姜黄素对口腔黏膜下纤维性变SD大鼠模型抗纤维化作用及机制的研究
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摘要
背景与目的
口腔黏膜下纤维性变(oral submucous fibrosis, OSF)是发生于口腔黏膜的一种慢性、隐匿性疾病,其发病与咀嚼槟榔习惯关系密切,已经被世界卫生组织定义为癌前状态。与其他纤维化疾病一样,OSF目前尚无特效的治疗方法。同时合适动物模型的缺乏已经制约了对其具体病因、发病机制及治疗方法的进一步研究。
姜黄素是中药姜黄的主要活性成分,已有报道称其具有较好的抗纤维化的作用。本研究拟通过局部注射博来霉素(Bleomycin, BLM)制备出重复性较好的OSF动物模型,然后在此基础上结合体外实验探讨姜黄素用于治疗OSF的可行性及作用机理。
方法
首先,进行动物模型的制备。SD大鼠100只,随机分为正常组、对照组和实验组。实验组大鼠在异氟烷的麻醉状态下,于双侧颊黏膜下注射BLM稀释液,每天一次,共持续八周。对照组采用磷酸盐缓冲液(Phosphate Buffered Saline, PBS)代替BLM稀释液。正常组不给任何干预。在规定时间处死大鼠后,采用HE染色、masson染色、羟脯氨酸碱水解法、免疫组化、western blotting及透射电镜分别检测各组大鼠颊黏膜组织病理、胶原水平、肌成纤维细胞(myofibroblast, MFB)、TGF-β1、IFN-γ及超微结构的变化情况。
然后,SD大鼠35只,随机分为正常组、对照组、低剂量姜黄素组和高剂量姜黄素组。正常组大鼠不给予任何干预。其余大鼠在颊黏膜局部注射BLM4周后,采用不同剂量的姜黄素模型大鼠进行灌胃4周。大鼠处死后,采用HE染色、免疫组化和western blotting观察其颊黏膜组织病理、MFB、胶原水平、TGF-β1、 IFN-y和IL-13的表达水平。
最后,采用体外细胞原代培养的方法,培养人正常颊黏膜成纤维细胞(fibroblast, FB),并利用TGF-β1将其诱导成为MFB表型。不同浓度姜黄素干预后,利用MTT、流式细胞术、western blotting及ELISA分别观察细胞增殖、细胞周期、凋亡、相关凋亡蛋白及上清液中Ⅰ、Ⅲ型胶原的改变。
结果
1、SD大鼠颊黏膜局部注射1mg/ml的BLM8周可以诱导出临床和病理上与人OSF相似的改变；
2、较高剂量姜黄素可以降低BLM局部注射4周(病理改变接近人OSF早、中期)的SD大鼠颊黏膜组织中TGF-β1和IL-13的表达,提高IFN-y的表达,减少MFB；但对Ⅰ、Ⅲ型胶原的改变不明显；
3、2.5-40μM的姜黄素可以抑制体外培养的FB和MFB增殖,且对MFB的抑制作用更加明显,并且将MFB阻滞在G0/G1期。10-40μM的姜黄素可以诱导MFB凋亡,提高Bax蛋白的表达,降低Bcl-2蛋白的表达,降低其上清液中Ⅰ、Ⅲ型胶原的表达水平。
结论
1、SD大鼠颊黏膜局部注射1mg/ml的BLM8周可以制备出类似人OSF病变的实验性OSF大鼠模型；该模型制作快捷,重复性好,但仍然存在一定的局限性。
2、姜黄素可以改善lmg/ml BLM颊黏膜局部注射4周的(病理改变接近人OSF早、中期)SD大鼠的张口度,降低主要致纤维化细胞因子TGF-β1的表达,阻止纤维化的进一步发展；
3、在体外姜黄素可以通过抑制MFB增殖,促进其凋亡,减少Ⅰ、Ⅲ型胶原生成,发挥抗纤维化作用。
Background and Objective
Oral submucous fibrosis (OSF) is a chronic and concealed disease of oral mucosa. It is closely related to betel quid (BQ) chewing habit and has been defined by WHO as one of the precancerous conditions. The same as other fibrotic diseases, there is still no definitive and effective treatment for OSF in the moment. The shortage of satisfied animal model of OSF has become a bottleneck slowing down the researches on the pathogeny, pathogenesis and clinical treatment of OSF.
Curcumin is the primary active substance isolated from Curcuma Longa L. rhizome, and has been reported as an anti-fibrotic drug. Regard this as the starting point, we expected to create a stable and reliable animal model of OSF by locally injecting bleomycin (BLM), and then explored the feasibility of treatment with curcumin for OSF combined with in vivo and vitro experiment.
Methods
Firstly,100Sprague-Dawley (SD) rats were randomly divided into3groups. Rats in the experimental group were injected BLM diluent to the bilateral buccal mucous membrane, once a day for8weeks, when they were under Isoflurane (inhalation) anesthesia. Rats in the control group were injected PBS instead of BLM diluents. Rats in the normal group did not receive any intervention. After the rats were executed, HE staining, masson staining, the soda hydrolysis in the measurement of hydroxyproline, immunohistochemistry, western blotting and transmission electron microscope were used to detect the changes of the histopathological features, levels of collagens, myofibroblast (MFB), TGF-β1、IFN-γ and ultrastructure.
Secondly,35SD rats were randomly divided into4groups. Rats in the normal group did not receive any intervention. Rats in the control group, high curcumin group and low curcumin group were injected BLM diluent to the bilateral buccal mucous membrane, once a day for4weeks. Then curcumin solution of different dosages was given to the30rats by gavages, once a day for4weeks. After all the rats were executed, HE staining, immunohistochemistry and western blotting were used to detect the changes of the histopathological features, levels of collagens, MFB, TGF-β1、IFN-γ and IL-13.
Thirdly, MFB were generated by incubating fibroblasts, obtained from human oral mucosa, with TGF-β1. MTT, PI staining, and FACS assays were used to investigate curcumin's effect on proliferation and cell cycle of fibroblast (FB) and MFB. Annexin V/PI binding and FACS assays were used to examine apoptosis of MFB, western blotting to determine the levels of Bcl-2and Bax, and enzyme-linked immunosorbant assay was employed to examine the levels of collagen type Ⅰ and Ⅲ in the supernatants of myofibroblasts.
Results
1、Local injection of1mg/ml BLM diluent to the bilateral buccal mucous membrane of SD rats, once a day for8weeks, can create similar changes with human OSF in many ways of clinical symptoms and histopathological changes.
2、The higher doses of curcumin decreased the expression of TGF-β1and IL-13, increased the expression of IFN-y and reduced MFB in the bucal mucous of the rats which were injected BLM diluents for4weeks. The levels of type Ⅰ,Ⅲ collagens had no significant change.
3、Curcumin of2.5-40μmol/L inhibited proliferation of FB and MFB; MFB are more sensitive to curcumin than FB. Curcumin of10-40μmol/L also disturbed the cell cycle, induced apoptosis and decreases the generation of collagen type I and III in MFB. Curcumin induces apoptosis in MFB by down-regulating Bcl-2/Bax ratio.
Conclusions
1、Local injection of lmg/ml BLM diluent to the bilateral buccal mucous membrane of SD rats, once a day for8weeks, can create an experimental rat model of OSF. This model was of good repeatability and can be conveniently made. But there were still some defects in it.
2、Curcumin can improve the mouth opening degree of the model rats, decreases the expression of TGF-β1, and prevent the further development of fibrosis.
