GrowthFactor Rev,2004,15(4):255-273.
78Marra F, Gentilini A, Pinzani M, etal. PhosPhatidylinositol3-kinase is required forPlatelet-derived growth factor’s actions on hepatic stellate cells[J].Gastroenterology,1997,112(4):1297-1306.
79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.
80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.
81Hazzalin C A, Mahadevan L C. MAPK-regulated transcription: a continuously variablegene switch[J]. Nat Rev Mol Cell Biol,2002,3(1):30-40.
82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.
83Pinzani M, Marra F, Carloni V. Signal transduction in hepatic stellatecells[J].Liver,1998,18:2-3.
84Bachem MG，Sell KM，Melchior R,et al，Tumor necrosis Factor alpha and trans forminggrowth factor betal stimulate fibmnectin synthesis and the transdifibrentionof fat-storing cells in the rat liver into myofibroblasts[J]．Virehows Arch B cellPathol，1993，63:123
85杨永平.干扰素对肝星状细胞表达al(Ⅰ) mRNA信号传递途径的影响[J].中华肝脏病杂志,2000,8:123-124.
86Chinnaiyan AM, Tepper CU, Seldin M F, et al. FADD/MORT1is acommon mediator of CD95(Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis[J]. J Biol Chem,1996,271:4961.
87Tsushima H, Kawata S, Tamara S,et al. Reduced plasma transforming growth factor-beta1levels in patients with chronic hepatitis C after interferon-alpha therapy:Association with regression of hepatic fibrosis[J]. J Hepatol,1999,30(1):1-7.
88Kasperk C. Studies of the mechanism by which androgens enhancem ito-genes anddifferentiatoin in bone cells[J].J C lin EndocrinolM etab,1990,71:1322-1329.
89Sullivan DE， Ferris M， Pociask D， et al. Tumor necrosis factoralpha inducestransforming growth factor-betal expression in lung fibroblasts through theextracellular signal regulated kinase pathway［J］. Am J Respir Cell Mol Biol，2005,32（4）：342-349.
90吴晓梅,王欣燕,陈复辉.两种细胞因子与特发性肺纤维化的关系[J].中国危重病急救医学,2003,15(6):362-364.
91王献华，郝小惠，赵静，等. SiO2对血小板源性生长因子蛋白表达及胶原合成的影响［J］.中华劳动卫生职业病杂志，2009，27（4）:218-221.
92Zhuo Y，Zhang J，Laboy M，et al. Modulation of PDGF-C and PDGF-D expression duringbleomycin-induced lung fibrosis ［J］.Am J Physiol Lung Cell Mol Physiol，2004，286（1）：L182-L188.
93李莉，李燕芹.格列卫对博莱霉素致小鼠肺纤维化的干预作用［J］.中国危重病急救医学，2007，19（4）：229-232.
94Selman M, Thannickal VJ, Pardo A,et al. Idiopathic pulmonary fibrosis: Pathogenesisand therapeutic approaches[J].Drugs,2004;64:405-430.
95Majumdar S,Li D,Ansari T,et al.Different cytokine profiles in cryptogenic fibrosingalveolitis and fibrosing alveolitis associat2ed with systemic sclerosis:aquantitative study of open lung biopsies[J]. Eur Respir J,1999;14:251-257.
96Segel MJ,Izbicki G,Cohen PY,et al. Role of interferon2gamma in the evolution ofmurine bleomycin lung fibrosis[J].AmJ Physiol Lung Cell Mol Physiol，2003,285：1255-1262.
97Chen ES, Greenlee BM, Wills-Karp M, et al. Attenuation of lung inflammation andfibrosis in interferon-gamma-deficient mice after intratracheal bleomycin [J].AmJRespir Cell Mol Biol,2001,24:545-555.
98Guzzman RC, Osborn RC, Richards JE, et al. Effects of phorbol esters on normal andtumorous mouse mammary epithelial cells epithelial in collagen gels[J]. J.NatlCancer Inst,1983,71:69-72.
99Emmrieh J，Weber l，Sparmann GH，et al. Aetivation of panereatie of pancreatic stellatecells in experimental chronic panereatitis in rats [J]. Gastroen-terology,2000,118:A166.
100孙慧敏,张晓红,袁佳琴,等.肿瘤坏死因子-A和转化生长因子-B2对牛晶状体上皮细胞分化的影响[J].中华眼科杂志，2002，3（11）：697-698.
101Sedlaczek N，Jia JD，Bauer M，et a1．Proliferating bile duct epithelial cells area major source of connective tissue growth factor in rat biliary fibrosis [J]．AmJ Pathol，2001，158：1239—1244．
102FRAZIER K,WILLIAMS S,KOTHAPALLI D,et al.Stimulation of fibroblast cellgrowth,matrix production,and granulation tissue formation by connective tissuegrowth factor[J].J Invest Dermatol,1996,107(3):404-411.
103王延叶,李荣山.TGF-B1PSmad与肾脏间质纤维化[J].国外医学泌尿系统分册,2005,25(6):840-843.
104邢静萍,陈楠. Smad与肾纤维化[J].中国中西医结合肾病杂志,2005,6(5):302-304.
105Quillard T et al. Inflammation dysregulates Notch signaling in endothelial cells:Implicationof Notch2and Notch4to endothelial dysfunction[J]. BiochemicalPharmacology,2010,80:2032-2041.