3. Curcumin play an anti-fibrosis role in vitro by inhibitting MFB proliferation, inducing apoptosis and decreasing the generation of collagen type Ⅰ and Ⅲ.
口腔黏膜下纤维性变(oral submucous fibrosis, OSF)是发生于口腔黏膜的一种慢性、隐匿性疾病,其发病与咀嚼槟榔习惯关系密切,已经被世界卫生组织定义为癌前状态。与其他纤维化疾病一样,OSF目前尚无特效的治疗方法。同时合适动物模型的缺乏已经制约了对其具体病因、发病机制及治疗方法的进一步研究。
姜黄素是中药姜黄的主要活性成分,已有报道称其具有较好的抗纤维化的作用。本研究拟通过局部注射博来霉素(Bleomycin, BLM)制备出重复性较好的OSF动物模型,然后在此基础上结合体外实验探讨姜黄素用于治疗OSF的可行性及作用机理。
方法
首先,进行动物模型的制备。SD大鼠100只,随机分为正常组、对照组和实验组。实验组大鼠在异氟烷的麻醉状态下,于双侧颊黏膜下注射BLM稀释液,每天一次,共持续八周。对照组采用磷酸盐缓冲液(Phosphate Buffered Saline, PBS)代替BLM稀释液。正常组不给任何干预。在规定时间处死大鼠后,采用HE染色、masson染色、羟脯氨酸碱水解法、免疫组化、western blotting及透射电镜分别检测各组大鼠颊黏膜组织病理、胶原水平、肌成纤维细胞(myofibroblast, MFB)、TGF-β1、IFN-γ及超微结构的变化情况。
然后,SD大鼠35只,随机分为正常组、对照组、低剂量姜黄素组和高剂量姜黄素组。正常组大鼠不给予任何干预。其余大鼠在颊黏膜局部注射BLM4周后,采用不同剂量的姜黄素模型大鼠进行灌胃4周。大鼠处死后,采用HE染色、免疫组化和western blotting观察其颊黏膜组织病理、MFB、胶原水平、TGF-β1、 IFN-y和IL-13的表达水平。
最后,采用体外细胞原代培养的方法,培养人正常颊黏膜成纤维细胞(fibroblast, FB),并利用TGF-β1将其诱导成为MFB表型。不同浓度姜黄素干预后,利用MTT、流式细胞术、western blotting及ELISA分别观察细胞增殖、细胞周期、凋亡、相关凋亡蛋白及上清液中Ⅰ、Ⅲ型胶原的改变。
结果
1、SD大鼠颊黏膜局部注射1mg/ml的BLM8周可以诱导出临床和病理上与人OSF相似的改变；
2、较高剂量姜黄素可以降低BLM局部注射4周(病理改变接近人OSF早、中期)的SD大鼠颊黏膜组织中TGF-β1和IL-13的表达,提高IFN-y的表达,减少MFB；但对Ⅰ、Ⅲ型胶原的改变不明显；
3、2.5-40μM的姜黄素可以抑制体外培养的FB和MFB增殖,且对MFB的抑制作用更加明显,并且将MFB阻滞在G0/G1期。10-40μM的姜黄素可以诱导MFB凋亡,提高Bax蛋白的表达,降低Bcl-2蛋白的表达,降低其上清液中Ⅰ、Ⅲ型胶原的表达水平。
结论
1、SD大鼠颊黏膜局部注射1mg/ml的BLM8周可以制备出类似人OSF病变的实验性OSF大鼠模型；该模型制作快捷,重复性好,但仍然存在一定的局限性。
2、姜黄素可以改善lmg/ml BLM颊黏膜局部注射4周的(病理改变接近人OSF早、中期)SD大鼠的张口度,降低主要致纤维化细胞因子TGF-β1的表达,阻止纤维化的进一步发展；
3、在体外姜黄素可以通过抑制MFB增殖,促进其凋亡,减少Ⅰ、Ⅲ型胶原生成,发挥抗纤维化作用。
Background and Objective
Oral submucous fibrosis (OSF) is a chronic and concealed disease of oral mucosa. It is closely related to betel quid (BQ) chewing habit and has been defined by WHO as one of the precancerous conditions. The same as other fibrotic diseases, there is still no definitive and effective treatment for OSF in the moment. The shortage of satisfied animal model of OSF has become a bottleneck slowing down the researches on the pathogeny, pathogenesis and clinical treatment of OSF.
Curcumin is the primary active substance isolated from Curcuma Longa L. rhizome, and has been reported as an anti-fibrotic drug. Regard this as the starting point, we expected to create a stable and reliable animal model of OSF by locally injecting bleomycin (BLM), and then explored the feasibility of treatment with curcumin for OSF combined with in vivo and vitro experiment.
Methods
Firstly,100Sprague-Dawley (SD) rats were randomly divided into3groups. Rats in the experimental group were injected BLM diluent to the bilateral buccal mucous membrane, once a day for8weeks, when they were under Isoflurane (inhalation) anesthesia. Rats in the control group were injected PBS instead of BLM diluents. Rats in the normal group did not receive any intervention. After the rats were executed, HE staining, masson staining, the soda hydrolysis in the measurement of hydroxyproline, immunohistochemistry, western blotting and transmission electron microscope were used to detect the changes of the histopathological features, levels of collagens, myofibroblast (MFB), TGF-β1、IFN-γ and ultrastructure.
Secondly,35SD rats were randomly divided into4groups. Rats in the normal group did not receive any intervention. Rats in the control group, high curcumin group and low curcumin group were injected BLM diluent to the bilateral buccal mucous membrane, once a day for4weeks. Then curcumin solution of different dosages was given to the30rats by gavages, once a day for4weeks. After all the rats were executed, HE staining, immunohistochemistry and western blotting were used to detect the changes of the histopathological features, levels of collagens, MFB, TGF-β1、IFN-γ and IL-13.
Thirdly, MFB were generated by incubating fibroblasts, obtained from human oral mucosa, with TGF-β1. MTT, PI staining, and FACS assays were used to investigate curcumin's effect on proliferation and cell cycle of fibroblast (FB) and MFB. Annexin V/PI binding and FACS assays were used to examine apoptosis of MFB, western blotting to determine the levels of Bcl-2and Bax, and enzyme-linked immunosorbant assay was employed to examine the levels of collagen type Ⅰ and Ⅲ in the supernatants of myofibroblasts.
Results
1、Local injection of1mg/ml BLM diluent to the bilateral buccal mucous membrane of SD rats, once a day for8weeks, can create similar changes with human OSF in many ways of clinical symptoms and histopathological changes.
2、The higher doses of curcumin decreased the expression of TGF-β1and IL-13, increased the expression of IFN-y and reduced MFB in the bucal mucous of the rats which were injected BLM diluents for4weeks. The levels of type Ⅰ,Ⅲ collagens had no significant change.
3、Curcumin of2.5-40μmol/L inhibited proliferation of FB and MFB; MFB are more sensitive to curcumin than FB. Curcumin of10-40μmol/L also disturbed the cell cycle, induced apoptosis and decreases the generation of collagen type I and III in MFB. Curcumin induces apoptosis in MFB by down-regulating Bcl-2/Bax ratio.
Conclusions
1、Local injection of lmg/ml BLM diluent to the bilateral buccal mucous membrane of SD rats, once a day for8weeks, can create an experimental rat model of OSF. This model was of good repeatability and can be conveniently made. But there were still some defects in it.