106Aoyaqi-ikeda K et al. Notch induces myofibroblast differentiation of alveolarepithelial cells via TGF-ss/Smad3pathway[J]. Am J Respir Cell Mol Biol,2011,45:136-144.
107Fitau J et al. The adaptor molecule Lnk negatively regulates tumor necrosisfactor-a-dependent VCAM-1expression in endothelial cells through inhibition ofthe ERK1and-2pathways[J]. J Biol Chem,2006,281:20148-20159.
108Hashimoto S，Gon Y，Takeshita I，et al． Transforming growth Factor－beta1inducesphenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-termi nal kinase-dependent pathway.Am J Respir Crit Care Med，2001，163（1）：152-157．
109Zhang A，Ding Q，Huang S，et al． c-Jun NH2-terminal kinase mediation of angiotensinⅡ-induced proliferation of human mesangial cells． Am J Physiol Renal Physiol，2005，288（6）：1118-1124．
110胡月媛，刘学军，杜毓锋,等. JNK信号通路对大鼠肺纤维化Ι型胶原的影响[J],中国药物与临床,2012,12(3):306-307.
111刘素娟，邢玲玲，李建英，等.细胞因子信号转导抑制蛋白-1对白介素-1β诱导的人肾小管上皮细胞转分化的影响[J].中国细胞生物学学报，2012,34（1）：41-48.
112程石，宋茂民，史敬东．核因子kappa B活化对急性坏死性胰腺炎肺泡巨噬细胞炎症介质表达的影响及意义[J]．中华肝胆外科杂志，2006，12(11)764—766．
113Syed MM，Phulwani NK，Kielian T．Tumor necrosis factor-alpha (TNF-alpha) regulatesToll-like receptor2(TLR2)expression in micmglia[J]．J Neurochem，2007，103(4)：l46l-l471．
114Hayden MS，Ghosh S．Signaling to NF—kappaB[J]．GenesDev，2004．18(18)：2195-2224．
115董瑞,马庆久,王青,等.炎性相关刺激因子诱导乳腺癌上皮间质转分化的机制[J].医学研究生学报,2010,23(1):17-20.
116Baluk P, Yao LC, Feng J, Romano T, Jung SS, et al.(2009) TNF-alpha drives remodelingof blood vessels and lymphatics in sustained airway inflammation inmice[J]. J ClinInvest119:2954-2964.
117Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, et al.(2006) Evidenceof a roleof tumor necrosis factor alpha in refractory asthma[J]. N Engl J Med354:697-708.
118Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, et al.(2005) Tumour necrosis factor(TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependentasthma[J]. Thorax60:1012-1018.
119Lin J, Liliensiek B, Kanitz M, Schimanski U, Bohrer H, et al.(1998) Molecular cloningof genes differentially regulated by TNF-alpha in bovine aortic endothelial cells,fibroblasts and smooth muscle cells[J]. Cardiovasc Res38:802-813.
120Xie S, Sukkar MB, Issa R, Oltmanns U, Nicholson AG, et al.(2005) Regulation ofTGF-beta1-induced connective tissue growth factor expression in airway smoothmuscle cells[J]. Am J Physiol Lung Cell Mol Physiol288: L68-76.
121Blom IE, Goldschmeding R, Leask A (2002) Gene regulation of connective tissue growthfactor: new targets for antifibrotic therapy?[J].Matrix Biol21:473-482.
122曾莉,徐庆,陈卫平,等.活血通腑方优选方对TNF-α诱导下腹膜间皮细胞TGF-β1、FN、CTGF蛋白含量的影响[J].南京中医药大学学报，2008,24（5）：324-326.
123Frazier KS, Seely JC, Hard GC，et al. Proliferative and nonproliferative lesions ofthe rat and mouse urinary system[J]. Toxicologic pathology,2012,40(4Suppl):14S-86S.
124杨磊，赵飞艳，王凤龙，等.肿瘤坏死因子-α对奶牛乳腺成纤维细胞增殖的影响[J].黑龙江畜牧兽医，2010,356（5）：20-22.
125章建林. TNF及其受体基因在增生性瘢痕中的动态表达及其意义研究[D]第二军医大学博士学位论文，2002.
126张勉之. TNF-α对肾间质纤维化细胞表型变化的作用及补肾活血法中药对肾小管上皮细胞转分化的抑制作用.[D]河北医科大学博士毕业论文，2004.
127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.
128Iredale J P, Benyon R C, Pichering J, et al. Mechanisms of spontaneous resolutionof rat liver fibrosis: Hepatic stellate cell apoptosis and reduced hepatic expressionof metalloproteinase inhibitors [J]. Clin Invest,1998,102（3）：538-549.
129周俊英,甄真,姚树坤.肝星状细胞凋亡与肝纤维化逆转[J].国内外医学分册，2004,9:403-406.
130Voloshenyuk TG，Hart AD，Khoutorova E，et al. TNF-α increases cardiac fibroblastlysyl oxidase expression through TGF-β and PI3Kinase signaling pathways [J]. BiochemBiophys Res Commun，2011，413（2）：370-375.
131王敬春,徐波,张春.生脉饮对TNF-α诱导的大鼠心肌成纤维细胞胶原合成的影响[J].中国医药导报，2012,9（34）：24-26.
132吴颖芳，彭解英，方厂云. TNF-α和IFN-γ对OSF成纤维细胞胶原合成的影响[J].中国现代医学杂志，2005，15（12）：1803-1805.
133陈厚文,郭梦舟,陈琦,等. T N F-α和IL-13对人肺成纤维细胞胶原蛋白生成的影响[J].中国细胞生物学学报，20ll,33(6):667一73.
134Boguniewicz M, Martin RJ, Martin D, Gibson U, Celniker A, et al. The effects ofnebulized recombinant interferon-gamma in asthmatic airways[J].J Allergy ClinImmunol,1995,95:133-135.
135曾军,杨镇.肝星状细胞、相关因子与肝纤维化关系的研究进展[J].中华肝胆外科杂志,2005,11(6):427-429.
136Gurujeyalakshmi G, Giri SN.Molecular mechanisms of antifibrotic effect of interferongamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta andprocollagen I and III gene expression[J]. Exp Lung Res,1995,21:791-808.
137Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH A preliminarystudy of long-term treatment with interferon gamma-1b and low-dose prednisolone inpatients with idiopathic pulmonary fibrosis[J]. N Engl J Med,1999,341:1264-1269.
138Friesel R, Komoriya A, Maciag T. Inhibition of endothelial cell proliferation bygamma-interferon[J]. J Cell Biol,1987,104:689-696.
139Fitzner B, Brock P, Nechutova H, et al. Inhibitory effects of interferon-gamma onactivation of rat pancreatic stellate cells are mediated by STAT1and involvedown-regulation of CTGF expression[J]. Cell Signal,2007,19:782-790.
140Li Q, Fan JM, Pu L, et al. Effects of interferon-gamma on tubular epithelial-myofibroblast transdifferentiation in vitro[J]. Sichuan Da Xue Xue Bao Yi XueBan,2008,39:895-899.
141Liu JQ, Hu DH, Zhang ZF, et al. Effects of interferongamma on the transforming growthfactor beta/Smad pathway in keloid-derived fibroblasts[J]. Zhonghua Shao Shang ZaZhi,2009,25:454-459.
142张德平,庄谊,孟凡清,等. γ干扰素对实验性肺纤维化大鼠肺泡炎和肺纤维化的影响[J].中国呼吸与危重监护杂志,2006,5(3):189-192.
143杨磊.奶牛乳腺炎乳汁三种细胞因子检测及TNF-α对乳腺细胞凋亡和增殖的影响[D].内蒙古农业大学硕士论文，2010.
144丁旭娜.TGF-β1、bFGF和PDGF在奶牛乳腺纤维化中作用的研究[D].内蒙古农业大学博士论文，2012.
145Parapuram SK, Chang B, Li L, et al. Differential effects of TGFβ and Vitreous onthe transformation of retinal pigment epithelial cells[J]. Invest Ophthalmol VisSci,2009,50(12):5965-5974.
146Stewart RJ, Kashour TS, Marsden PA Vascular endothelial platelet endothelial adhesionmolecule-1(PECAM-1) expression is decreased by TNF-alpha and IFN-gamma. Evidencefor cytokine-induced destabilization of messenger ribonucleic acid transcripts inbovine endothelial cells[J]. J Immunol1996，156:1221-1228.
147Matsuda A, Fukuda S, Matsumoto K, Saito H Th1/Th2cytokines reciprocally regulatein vitro pulmonary angiogenesis via CXC chemokine synthesis[J]. Am J Respir CellMol Biol,2008,38:168-175.
148Drew PD, Franzoso G, Becker KG, Bours V, Carlson LM, et al. NF kappa B and interferonregulatory factor1physically interact and synergistically induce majorhistocompatibility class I gene expression[J]. J Interferon Cytokine Res,1995,15:1037-1045.
149Liu X, Wu W, Chen H Effects of CTGF gene silencing on the proliferation andmyofibroblast differentiation of human lung fibroblasts[J]. Sheng Wu Yi Xue GongCheng Xue Za Zhi,2008,25:407-412.
150Roderich Laug, Markus Fehrholz, Norbert Schutze,et al. IFN-c and TNF-a Synergizeto Inhibit CTGF Expression in Human Lung Endothelial Cells[J].PLOS ONE,2012,7(9):1-10.
2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.
3陈健琦.奶牛乳房炎综合防治初探[J].中国畜禽传染病,1990,(6):38-39.
4林曦.家畜病理学[M].第三版.北京:中国农业出版社，1999.
5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.
6马学恩.家畜病理学[M].第四版.呼和浩特:中国农业出版社,2007.
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卫张蕊,周国锋.炎症细胞和细胞因子在肺纤维化中作用的研究进展[J].细胞与分子免疫学杂志,2005,21(1):85-87.
10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.
12Parapuram SK, Chang B, Li L, et al. Differential effects of TGF beta and vitreouson the transformation of retinal pigment epithelial cells[J]. Invest Ophthalmol VisSci,2009,50(12):5965-5974.
13Wen FQ, Kohyama T, Skold CM, et al. Glucocorticoids molecular TGF beta productionby human fetal lung fibroblasts. In flam at ion,2003,27(9):19.
14赵国仁,朱凌冬,安纲.乳腺癌中转化生长因子TGFβ1mRNA及蛋白表达及意义[J].中国实用医药，2008,3（13）：15-17.
15MARLEEN ROELOFS, LUIGI FAGGIAN, FRANCESCA PAMPINELLA, et al. Transforming growthfactor β1involvement in the conversion of fibroblasts to smooth muscle cells inthe rabbit bladder serosa[J]. Histochemical Journal,1998,30(5):393-404.