2、Curcumin can improve the mouth opening degree of the model rats, decreases the expression of TGF-β1, and prevent the further development of fibrosis.
3. Curcumin play an anti-fibrosis role in vitro by inhibitting MFB proliferation, inducing apoptosis and decreasing the generation of collagen type Ⅰ and Ⅲ.
引文
[1]WORLD HEALTH ORGANIZATION, International Agency for Research on Cancer. WHO classification of tumors:pathology and genetics of head and neck tumors [M]. IARC Press,2005.
[2]ARIYAWARDANA A, ATHUKORALA A D, ARULANANDAM A. Effect of betel chewing, tobacco smoking and alcohol consumption on oral submucous fibrosis: a case-control study in Sri Lanka [J]. J Oral Pathol Med,2006,35(4):197-201.
[3]HAIDER S M, MERCHANT A T, FIKREE F F, et al. Clinical and functional staging of oral submucous fibrosis [J]. Br J Oral Maxillofac Surg,2000,38(1):12-5.
[4]RANGANATHAN K, DEVI M U, JOSHUA E, et al. Oral submucous fibrosis:a case-control study in Chennai, South India [J]. J Oral Pathol Med,2004,33(5):274-7.
[5]JACOB B J, STRAIF K, THOMAS G, et al. Betel quid without tobacco as a risk factor for oral precancers [J]. Oral Oncol,2004,40(7):697-704.
[6]YANG Y H, LIEN Y C, HO P S, et al. The effects of chewing areca/betel quid with and without cigarette smoking on oral submucous fibrosis and oral mucosal lesions [J]. Oral Dis,2005,11(2):88-94.
[7]张姗姗,凌天牖,贺达仁.槟榔时尚与疾病[J].医学与哲学(人文社会医学版),2010,(10)：42-3+8.
[8]RAJALALITHA P, VALI S. Molecular pathogenesis of oral submucous fibrosis--a collagen metabolic disorder [J]. J Oral Pathol Med,2005,34(6):321-8.
[9]UTSUNOMIYA H, TILAKARATNE W M, OSHIRO K, et al. Extracellular matrix remodeling in oral submucous fibrosis:its stage-specific modes revealed by immunohistochemistry and in situ hybridization [J]. J Oral Pathol Med,2005,34(8): 498-507.
[10]JIANG X, HU J. Drug treatment of oral submucous fibrosis:a review of the literature [J]. J Oral Maxillofac Surg,2009,67(7):1510-5.
[11]FEDOROWICZ Z, CHAN SHIH-YEN E, DORRI M, et al. Interventions for the management of oral submucous fibrosis [J]. Cochrane Database Syst Rev,2008,8(4): CD007156.
[12]SIRS AT S M, KHANOLKAR V R. Submucous fibrosis of the palate. Induction by local painting of capsaicin in Wistar rats treated with desoxycorticosterone acetate--an optical and electron microscopic study [J]. Arch Pathol,1960,70:180-7.
[13]SIRS AT S M, KHANOLKAR V R. Submucous fibrosis of the palate in diet-preconditioned Wistar rats. Induction by local painting of capsaicin--an optical and electron microscopic study [J]. Arch Pathol,1960,70:171-9.
[14]SIRS AT S M, KHANOLKAR V R. The effect of arecoline on the palatal and buccal mucosa of the Wistar rat. An optical and electron microscope study [J]. Indian J Med Sci,1962,16:198-202.
[15]MACDONALD D G. Effects of arecaidine application to hamster cheek pouch [J]. J Oral Med,1987,42(1):61-2.
[16]KHRIME R D, MEHRA Y N, MANN S B, et al. Effect of instant preparation of betel nut (pan masala) on the oral mucosa of albino rats [J]. Indian J Med Res,1991, 94:119-24.
[17]SUMETH PERERA M W, GUNASINGHE D, PERERA P A, et al. Development of an in vivo mouse model to study oral submucous fibrosis [J]. J Oral Pathol Med, 2007,36(5):273-80.
[18]王燕,王真,何琪杨.博来霉素族抗生素作用机制的研究进展[J].国外医药(抗生素分册),2009,(1)：5-8+18.
[19]CHAUDHARY N I, SCHNAPP A, PARK J E. Pharmacologic differentiation of inflammation and fibrosis in the rat bleomycin model [J]. Am J Respir Crit Care Med, 2006,173(7):769-76.
[20]USUKI J, FUKUDA Y. Evolution of three patterns of intra-alveolar fibrosis produced by bleomycin in rats [J]. Pathol Int,1995,45(8):552-64.
[21]CHUA F, GAULDIE J, LAURENT G J. Pulmonary fibrosis:searching for model answers [J]. Am J Respir Cell Mol Biol,2005,33(1):9-13.
[22]ABRAHAM D J, VARGA J. Scleroderma:from cell and molecular mechanisms to disease models [J]. Trends Immunol,2005,26(11):587-95.
[23]巫婷婷,周京国.硬皮病动物模型及其应用研究进展[J].动物医学进展,2008,(2)：102-5.
[24]YAMAMOTO T, TAKAGAWA S, KATAYAMA I, et al. Animal model of sclerotic skin. I:Local injections of bleomycin induce sclerotic skin mimicking scleroderma [J]. J Invest Dermatol,1999,112(4):456-62.
[25]YAMAMOTO T, TAKAHASHI Y, TAKAGAWA S, et al. Animal model of sclerotic skin. II. Bleomycin induced scleroderma in genetically mast cell deficient WBB6F1-W/W(V) mice [J]. J Rheumatol,1999,26(12):2628-34.
[26]BAGCHI M, BALMOORI J, BAGCHI D, et al. Role of reactive oxygen species in the development of cytotoxicity with various forms of chewing tobacco and pan masala [J]. Toxicology,2002,179(3):247-55.
[27]WILLIAMS M S, KWON J. T cell receptor stimulation, reactive oxygen species, and cell signaling [J]. Free Radic Biol Med,2004,37(8):1144-51.
[28]翦新春,郑廉.口腔黏膜下纤维性变研究进展[J].中国实用口腔科杂志,2011,(2)：65-8.
[29]POWELL D W, MIFFLIN R C, VALENTICH J D, et al. Myofibroblasts. I. Paracrine cells important in health and disease [J]. Am J Physiol,1999,277(1 Pt 1): C1-9.
[30]WYNN T A. Cellular and molecular mechanisms of fibrosis [J]. J Pathol,2008, 214(2):199-210.
[31]李霞,凌天牖,高义军a-Sma在口腔粘膜下纤维性变成纤维细胞中的表达[J].中国免疫学杂志,2007,(9)：851-6.
[32]ANGADI P V, KALE A D, HALLIKERIMATH S. Evaluation of myofibroblasts in oral submucous fibrosis:correlation with disease severity [J]. J Oral Pathol Med, 2011,40(3):208-13.
[33]张姗姗,凌天牖HGF/c-met在口腔黏膜下纤维化组织中表达的研究[J].实用口腔医学杂志,2012,(1)：110-3.
[34]HAQUE M F, HARRIS M, MEGHJI S, et al. Immunolocalization of cytokines and growth factors in oral submucous fibrosis [J]. Cytokine,1998,10(9):713-9.
[35]PINDBORG J J, MEHTA F S, GUPTA P C, et al. Prevalence of oral submucous fibrosis among 50,915 Indian villagers [J]. Br J Cancer,1968,22(4):646-54.
[36]中华口腔医学会口腔黏膜病专业委员会,口腔黏膜下纤维性变的诊断标准(试行稿)[J].,2009,44(3)：2.