16Luttenberger T，Schmlid一Kotsas A，Menke A，et al. Platelet-derived growth factorsstimulate Prolierfation and extacellular matrix synthesis of Pancreatic Stellatecells: implications in pathogenesis of pancreas fibrosis[J].Lab Invest，2000，80(l):47-55.
17Sbrucker KA, Peterson TC[J].Toxicol ApplPharmacol,1998,149(1):120-126.
18Schlessinger J. Common and distinct elements in cellular signaling via EGF and FGFreceptors[J]. Science,2004,306(5701):1506.
19Duncan MR, Berman B. Differencial regulation of collagen, glycosaminoglycan,fibronection and collagenase activity production in cultured human adult dermalfibroblasts by interleukin1-α and β and TNF-α and β [J].J InestDermatol,1989,92(5):699-706.
20Bachem MG, Sell KM, Melchior B, et al. Tumor necrosis factor alpha (TNF alpha) andtransforming growth factor beta1(TGF beta1) stimulate fibronectin synthesis andthe transdifferentiation of fat-storing cells in the rat liver into myofibroblasts[J]. Virchows Arch B Cell Pathol Incl Mol Pathol，1993,63(2):123-130.
21杨永平.γ-干扰素对肝星状细胞表达al(Ⅰ) mRNA信号传递途径的影响[J].中华肝脏病杂志,2000,8:123-124.
22Ziesche R,Hofbauer E,Wittmann K, et al. A preliminary study of long-term treatmentwith interferon gamma-1β and low-dose prednisolone in patients with idiopathicpulmonary fibrosis[J]. N Engl J Med,1999，341:1264-1269.
23魏林,王海燕.细胞外基质在人系膜细胞增生性肾小球肾炎中的变化[J].中华病理杂志,1994,23:7.
24Ayo SH, Radnik RA, Graoni J. High glucose causes an in crease in extracellular matrixproteins in cultured mesangial cells[J].Am J Pathol,1990,136:1339.
25Wakisaka M, Spiro M J, Spiro RG. Synthesis of type Ⅵ collagen by cultured glomerularcells and comprison of its regulation by glucose and other factors with that of typeⅣ collagen [J]. Diabetes,1994,43:95.
26Kitagawa T, Masumi A, Akamatsu Y. Transforming growth factor-β1stimulates glucoseuptake and the expression of glucose transporter mRNA in quiescent Swiss mouse3T3cell [J]. J Biol Chem,1991,266:18066.
27Fu XD, Maniatis T. Isolation of a complementary DNA that encodes the mammalian splicingfactor SC35[J]. Science.1992,256(5056):535-538.
28金伯泉.细胞与分子免疫学.[M]北京:世界图书出版公司,2001:64-88.
29Eisenberg LM, Eisenberg CA. Stem cell plasticity, cell fusion, and transdifferen-tiation[J]. Birth Defects Res C Embryo Today,2003,69(3):209-218.
30Krause DS, Theise ND, Collector MI, et al. Multi-organ, multi-lineage engraftmentby a single bone marrow-derived stem cell[J]. Cell,2001,105(3):369-377.
31Horb ME, Shen CN, Tosh D, et al. Experimental conversion of liver to pancreas[J].CurrBiol,2003,13(2):105-115.
32Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions indevelopment and disease[J].Cell,2009,139(5):871-890.
33张彦洁，王俊青，任建敏等.上皮细胞转分化及其表观遗传学调控[J].生命科学，2012,24（2）：191-197.
34Kornelia Polyak, Robert A, Weinberg. Transitions between epithelial and mesenchymalstates: acquisition of malignant and stem cell traits[J].Focus Migration andMetastasis,2009,4(9):265-273.
35Dumont, N. et al. Sustained induction of epithelial to mesenchymal transitionactivates DNA methylation of genes silenced in basal like breast cancers[J]. Proc.Natl Acad. Sci.2008，105:14867-14872.
36Ozdamar, B. et al. Regulation of the polarity protein Par6by TGFβ receptors controlsepithelial cell plasticity[J]. Science2005,307:1603-1609.
37Come, C. et al. Snail and slug play distinct roles during breast carcinomaprogression[J].Clin Cancer Res.2006,12:5395-5402.
38Yang, J.&Weinberg, R. A. Epithelial mesenchymal transition: at the crossroads ofdevelopment and tumor metastasis[J]. Dev. Cell,2008,14:818-829.
39Mani, S. A. et al. The epithelial mesenchymal transition generates cells withproperties of stem cells[J]. Cell,2008,133:704-715.
40James D, Levine A.J, Besser D. Hemmati Brivanlou, A. TGFβ/activin/nodal signalingis necessary for the maintenance of pluripotency in human embryonic stem cells[J].Development,2005,132:1273-1282.
41Ozdamar, B. et al. Regulation of the polarity protein Par6by TGFβ receptors controlsepithelial cellplasticity[J]. Science,2005,307:1603-1609.
42Bissell DM， Hepat olo gy， et al.Expression of variant fibronectins in wound healing:cellular source and biological activity of the EIIIA segment in rat hepaticfibrogenesis[J].Semin Liver Dis,1990,11(3):488-498.
43Carswell E, Old L, Kassel R, et al. An Endotoxin-Induced Serum Factor that CausesNecrosis of Tumors[J]. Proceedings of the National Academy of Science,1975,72(9):3666-3670.