[37]PINDBORG J J, SIRSAT S M. Oral submucous fibrosis [J]. Oral Surg Oral Med Oral Pathol,1966,22(6):764-79.
[38]KAMATA Y, ITOH Y, KAJIYA A, et al. Quantification of neutral cysteine protease bleomycin hydrolase and its localization in rat tissues [J]. J Biochem,2007, 141(1):69-76.
[39]张自强,赵东旭,杨新林.羟脯氨酸的研究与开发[J].氨基酸和生物资源,2006,(1)：55-8+62.
[40]胥红,刘蜀凡,沈子华,等.口腔粘膜下纤维性变组织中Ⅰ型和Ⅲ型胶原免疫组化及定量分析[J].实用口腔医学杂志,2000,(1)：52-4.
[41]PHAN S H. Biology of fibroblasts and myofibroblasts [J]. Proc Am Thorac Soc, 2008,5(3):334-7.
[42]WATSKY M A, WEBER K T, SUN Y, et al. New insights into the mechanism of fibroblast to myofibroblast transformation and associated pathologies [J]. Int Rev Cell Mol Biol,2010,282:165-92.
[43]YANJIA H, XINCHUN J. The role of epithelial-mesenchymal transition in oral squamous cell carcinoma and oral submucous fibrosis [J]. Clin Chim Acta,2007, 383(1-2):51-6.
[44]张姗姗,凌天牖.成纤维细胞、肌成纤维细胞与口腔黏膜下纤维性变[J].临床口腔医学杂志,2012,(2)：118-20.
[45]PHAN S H, KUNKEL S L. Lung cytokine production in bleomycin-induced pulmonary fibrosis [J]. Exp Lung Res,1992,18(1):29-43.
[46]RAGHOW B, IRISH P, KANG A H. Coordinate regulation of transforming growth factor beta gene expression and cell proliferation in hamster lungs undergoing bleomycin-induced pulmonary fibrosis [J]. J Clin Invest,1989,84(6):1836-42.
[47]BAECHER-ALLAN C M, BARTH R K. PCR analysis of cytokine induction profiles associated with mouse strain variation in susceptibility to pulmonary fibrosis [J]. Reg Immunol,1993,5(3-4):207-17.
[48]ZHANG K, FLANDERS K C, PHAN S H. Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis [J]. Am J Pathol,1995,147(2):352-61.
[49]高义军,凌天牖,吴汉江,等.口腔粘膜下纤维性变组织中转化生长因子β_1mRNA表达水平[J].华西口腔医学杂志,1996,(1)：20-2+34+77.
[50]邱慧张.干扰素-γ治疗特发性肺纤维化的研究进展[J].国外医学呼吸系统分册,2005,(5)：376-9.
[51]ULLOA L, DOODY J, MASS AGUE J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway [J]. Nature, 1999,397(6721):710-3.
[52]STRIETER R M. Mechanisms of pulmonary fibrosis:conference summary [J]. Chest,2001,120(1 Suppl):77S-85S.
[53]GURUJEYALAKSHMI G, GIRI S N. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression [J]. Exp Lung Res,1995,21(5):791-808.
[54]胥红,彭解英,刘蜀凡,等.口腔粘膜下纤维性变中胶原纤维的超微结构研究[J].临床口腔医学杂志,1998,(3)：172-4.
[55]胥红,刘蜀凡,沈子华,等.口腔粘膜下纤维性变中成纤维细胞的超微结构 观察[J].临床口腔医学杂志,2000,(1)：8-9.
[56]刘蜀藩,彭解英,沈子华,等.口腔粘膜下纤维性变中毛细血管损伤的超微结构研究[J].中华口腔医学杂志,1999,(2)：46.
[57]司静懿,韩日才,李昆,等.口腔粘膜下纤维变病理发生的超微结构研究[J].电子显微学报,1993,(1)：65.
[58]苏葵,刘蜀藩,沈子华,等.肥大细胞与口腔粘膜下纤维性变的超微结构研究[J].湖南医科大学学报,1995,(4)：327-9.
[59]SABARINATH B, SRIRAM G, SARASWATHI T R, et al. Immunohistochemical evaluation of mast cells and vascular endothelial proliferation in oral submucous fibrosis [J]. Indian J Dent Res,2011,22(1):116-21.
[60]GUPTA P C, WARNAKULASURIYA S. Global epidemiology of areca nut usage [J]. Addict Biol,2002,7(1):77-83.
[61]KO Y C, CHIANG T A, CHANG S J, et al. Prevalence of betel quid chewing habit in Taiwan and related sociodemographic factors [J]. J Oral Pathol Med,1992, 21(6):261-4.
[62]LEE C H, KO A M, WARNAKULASURIYA S, et al. Intercountry prevalences and practices of betel-quid use in south, southeast and eastern Asia regions and associated oral preneoplastic disorders:an international collaborative study by Asian betel-quid consortium of south and east Asia [J]. Int J Cancer,2011,129(7):1741-51.
[63]ZHANG S S, LI W H, GAO Y J, et al. Betel-quid and oral submucous fibrosis:a cross-sectional study in Hunan province, China [J]. J Oral Pathol Med,2012,
[64]高义军,彭海艳,尹晓敏,等.湖南省娄底市城区中小学生嚼槟榔情况调查[J].中华口腔医学杂志,2009,44(11)：686-89.
[65]ZHANG X, REICHART P A. A review of betel quid chewing, oral cancer and precancer in Mainland China [J]. Oral Oncol,2007,43(5):424-30.
[66]TILAKARATNE W M, KLINIKOWSKI M F, SAKU T, et al. Oral submucous fibrosis:review on aetiology and pathogenesis [J]. Oral Oncol,2006,42(6):561-8.
[67]GUPTA P C, SINOR P N, BHONSLE R B, et al. Oral submucous fibrosis in India:a new epidemic? [J]. Natl Med J India,1998,11(3):113-6.
[68]LEE C H, KO Y C, HUANG H L, et al. The precancer risk of betel quid chewing, tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan [J]. Br J Cancer,2003,88(3):366-72.
[69]MURTI P R, BHONSLE R B, PINDBORG J J, et al. Malignant transformation rate in oral submucous fibrosis over a 17-year period [J]. Community Dent Oral Epidemiol,1985,13(6):340-1.
[70]PINDBORG J J, POULSEN H E, ZACHARIAH J. Oral epithelial changes in thirty Indians with oral cancer and submucous fibrosis [J]. Cancer,1967,20(7): 1141-6.
[71]吴颖芳,彭解英,阙国鹰,等.中西医结合治疗口腔黏膜下纤维化的疗效[J].中南大学学报(医学版),2011,(4)：358-64.
[72]CHOLE R H, GONDIVKAR S M, GADBAIL A R, et al. Review of drug treatment of oral submucous fibrosis [J]. Oral Oncol,2011,48(5):393-8.
[73]KERR A R, WARNAKULASURIYA S, MIGHELL A J, et al. A systematic review of medical interventions for oral submucous fibrosis and future research opportunities [J]. Oral Dis,2011,17 Suppl 1:42-57.
[74]鲍华英.姜黄素的研究进展[J].国外医学(儿科学分册),2003,(5)：254-6.
[75]STRIMPAKOS A S, SHARMA R A. Curcumin:preventive and therapeutic properties in laboratory studies and clinical trials [J]. Antioxid Redox Signal,2008, 10(3):511-45.
[76]GOEL A, JHURANI S, AGGARWAL B B. Multi-targeted therapy by curcumin: how spicy is it? [J]. Mol Nutr Food Res,2008,52(9):1010-30.