44Shalaby AS,Ramadan AA,Osman SE, et al. Studies of the accessory genital glands(colleterial glands) of the female Spodoptera littoralis (Boisd.)(Lepidoptera,Noctuidae).I.An anatomical and histological study[J]. Folia morphologica,1985,33(3):266-270.
45张东波,张喜丰,张秀英.临床型乳腺炎奶牛乳清和血清中IL-6、TNF-α水平测定.[J]贵州畜牧兽医,2009,33(2):8-9.
46Saile B, Nlatthes N, Knittel T, et al.Transforming growth factor beta and tumornecrosis factor alpha inhibit both apoptosis and proliferation of activated rathepatic stellate cells[J]. Hepatology,1999,30:196-202.
47Bachem MG, Meyer D, Melchior R, et al. Activation of rat liver perisinusoidal lipocytesby transforming growth factors derived from myofibroblast-like cells[J]. J ClinInvest1992;8919-27.
48Verrecchia F, Wagner EF, Mauviel A. Distinct involvement of the Jun-N-terminal kinaseand NF-kappaB pathways in the repression of the human COL1A2gene by TNF-alpha[J].EMBO Rep,2002,3:1069-1074.
49Zhang F, Laiho M.On and off: proteasome and TGF-beta signaling[J]. ExpCell Res,2003,291:275-281
50Mytien T. Goldberg, Yuan-Ping Han, Chunli Yan, et al. TNF-a Suppresses a-Smooth MuscleActin Expression in Human Dermal Fibroblasts: An Implication for Abnormal WoundHealing[J] Journal of Investigative Dermatology,2007,127:2645-2655.
51Zhang HG,Huang N,Liu D,et al.Gene therapy that inhibits nuclear thranslocation ofnuclear factor KB results in tumor necrosis factor-induced apoptosis of human synovialfibroblasts[J].Arithritis Rheum,2000,43(5),1094-105.
52Ryffel B,Brockhaus M,Greiner B,et al.TNF receptor distribution in human lymphoidtissues[J].Immunol,1991,74(3):446-452.
53Lepidi H,Ciubotariu R,Bongrand P,et al.Protein tyrosine kinases and TNF-alphasecretion in human monocyte[J].Int J Immunopharmacol,1994,16(5-6):407-12.
54Lee JC,Prabhakar U,Griswold DE,et al.Low molecular-weight TNF biosynthesisinhibors:strategies and prospectives[J].Circ Shock,1994,44(3):97-103.
55Strassmann BG,patil-Koota V,Finkelman F,et al.Evidence for the involvement ofinterleukine10in the differential deactivation of murine peritoneal macrophagesbyprostaglandin E2[J] J Exp Med,1994,180(6):2365-2370.
56Rothe J,Gehr G,Loerscher H.TNF receptor-structure and function [J]. ImmunolRes,1992,11(2):81-90.
57Hohmann HP, Remy R, Brockhaus M, et al. Two different cell types have differentmajor receptors for human tumor necrosis factor (TNFalpha)[J].JBiolChem,1989,264(25):14927-14934.
58Erickson SL, de-Sauvage FL, Kikly K, et al. Decreased sensitivity to tumor necrosisfactor but normal T-cell development in TNF receptor-2-deficient mice[J].Nature,1994,372(6506):560-563.
59王辉.肿瘤坏死因子相关调亡诱导配体与肝病.[J]实用医院临床杂志,2008,5(3):109-111.
60Iredale JP,Benyon RC,Pickering J,et al.Mechanisms of spontaneous resolusion of ratliver fibrosis.Hepatic stellate cell apoptosis and resuced hepatic expression ofmetalloproteinase inhibitors[J].J Clin Invest,1998,102:538.
61Baroni GS,Ambrosio AD,Curto P,et al.Interferon gamma decreases hepatic stellate cellactivation and extracellular matric deposition in rat liver fibrosis [J].Hepatology,1996,23:1189-1199.
62Rockey DC,Maher JJ,Jarnagin WR,et al.Inhibition of rat hepatic lipocyte activationin culture by interferon-gamma[J].Hepatology,1992,16,776-784.
63陈燕清，张复春，等。干扰素-γ与干扰素-α治疗肝纤维化的对比研究[J]。实用医学杂志，2003，19：366-367.
64Eddy A A. Molecular basis renal fibrosis[J]. Pediatr Nephrol,2000,15(34):290-301.
65Yang JW, Liu YH. Dissection of key events in tubular epithelial to myofibroblasttransition and its implications in renal interstitial fibrosis[J]. AmericanJournal of Pathology,2001,159(4):1465-1475.
66Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2in epithelial-mesenchymal transformation[J]. KidneyInt,2002,61(5):1714-1728.
67Fan JM, Huang XR, Ng YY, et al. Interleukin-1induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta1dependent mechanism in vitro[J]. Am J Kidney Dis,2001,37(4):820-831.
68Cheng S, Lovett DH. Gelatinase A (MMP-2) is necessary and sufficient for renal tubularcell epithelial-mesenchymal transformation[J]. Am J Pathol,2003,162(6):1937-1949.
69Taal MW，Zandi-Nejad K，Weening B，et al.Proinflammatory gene expression andmacrophage recruitment in the rat remnant kidney[J]. Kidney Int，2000，58:1664-1676.
70Valles PG，Pascual L，Manucha W，et al.Role of endogenous nitric oxide in unilateralureteropelvic junction obstruction in children[J]. Kidney Int，2003，63:1104-1115.