[77]李或,杨丽霞,李亚东,等.姜黄素抗纤维化作用研究进展[J].北京中医药大学学报,2008,(6)：408-11.
[78]刘永刚,陈厚昌,蒋毅萍.姜黄素抗肝纤维化的实验研究[J].时珍国医国药,2002,05)：273-5.
[79]鲍华英,陈荣华,郭梅,等.姜黄素在肾毒血清肾炎中防治作用的初步研究[J].南京医科大学学报(自然科学版),2003,(4)：305-8+2.
[80]鲍华英,陈荣华,郭梅,等.姜黄素对肾毒血清肾炎大鼠肾组织超微结构及细胞增殖的影响[J].江苏医药,2004,(2)：104-6+80.
[81]PUNITHAVATHI D, VENKATESAN N, BABU M. Curcumin inhibition of bleomycin-induced pulmonary fibrosis in rats [J]. Br J Pharmacol,2000,131(2): 169-72.
[82]李银生,牛建昭,王继峰,等.姜黄素对肺纤维化大鼠肺组织胶原沉积及转化生长因子β-1表达的影响[J].中华中医药学刊,2007,(1)：55-7.
[83]AGGARWAL B B, HARIKUMAR K B. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases [J]. Int J Biochem Cell Biol,2009, 41(1):40-59.
[84]高伟,张东,刘江伟.环氧化酶-2与肺损伤[J].现代生物医学进展,2009,(15)：2992-4.
[85]KHAFIF A, SCHANTZ S P, CHOU T C, et al. Quantitation of chemopreventive synergism between (-)-epigallocatechin-3-gallate and curcumin in normal, premalignant and malignant human oral epithelial cells [J]. Carcinogenesis,1998, 19(3):419-24.
[86]PERKINS S, VERSCHOYLE R D, HILL K, et al. Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+mouse, a model of familial adenomatous polyposis [J]. Cancer Epidemiol Biomarkers Prev,2002,11(6):535-40.
[87]LEV-ARI S, MAIMON Y, STRIER L, et al. Down-regulation of prostaglandin E2 by curcumin is correlated with inhibition of cell growth and induction of apoptosis in human colon carcinoma cell lines [J]. J Soc Integr Oncol,2006,4(1):21-6.
[88]SINGH S, AGGARWAL B B. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected] [J]. J Biol Chem,1995, 270(42):24995-5000.
[89]BIERHAUS A, ZHANG Y, QUEHENBERGER P, et al. The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA and activation of NF-kappa B [J]. Thromb Haemost,1997,77(4): 772-82.
[90]SHISHODIA S, AMIN H M, LAI R, et al. Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma [J]. Biochem Pharmacol,2005,70(5): 700-13.
[91]赵承光,梁广,邵丽丽,等.姜黄素类化合物抗炎和细胞保护作用的构效关系研究进展[J].中草药,2008,(04)：619-22.
[92]JOE B, LOKESH B R. Role of capsaicin, curcumin and dietary n-3 fatty acids in lowering the generation of reactive oxygen species in rat peritoneal macrophages [J]. Biochim Biophys Acta,1994,1224(2):255-63.
[93]S M K, PRIYADARSINI K I, VENKATESAN P, et al. Free radical scavenging ability and antioxidant efficiency of curcumin and its substituted analogue [J]. Biophys Chem,1999,80(2):85-91.
[94]SREEJAYAN N, RAO M N. Free radical scavenging activity of curcuminoids [J]. Arzneimittelforschung,1996,46(2):169-71.
[95]DEROJAS-WALKER T, TAMIR S, JI H, et al. Nitric oxide induces oxidative damage in addition to deamination in macrophage DNA [J]. Chem Res Toxicol,1995, 8(3):473-7.
[96]GRAZIEWICZ M, WINK D A, LAVAL F. Nitric oxide inhibits DNA ligase activity:potential mechanisms for NO-mediated DNA damage [J]. Carcinogenesis, 1996,17(11):2501-5.
[97]BROUET I, OHSHIMA H. Curcumin, an anti-tumour promoter and anti-inflammatory agent, inhibits induction of nitric oxide synthase in activated macrophages [J]. Biochem Biophys Res Commun,1995,206(2):533-40.
[98]CHAN M M, HUANG H I, FENTON M R, et al. In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties [J]. Biochem Pharmacol,1998,55(12):1955-62.
[99]D N. Clinical development plan:curcumin [J]. J Cell Biochem Suppl,1996, 26:72-85.
[100]RAO C V, RIVENSON A, SIMI B, et al. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound [J]. Cancer Res,1995,55(2):259-66.
[101]AGGARWAL B B, SUNG B. Pharmacological basis for the role of curcumin in chronic diseases:an age-old spice with modern targets [J]. Trends Pharmacol Sci, 2009,30(2):85-94.
[102]WOO J H, KIM Y H, CHOI Y J, et al. Molecular mechanisms of curcumin-induced cytotoxicity:induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt [J]. Carcinogenesis,2003,24(7):1199-208.
[103]TAN T W, TSAI H R, LU H F, et al. Curcumin-induced cell cycle arrest and apoptosis in human acute promyelocytic leukemia HL-60 cells via MMP changes and caspase-3 activation [J]. Anticancer Res,2006,26(6B):4361-71.
[104]HUSSAIN A R, AL-RASHEED M, MANOGARAN P S, et al. Curcumin induces apoptosis via inhibition of PI3'-kinase/AKT pathway in acute T cell leukemias [J]. Apoptosis,2006,11(2):245-54.
[105]REUTER S, EIFES S, DICATO M, et al. Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells [J]. Biochem Pharmacol,2008,76(11):1340-51.
[106]GURURAJ A E, BELAKAVADI M, VENKATESH D A, et al. Molecular mechanisms of anti-angiogenic effect of curcumin [J]. Biochem Biophys Res Commun,2002,297(4):934-42.
[107]DORAI T, CAO Y C, DORAI B, et al. Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo [J]. Prostate,2001,47(4): 293-303.
[108]SHIM J S, KIM J H, CHO H Y, et al. Irreversible inhibition of CD13/aminopeptidase N by the antiangiogenic agent curcumin [J]. Chem Biol,2003, 10(8):695-704.
[109]HU M, DU Q, VANCUROVA I, et al. Proapoptotic effect of curcumin on human neutrophils:activation of the p38 mitogen-activated protein kinase pathway [J]. Crit Care Med,2005,33(11):2571-8.
[110]CHAN M M. Inhibition of tumor necrosis factor by curcumin, a phytochemical [J]. Biochem Pharmacol,1995,49(11):1551-6.
[111]GAO X, KUO J, JIANG H, et al. Immunomodulatory activity of curcumin: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production in vitro [J]. Biochem Pharmacol,2004,68(1):51-61.
[112]YADAV V S, MISHRA K P, SINGH D P, et al. Immunomodulatory effects of curcumin [J]. Immunopharmacol Immunotoxicol,2005,27(3):485-97.
[113]HAN S S, CHUNG S T, ROBERTSON D A, et al. Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53 [J]. Clin Immunol,1999,93(2):152-61.
[114]JOSHI B H, HOGABOAM C, DOVER P, et al. Role of interleukin-13 in cancer, pulmonary fibrosis, and other T(H)2-type diseases [J]. Vitam Horm,2006, 74:479-504.