71Guo G，Morrissey J，McCracken R，et al.Role of TNFR1and TNFR2receptors intubulointerstitial fibrosis of obstructive nephropathy[J].Am J Physiol，1999，277：766-772.
72Ruiz-Ortega M，Ruperez M，Lorenzo O，et al.Angiotensin II regulates the synthesisof proinflammatory cytokines and chemokines in the kidney[J].Kidney Int Suppl，2002，82:12-22.
73Fan-Chi Chang, Yu-Hsiang Chou, Yi-Ting Chen. Novel insights into pericyte-myofibroblast transition and therapeutic targets in renal fibrosis[J]. Journal ofthe Formosan Medical Association,2012,111:589-598.
74Derynck R, Jarrett J A, Chen E Y, et al. Human transforming growth factor-betacomplementary DNA sequence and expression in normal and transformed cells[J]. Nature,1985,316(6030):701-705.
75Purchio A F, Cooper J A, Brunner A M, et al. Identification of mannose6-phosphatein two asparagine-linked sugar chains of recombinant transforming growth factor-beta1precursor[J]. J Biol Chem,1988,263(28):14211-14215.
76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.
77Bonner JC. Regulation of PDGF and its recptors in fibrotic diseases[J]. Cytokine GrowthFactor Rev,2004,15(4):255-273.
78Marra F, Gentilini A, Pinzani M, etal. PhosPhatidylinositol3-kinase is required forPlatelet-derived growth factor’s actions on hepatic stellate cells[J].Gastroenterology,1997,112(4):1297-1306.
79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.
80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.
81Hazzalin C A, Mahadevan L C. MAPK-regulated transcription: a continuously variablegene switch[J]. Nat Rev Mol Cell Biol,2002,3(1):30-40.
82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.
83Pinzani M, Marra F, Carloni V. Signal transduction in hepatic stellatecells[J].Liver,1998,18:2-3.
84Bachem MG，Sell KM，Melchior R,et al，Tumor necrosis Factor alpha and trans forminggrowth factor betal stimulate fibmnectin synthesis and the transdifibrentionof fat-storing cells in the rat liver into myofibroblasts[J]．Virehows Arch B cellPathol，1993，63:123
85杨永平.干扰素对肝星状细胞表达al(Ⅰ) mRNA信号传递途径的影响[J].中华肝脏病杂志,2000,8:123-124.
86Chinnaiyan AM, Tepper CU, Seldin M F, et al. FADD/MORT1is acommon mediator of CD95(Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis[J]. J Biol Chem,1996,271:4961.
87Tsushima H, Kawata S, Tamara S,et al. Reduced plasma transforming growth factor-beta1levels in patients with chronic hepatitis C after interferon-alpha therapy:Association with regression of hepatic fibrosis[J]. J Hepatol,1999,30(1):1-7.
88Kasperk C. Studies of the mechanism by which androgens enhancem ito-genes anddifferentiatoin in bone cells[J].J C lin EndocrinolM etab,1990,71:1322-1329.
89Sullivan DE， Ferris M， Pociask D， et al. Tumor necrosis factoralpha inducestransforming growth factor-betal expression in lung fibroblasts through theextracellular signal regulated kinase pathway［J］. Am J Respir Cell Mol Biol，2005,32（4）：342-349.
90吴晓梅,王欣燕,陈复辉.两种细胞因子与特发性肺纤维化的关系[J].中国危重病急救医学,2003,15(6):362-364.
91王献华，郝小惠，赵静，等. SiO2对血小板源性生长因子蛋白表达及胶原合成的影响［J］.中华劳动卫生职业病杂志，2009，27（4）:218-221.
92Zhuo Y，Zhang J，Laboy M，et al. Modulation of PDGF-C and PDGF-D expression duringbleomycin-induced lung fibrosis ［J］.Am J Physiol Lung Cell Mol Physiol，2004，286（1）：L182-L188.
93李莉，李燕芹.格列卫对博莱霉素致小鼠肺纤维化的干预作用［J］.中国危重病急救医学，2007，19（4）：229-232.
94Selman M, Thannickal VJ, Pardo A,et al. Idiopathic pulmonary fibrosis: Pathogenesisand therapeutic approaches[J].Drugs,2004;64:405-430.
95Majumdar S,Li D,Ansari T,et al.Different cytokine profiles in cryptogenic fibrosingalveolitis and fibrosing alveolitis associat2ed with systemic sclerosis:aquantitative study of open lung biopsies[J]. Eur Respir J,1999;14:251-257.
96Segel MJ,Izbicki G,Cohen PY,et al. Role of interferon2gamma in the evolution ofmurine bleomycin lung fibrosis[J].AmJ Physiol Lung Cell Mol Physiol，2003,285：1255-1262.
97Chen ES, Greenlee BM, Wills-Karp M, et al. Attenuation of lung inflammation andfibrosis in interferon-gamma-deficient mice after intratracheal bleomycin [J].AmJRespir Cell Mol Biol,2001,24:545-555.
98Guzzman RC, Osborn RC, Richards JE, et al. Effects of phorbol esters on normal andtumorous mouse mammary epithelial cells epithelial in collagen gels[J]. J.NatlCancer Inst,1983,71:69-72.
99Emmrieh J，Weber l，Sparmann GH，et al. Aetivation of panereatie of pancreatic stellatecells in experimental chronic panereatitis in rats [J]. Gastroen-terology,2000,118:A166.
100孙慧敏,张晓红,袁佳琴,等.肿瘤坏死因子-A和转化生长因子-B2对牛晶状体上皮细胞分化的影响[J].中华眼科杂志，2002，3（11）：697-698.
101Sedlaczek N，Jia JD，Bauer M，et a1．Proliferating bile duct epithelial cells area major source of connective tissue growth factor in rat biliary fibrosis [J]．AmJ Pathol，2001，158：1239—1244．
102FRAZIER K,WILLIAMS S,KOTHAPALLI D,et al.Stimulation of fibroblast cellgrowth,matrix production,and granulation tissue formation by connective tissuegrowth factor[J].J Invest Dermatol,1996,107(3):404-411.
103王延叶,李荣山.TGF-B1PSmad与肾脏间质纤维化[J].国外医学泌尿系统分册,2005,25(6):840-843.
104邢静萍,陈楠. Smad与肾纤维化[J].中国中西医结合肾病杂志,2005,6(5):302-304.
105Quillard T et al. Inflammation dysregulates Notch signaling in endothelial cells:Implicationof Notch2and Notch4to endothelial dysfunction[J]. BiochemicalPharmacology,2010,80:2032-2041.
106Aoyaqi-ikeda K et al. Notch induces myofibroblast differentiation of alveolarepithelial cells via TGF-ss/Smad3pathway[J]. Am J Respir Cell Mol Biol,2011,45:136-144.
107Fitau J et al. The adaptor molecule Lnk negatively regulates tumor necrosisfactor-a-dependent VCAM-1expression in endothelial cells through inhibition ofthe ERK1and-2pathways[J]. J Biol Chem,2006,281:20148-20159.
108Hashimoto S，Gon Y，Takeshita I，et al． Transforming growth Factor－beta1inducesphenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-termi nal kinase-dependent pathway.Am J Respir Crit Care Med，2001，163（1）：152-157．
109Zhang A，Ding Q，Huang S，et al． c-Jun NH2-terminal kinase mediation of angiotensinⅡ-induced proliferation of human mesangial cells． Am J Physiol Renal Physiol，2005，288（6）：1118-1124．
110胡月媛，刘学军，杜毓锋,等. JNK信号通路对大鼠肺纤维化Ι型胶原的影响[J],中国药物与临床,2012,12(3):306-307.
111刘素娟，邢玲玲，李建英，等.细胞因子信号转导抑制蛋白-1对白介素-1β诱导的人肾小管上皮细胞转分化的影响[J].中国细胞生物学学报，2012,34（1）：41-48.
112程石，宋茂民，史敬东．核因子kappa B活化对急性坏死性胰腺炎肺泡巨噬细胞炎症介质表达的影响及意义[J]．中华肝胆外科杂志，2006，12(11)764—766．
113Syed MM，Phulwani NK，Kielian T．Tumor necrosis factor-alpha (TNF-alpha) regulatesToll-like receptor2(TLR2)expression in micmglia[J]．J Neurochem，2007，103(4)：l46l-l471．
114Hayden MS，Ghosh S．Signaling to NF—kappaB[J]．GenesDev，2004．18(18)：2195-2224．
115董瑞,马庆久,王青,等.炎性相关刺激因子诱导乳腺癌上皮间质转分化的机制[J].医学研究生学报,2010,23(1):17-20.
116Baluk P, Yao LC, Feng J, Romano T, Jung SS, et al.(2009) TNF-alpha drives remodelingof blood vessels and lymphatics in sustained airway inflammation inmice[J]. J ClinInvest119:2954-2964.
117Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, et al.(2006) Evidenceof a roleof tumor necrosis factor alpha in refractory asthma[J]. N Engl J Med354:697-708.
118Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, et al.(2005) Tumour necrosis factor(TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependentasthma[J]. Thorax60:1012-1018.
119Lin J, Liliensiek B, Kanitz M, Schimanski U, Bohrer H, et al.(1998) Molecular cloningof genes differentially regulated by TNF-alpha in bovine aortic endothelial cells,fibroblasts and smooth muscle cells[J]. Cardiovasc Res38:802-813.
120Xie S, Sukkar MB, Issa R, Oltmanns U, Nicholson AG, et al.(2005) Regulation ofTGF-beta1-induced connective tissue growth factor expression in airway smoothmuscle cells[J]. Am J Physiol Lung Cell Mol Physiol288: L68-76.
121Blom IE, Goldschmeding R, Leask A (2002) Gene regulation of connective tissue growthfactor: new targets for antifibrotic therapy?[J].Matrix Biol21:473-482.
122曾莉,徐庆,陈卫平,等.活血通腑方优选方对TNF-α诱导下腹膜间皮细胞TGF-β1、FN、CTGF蛋白含量的影响[J].南京中医药大学学报，2008,24（5）：324-326.
123Frazier KS, Seely JC, Hard GC，et al. Proliferative and nonproliferative lesions ofthe rat and mouse urinary system[J]. Toxicologic pathology,2012,40(4Suppl):14S-86S.
124杨磊，赵飞艳，王凤龙，等.肿瘤坏死因子-α对奶牛乳腺成纤维细胞增殖的影响[J].黑龙江畜牧兽医，2010,356（5）：20-22.
125章建林. TNF及其受体基因在增生性瘢痕中的动态表达及其意义研究[D]第二军医大学博士学位论文，2002.