[115]JAKUBZICK C, KUNKEL S L, PURI R K, et al. Therapeutic targeting of IL-4-and IL-13-responsive cells in pulmonary fibrosis [J]. Immunol Res,2004,30(3): 339-49.
[116]ELIAS J A, KANG M J, CROTHERS K, et al. State of the art. Mechanistic heterogeneity in chronic obstructive pulmonary disease:insights from transgenic mice [J]. Proc Am Thorac Soc,2006,3(6):494-8.
[117]FULKERSON P C, FISCHETTI C A, HASSMAN L M, et al. Persistent effects induced by IL-13 in the lung [J]. Am J Respir Cell Mol Biol,2006,35(3):337-46.
[118]LANONE S, ZHENG T, ZHU Z, et al. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and-12 in IL-13-induced inflammation and remodeling [J]. J Clin Invest,2002,110(4):463-74.
[119]KAVIRATNE M, HESSE M, LEUSINK M, et al. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent [J]. J Immunol,2004, 173(6):4020-9.
[120]VALKOVA M. Hepatic fibrogenesis [J]. Bratisl Lek Listy,2002,103(2):76-85.
[121]SELMAN M, THANNICKAL V J, PARDO A, et al. Idiopathic pulmonary fibrosis:pathogenesis and therapeutic approaches [J]. Drugs,2004,64(4):405-30.
[122]李霞.细胞因子与口腔粘膜下纤维性变[J].国外医学口腔医学分册,2002,(2)：92-4.
[123]NATHAN C, DING A. Nonresolving inflammation [J]. Cell,2010,140(6): 871-82.
[124]MANTOVANI A, ALLAVENA P, SIC A A, et al. Cancer-related inflammation [J]. Nature,2008,454(7203):436-44.
[125]ZIMMERMAN C M, PADGETT R W. Transforming growth factor beta signaling mediators and modulators [J]. Gene,2000,249(1-2):17-30.
[126]HASHIMOTO S, GON Y, TAKESHITA I, et al. Transforming growth Factor-betal induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway [J]. Am J Respir Crit Care Med,2001,163(1):152-7.
[127]胡永斌,冯德云,彭劲武,等.转化生长因子β1和丝裂原活化激酶通路调控人肺成纤维细胞表型[J].中华劳动卫生职业病杂志,2005,(2)：109-12.
[128]HINZ B, PHAN S H, THANNICKAL V J, et al. The myofibroblast:one function, multiple origins [J]. Am J Pathol,2007,170(6):1807-16.
[129]WANG R, RAMOS C, JOSHI I, et al. Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides [J]. Am J Physiol,1999,277(6 Pt 1):L1158-64.
[130]WAGHRAY M, CUI Z, HOROWITZ J C, et al. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts [J]. FASEB J,2005,19(7):854-6.
[131]张雁林,赵金垣.血红素加氧酶-1的细胞保护作用研究进展[J].环境与职业医学,2008,(2)：197-202.
[132]NISHINAKA T, ICHIJO Y, ITO M, et al. Curcumin activates human glutathione S-transferase P1 expression through antioxidant response element [J]. Toxicol Lett, 2007,170(3):238-47.
[133]TOURKINA E, GOOZ P, OATES J C, et al. Curcumin-induced apoptosis in scleroderma lung fibroblasts:role of protein kinase cepsilon [J]. Am J Respir Cell Mol Biol,2004,31(1):28-35.
[134JELLEDGE S J. Cell cycle checkpoints:preventing an identity crisis [J]. Science, 1996,274(5293):1664-72.
[135]CHEN A, XU J. Activation of PPAR{gamma} by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR [J]. Am J Physiol Gastrointest Liver Physiol,2005,288(3):G447-56.
[136]PULIYAPPADAMBA V T, CHERIYAN V T, THULASIDASAN A K, et al. Nicotine-induced survival signaling in lung cancer cells is dependent on their p53 status while its down-regulation by curcumin is independent [J]. Mol Cancer,2010, 9:220.
[137]CHOUDHURI T, PAL S, DAS T, et al. Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner [J]. J Biol Chem,2005,280(20):20059-68.
[138]MIYASHITA T, KRAJEWSKI S, KRAJEWSKA M, et al. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo [J]. Oncogene, 1994,9(6):1799-805.
[139]MIYASHITA T, REED J C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene [J]. Cell,1995,80(2):293-9.
[140]PETROS A M, OLEJNICZAK E T, FESIK S W. Structural biology of the Bcl-2 family of proteins [J]. Biochim Biophys Acta,2004,1644(2-3):83-94.
[141]ZINKEL S, GROSS A, YANG E. BCL2 family in DNA damage and cell cycle control [J]. Cell Death Differ,2006,13(8):1351-9.
[142]沃兴德,洪行球,高承贤,等.姜黄素长期毒性试验[J].浙江中医学院学报,2000,(1)：61-5.
[143]DEODHAR S D, SETHI R, SRIMAL R C. Preliminary study on antirheumatic activity of curcumin (diferuloyl methane) [J]. Indian J Med Res,1980,71:632-4.
[144]CHENG A L, HSU C H, LIN J K, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions [J]. Anticancer Res,2001,21(4B):2895-900.
[1]Thompson, L. World Health Organization classification of tumours:pathology and genetics of head and neck tumours. [J] Ear, nose,& throat journal,2006,85(2): 74.
[2]Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis--a collagen metabolic disorder [J]. J Oral Pathol Med.,2005,34(6):321-8.
[3]Angadi PV, Kale AD, Hallikerimath S. Evaluation of myofibroblasts in oral submucous fibrosis:correlation with disease severity [J]. J Oral Pathol Med.,2011 Mar;40(3):208-13.
[4]Wynn TA. Cellular and molecular mechanisms of fibrosis [J].J Pathol.,2008 214(2):199-210
[5]李霞,凌天牖,高义军a-SMA在口腔粘膜下纤维性变成纤维细胞中的表达[J].中国免疫学杂志,2007,23(9)：851-6
[6]宋庆高,石冰.转化生长因子与软组织创面修复的研究进展[J].临床口腔医学杂志,2004,20(2)：126-7.
[7]Zimmerman CM, Padgett RW. Transforming growth factor beta signaling mediators and modulators [J].Gene,2000,249(1-2):17-30.
[8]Hashimoto S, Gon Y, Takeshita I, et al.Transforming growth factor-beta 1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway [J].Am J Respir Crit Care Med, 2001,163(1):152-157.
[9]胡永斌,冯德云,彭劲武,等.转化生长因子β1和丝裂原活化激酶通路调控人肺成纤维细胞表型[J].中华劳动卫生职业病杂志,2004,23(2)：109-112
[10]高义军,凌天牖,吴汉江,等.转化生长因子β-1在口腔粘膜下纤维性变角朊细胞中的表达[J].中华口腔医学杂志,1996,14(1)：20-2
[11]李霞,凌天牖,高义军,等.槟榔碱对口腔粘膜肌成纤维细胞分化的影响[J].中华口腔医学杂志,2007,42(7)：423-7
[12]余文林,曾东,苑凯华.结缔组织生长因子与器官纤维化[J].中国组织工程研究与临床康复,2007,11(23)：4610-3
[13]Folger PA, Zekaria D, Grotendorst G, et al. Transforming growth factor-beta-stimulated connective tissue growth factor expression during corneal myofibroblast differentiation [J]. Invest Ophthalmol Vis Sci.,2001,42(11): 2534-41.
[14]尹晓敏,高义军.结缔组织生长因子在口腔黏膜下纤维性变组织中的角质形成细胞中的表达[J],中国现代医学杂志,2006,16(10)：1483-1489
[15]Deng YT, Chen HM, Cheng SJ, et al. Arecoline-stimulated connective tissue growth factor production in human buccal mucosal fibroblasts:Modulation by curcumin [J]. Oral Oncol.,2009,45(9):e99-105.
[16]Shahar I, Fireman E, Topilsky M, et al. Effect of endothelin-1 on alpha-smooth muscle actin expression and on alveolar fibroblasts proliferation in interstitial lung diseases [J].Int J Immunpharmacol,1999,21(11):759-75.
[17]Shi-Wen X, Chen YL, Denton CP, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts [J]. Mol Biol Cell,2004,15(6):2707-19.
[18]冯云枝,凌天牖.槟榔提取物对人类口腔黏膜上皮角朊细胞分泌内皮素的影响[J].临床口腔医学杂志,2001,17(3)：215-8
[19]许春姣,彭解英,刘蜀凡.口腔粘膜下纤维性变组织中内皮素1的免疫组织化学和定量研究[J].华西口腔医学杂志,2000,18(6)：394-6
[20]许春姣,彭解英,刘蜀凡,等.口腔粘膜下纤维化组织中内皮素1的免疫电镜研究[J].中华口腔医学杂志,2000,35(3)：215-7
[21]Fraser D, Brunskill N, Ito T, et al. Long-term exposure of proximal tubular epithelial cells to glucose induces transforming growth factor-1 synthesis via an autocrine PDGF Loop [J]. Am J Pathol,2003,163(6):2565-74.
[22]韩为农,彭解英,刘蜀凡.血小板衍生生长因子-BB在口腔粘膜下纤维化中的表达和分布[J].中国病理生理杂志,2002,18(11)：1427-8
[23]韩为农,彭解英,徐锡萍,等.血小板衍生生长因子BB及其受体在口腔粘膜下纤维化的超微结构定位[J].华西口腔医学杂志,2002,20(4)：254-6
[24]吴颖芳,彭解英,韩为农,等.血小板衍生生长因子BB受体在口腔黏膜下纤维化组织中的表达和分布[J].临床口腔医学杂志,2004,20(1)：48-51
[25]Tang WW, Ulich TR, Lacey DL, et al. Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis[J]. Am J Pathol,1996,148 (4):1169-80.
[26]Cui Q, Wang Z, Jiang D, et al. HGF inhibits TGF-β1-induced myofibroblast differentiation and ECM deposition via MMP-2 in Achilles tendon in rat[J]. Eur J Appl Physiol.,2011,111(7):1457-63
[27]张姗姗,凌天牖HGF/c-met在口腔黏膜下纤维化组织中表达的研究[J].实用口腔医学杂志,2012,(1)：110-113
[28]Ramos C, Montano M, Garcia-Alvarez J, et al. Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression [J]. Am J Respir Cell Mol Biol., 2001,24(5):591-8.
[29]Wang R, Ramos C, Joshi I, et al. Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides[J]. Am J Physiol. 1999,277(6 Pt 1):L1158-64.
[30]WaghrayM, Cui Z, Horowitz JC, et al. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts [J].FASEB J,2005,19(7):854-6.
[31]Yanjia H, Xinchun J. The role of epithelial-mesenchymal transition in oral squamous cell carcinoma and oral submucous fibrosis [J]. Clin Chim Acta., 2007,383(1-2):51-6.
[1]陈谦明.口腔黏膜病学[M].第三版.北京：人民卫生出版社,2008：122-124
[2]Tilakaratne WM, Klinikowski MF, Saku T, et al. Oral submucous fibrosis:Review on aetiology and pathogenesis[J].Oral Oncol,2006,42(6):561-8,
[3]唐杰清,凌天牖.8例口腔粘膜下纤维性变喉镜检查结果报告[J].口腔医学,1997,17(1)：37-8
[4]International Agency for Research on Cancer. WHO classification of tumors: pathology and genetics of head and neck tumors [M]. Lyon:IARC Press,2005.181.
[5]Lee CH, Ko AM, Warnakulasuriya S, et al. Intercountry prevalences and practices of betel-quid use in south, southeast and eastern asia regions and associated oral preneoplastic disorders:An international collaborative study by asian betel-quid consortium of south and east Asia[J]. Int J Cancer.2011,129(7):1741-51.
[6]Khanna JN, Andrade NN. Oral submucous fibrosis:a new concept in surgical management. Report of 100 cases[J]. Int J Oral Maxillofac Surg.,1995,24(6):433-9.
[7]Maher R, Aga P, Johnson NW, et al. Evaluation of multiple micronutrient supplementation in the management of oral submucous fibrosis in Karachi, Pakistan [J]. Nutr Cance,1997,27(1):41-7.
[8]Lin HJ, Lin JC. Treatment of oral submucous fibrosis by collagenase:Effects on oral opening and eating function [J]. Oral Dis,2007,13(4):407-13.
[9]Rajendran R, Rani V, Shaikh S. Pentoxifylline therapy:A new adjunct in the treatment of oral submucous fibrosis[J]. Indian J Dent Res,2006,17(4):190-8.
[10]李新民,唐杰清.茶色素治疗口腔粘膜下纤维性变的临床观察[J].华西口腔医学杂志,1998,16(1)：50-2.
[11]吴颖芳,彭解英,阙国鹰,等.中西医结合治疗口腔黏膜下纤维化的疗效[J].中南大学学报(医学版),2010,35(4)：358-64.
[12]Gupta S, Reddy MVR, Harinath BC. Role of oxidative stress and antioxidants in aetiopathogenesis and management of oral submucous fibrosis[J]. Indian J Clin Biochem,2004,19(1):138-42.
[13]Kumar A, Bagewadi A, Keluskar V, et al. Efficacy of lycopene in the management of oral submucous fibrosis [J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod,2007,103(2):207-13.
[14]Rao PK. Efficacy of alpha lipoic acid in adjunct with intralesional steroids and hyaluronidase in the management of oral submucous fibrosis [J]. J Cancer Res Ther. 2010,6(4):508-10.
[15]Haque MF, Meghji S, Nazir R, et al. Interferon gamma (IFN-gamma) may reverse oral submucous fibrosis[J]. J Oral Pathol Med.2001,30(1):12-21.
[16]Tai YS, Liu BY, Wang JT, et al. Oral administration of milk from cows immunized with human intestinal bacteria leads to significant improvements of symptoms and signs in patients with oral submucous fibrosis[J]. J Oral Pathol Med, 2001,30(10):618-25.
[17]李新民,唐杰清,凌天牖.高压氧治疗口腔黏膜下纤维性变的临床观察[J].中华口腔医学杂志,1999,34(6)：340-2
[18]Cox S, Zoellner H. Physiotherapeutic treatment improves oral opening in oral submucous fibrosis. J Oral Pathol Med,2009,38(2):220-6.
[19]Chao CK, Chang LC, Liu SY, et al. Histologic examination of pedicled buccal fat pad graft in oral submucous fibrosis[J]. J Oral Maxillofac Surg,2002,60 (10):1131-4.
[20]Wei FC, Chang YM, Kildal M, et al. Bilateral small radial forearm flaps for the reconstruction of buccal mucosa after surgical release of submucosal fibrosis:a new, reliable approach[J]. Plast Reconstr Surg,2001,107(7):1679-1683.
[21]Huang IY, Wu CF, Shen YS, et al. Importance of patient's cooperation in surgical treatment for oral submucous fibrosis[J]. J Oral Maxillofac Surg,2008,66(4):699-703.