126张勉之. TNF-α对肾间质纤维化细胞表型变化的作用及补肾活血法中药对肾小管上皮细胞转分化的抑制作用.[D]河北医科大学博士毕业论文，2004.
127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.
128Iredale J P, Benyon R C, Pichering J, et al. Mechanisms of spontaneous resolutionof rat liver fibrosis: Hepatic stellate cell apoptosis and reduced hepatic expressionof metalloproteinase inhibitors [J]. Clin Invest,1998,102（3）：538-549.
129周俊英,甄真,姚树坤.肝星状细胞凋亡与肝纤维化逆转[J].国内外医学分册，2004,9:403-406.
130Voloshenyuk TG，Hart AD，Khoutorova E，et al. TNF-α increases cardiac fibroblastlysyl oxidase expression through TGF-β and PI3Kinase signaling pathways [J]. BiochemBiophys Res Commun，2011，413（2）：370-375.
131王敬春,徐波,张春.生脉饮对TNF-α诱导的大鼠心肌成纤维细胞胶原合成的影响[J].中国医药导报，2012,9（34）：24-26.
132吴颖芳，彭解英，方厂云. TNF-α和IFN-γ对OSF成纤维细胞胶原合成的影响[J].中国现代医学杂志，2005，15（12）：1803-1805.
133陈厚文,郭梦舟,陈琦,等. T N F-α和IL-13对人肺成纤维细胞胶原蛋白生成的影响[J].中国细胞生物学学报，20ll,33(6):667一73.
134Boguniewicz M, Martin RJ, Martin D, Gibson U, Celniker A, et al. The effects ofnebulized recombinant interferon-gamma in asthmatic airways[J].J Allergy ClinImmunol,1995,95:133-135.
135曾军,杨镇.肝星状细胞、相关因子与肝纤维化关系的研究进展[J].中华肝胆外科杂志,2005,11(6):427-429.
136Gurujeyalakshmi G, Giri SN.Molecular mechanisms of antifibrotic effect of interferongamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta andprocollagen I and III gene expression[J]. Exp Lung Res,1995,21:791-808.
137Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH A preliminarystudy of long-term treatment with interferon gamma-1b and low-dose prednisolone inpatients with idiopathic pulmonary fibrosis[J]. N Engl J Med,1999,341:1264-1269.
138Friesel R, Komoriya A, Maciag T. Inhibition of endothelial cell proliferation bygamma-interferon[J]. J Cell Biol,1987,104:689-696.
139Fitzner B, Brock P, Nechutova H, et al. Inhibitory effects of interferon-gamma onactivation of rat pancreatic stellate cells are mediated by STAT1and involvedown-regulation of CTGF expression[J]. Cell Signal,2007,19:782-790.
140Li Q, Fan JM, Pu L, et al. Effects of interferon-gamma on tubular epithelial-myofibroblast transdifferentiation in vitro[J]. Sichuan Da Xue Xue Bao Yi XueBan,2008,39:895-899.
141Liu JQ, Hu DH, Zhang ZF, et al. Effects of interferongamma on the transforming growthfactor beta/Smad pathway in keloid-derived fibroblasts[J]. Zhonghua Shao Shang ZaZhi,2009,25:454-459.
142张德平,庄谊,孟凡清,等. γ干扰素对实验性肺纤维化大鼠肺泡炎和肺纤维化的影响[J].中国呼吸与危重监护杂志,2006,5(3):189-192.
143杨磊.奶牛乳腺炎乳汁三种细胞因子检测及TNF-α对乳腺细胞凋亡和增殖的影响[D].内蒙古农业大学硕士论文，2010.
144丁旭娜.TGF-β1、bFGF和PDGF在奶牛乳腺纤维化中作用的研究[D].内蒙古农业大学博士论文，2012.
145Parapuram SK, Chang B, Li L, et al. Differential effects of TGFβ and Vitreous onthe transformation of retinal pigment epithelial cells[J]. Invest Ophthalmol VisSci,2009,50(12):5965-5974.
146Stewart RJ, Kashour TS, Marsden PA Vascular endothelial platelet endothelial adhesionmolecule-1(PECAM-1) expression is decreased by TNF-alpha and IFN-gamma. Evidencefor cytokine-induced destabilization of messenger ribonucleic acid transcripts inbovine endothelial cells[J]. J Immunol1996，156:1221-1228.
147Matsuda A, Fukuda S, Matsumoto K, Saito H Th1/Th2cytokines reciprocally regulatein vitro pulmonary angiogenesis via CXC chemokine synthesis[J]. Am J Respir CellMol Biol,2008,38:168-175.
148Drew PD, Franzoso G, Becker KG, Bours V, Carlson LM, et al. NF kappa B and interferonregulatory factor1physically interact and synergistically induce majorhistocompatibility class I gene expression[J]. J Interferon Cytokine Res,1995,15:1037-1045.
149Liu X, Wu W, Chen H Effects of CTGF gene silencing on the proliferation andmyofibroblast differentiation of human lung fibroblasts[J]. Sheng Wu Yi Xue GongCheng Xue Za Zhi,2008,25:407-412.
150Roderich Laug, Markus Fehrholz, Norbert Schutze,et al. IFN-c and TNF-a Synergizeto Inhibit CTGF Expression in Human Lung Endothelial Cells[J].PLOS ONE,2012,7(9):1-10.