[22]Ko EC, Shen YH, Yang CF, et al. Artificial dermis as the substitute for split-thickness skin graft in the treatment of oral submucous fibrosis [J]. J Craniofac Surg,2009,20(2):443-445.
[2]ARIYAWARDANA A, ATHUKORALA A D, ARULANANDAM A. Effect of betel chewing, tobacco smoking and alcohol consumption on oral submucous fibrosis: a case-control study in Sri Lanka [J]. J Oral Pathol Med,2006,35(4):197-201.
[3]HAIDER S M, MERCHANT A T, FIKREE F F, et al. Clinical and functional staging of oral submucous fibrosis [J]. Br J Oral Maxillofac Surg,2000,38(1):12-5.
[4]RANGANATHAN K, DEVI M U, JOSHUA E, et al. Oral submucous fibrosis:a case-control study in Chennai, South India [J]. J Oral Pathol Med,2004,33(5):274-7.
[5]JACOB B J, STRAIF K, THOMAS G, et al. Betel quid without tobacco as a risk factor for oral precancers [J]. Oral Oncol,2004,40(7):697-704.
[6]YANG Y H, LIEN Y C, HO P S, et al. The effects of chewing areca/betel quid with and without cigarette smoking on oral submucous fibrosis and oral mucosal lesions [J]. Oral Dis,2005,11(2):88-94.
[7]张姗姗,凌天牖,贺达仁.槟榔时尚与疾病[J].医学与哲学(人文社会医学版),2010,(10)：42-3+8.
[8]RAJALALITHA P, VALI S. Molecular pathogenesis of oral submucous fibrosis--a collagen metabolic disorder [J]. J Oral Pathol Med,2005,34(6):321-8.
[9]UTSUNOMIYA H, TILAKARATNE W M, OSHIRO K, et al. Extracellular matrix remodeling in oral submucous fibrosis:its stage-specific modes revealed by immunohistochemistry and in situ hybridization [J]. J Oral Pathol Med,2005,34(8): 498-507.
[10]JIANG X, HU J. Drug treatment of oral submucous fibrosis:a review of the literature [J]. J Oral Maxillofac Surg,2009,67(7):1510-5.
[11]FEDOROWICZ Z, CHAN SHIH-YEN E, DORRI M, et al. Interventions for the management of oral submucous fibrosis [J]. Cochrane Database Syst Rev,2008,8(4): CD007156.
[12]SIRS AT S M, KHANOLKAR V R. Submucous fibrosis of the palate. Induction by local painting of capsaicin in Wistar rats treated with desoxycorticosterone acetate--an optical and electron microscopic study [J]. Arch Pathol,1960,70:180-7.
[13]SIRS AT S M, KHANOLKAR V R. Submucous fibrosis of the palate in diet-preconditioned Wistar rats. Induction by local painting of capsaicin--an optical and electron microscopic study [J]. Arch Pathol,1960,70:171-9.
[14]SIRS AT S M, KHANOLKAR V R. The effect of arecoline on the palatal and buccal mucosa of the Wistar rat. An optical and electron microscope study [J]. Indian J Med Sci,1962,16:198-202.
[15]MACDONALD D G. Effects of arecaidine application to hamster cheek pouch [J]. J Oral Med,1987,42(1):61-2.
[16]KHRIME R D, MEHRA Y N, MANN S B, et al. Effect of instant preparation of betel nut (pan masala) on the oral mucosa of albino rats [J]. Indian J Med Res,1991, 94:119-24.
[17]SUMETH PERERA M W, GUNASINGHE D, PERERA P A, et al. Development of an in vivo mouse model to study oral submucous fibrosis [J]. J Oral Pathol Med, 2007,36(5):273-80.
[18]王燕,王真,何琪杨.博来霉素族抗生素作用机制的研究进展[J].国外医药(抗生素分册),2009,(1)：5-8+18.
[19]CHAUDHARY N I, SCHNAPP A, PARK J E. Pharmacologic differentiation of inflammation and fibrosis in the rat bleomycin model [J]. Am J Respir Crit Care Med, 2006,173(7):769-76.
[20]USUKI J, FUKUDA Y. Evolution of three patterns of intra-alveolar fibrosis produced by bleomycin in rats [J]. Pathol Int,1995,45(8):552-64.
[21]CHUA F, GAULDIE J, LAURENT G J. Pulmonary fibrosis:searching for model answers [J]. Am J Respir Cell Mol Biol,2005,33(1):9-13.
[22]ABRAHAM D J, VARGA J. Scleroderma:from cell and molecular mechanisms to disease models [J]. Trends Immunol,2005,26(11):587-95.
[23]巫婷婷,周京国.硬皮病动物模型及其应用研究进展[J].动物医学进展,2008,(2)：102-5.
[24]YAMAMOTO T, TAKAGAWA S, KATAYAMA I, et al. Animal model of sclerotic skin. I:Local injections of bleomycin induce sclerotic skin mimicking scleroderma [J]. J Invest Dermatol,1999,112(4):456-62.
[25]YAMAMOTO T, TAKAHASHI Y, TAKAGAWA S, et al. Animal model of sclerotic skin. II. Bleomycin induced scleroderma in genetically mast cell deficient WBB6F1-W/W(V) mice [J]. J Rheumatol,1999,26(12):2628-34.
[26]BAGCHI M, BALMOORI J, BAGCHI D, et al. Role of reactive oxygen species in the development of cytotoxicity with various forms of chewing tobacco and pan masala [J]. Toxicology,2002,179(3):247-55.
[27]WILLIAMS M S, KWON J. T cell receptor stimulation, reactive oxygen species, and cell signaling [J]. Free Radic Biol Med,2004,37(8):1144-51.
[28]翦新春,郑廉.口腔黏膜下纤维性变研究进展[J].中国实用口腔科杂志,2011,(2)：65-8.
[29]POWELL D W, MIFFLIN R C, VALENTICH J D, et al. Myofibroblasts. I. Paracrine cells important in health and disease [J]. Am J Physiol,1999,277(1 Pt 1): C1-9.
[30]WYNN T A. Cellular and molecular mechanisms of fibrosis [J]. J Pathol,2008, 214(2):199-210.
[31]李霞,凌天牖,高义军a-Sma在口腔粘膜下纤维性变成纤维细胞中的表达[J].中国免疫学杂志,2007,(9)：851-6.
[32]ANGADI P V, KALE A D, HALLIKERIMATH S. Evaluation of myofibroblasts in oral submucous fibrosis:correlation with disease severity [J]. J Oral Pathol Med, 2011,40(3):208-13.
[33]张姗姗,凌天牖HGF/c-met在口腔黏膜下纤维化组织中表达的研究[J].实用口腔医学杂志,2012,(1)：110-3.
[34]HAQUE M F, HARRIS M, MEGHJI S, et al. Immunolocalization of cytokines and growth factors in oral submucous fibrosis [J]. Cytokine,1998,10(9):713-9.
[35]PINDBORG J J, MEHTA F S, GUPTA P C, et al. Prevalence of oral submucous fibrosis among 50,915 Indian villagers [J]. Br J Cancer,1968,22(4):646-54.
[36]中华口腔医学会口腔黏膜病专业委员会,口腔黏膜下纤维性变的诊断标准(试行稿)[J].,2009,44(3)：2.
[37]PINDBORG J J, SIRSAT S M. Oral submucous fibrosis [J]. Oral Surg Oral Med Oral Pathol,1966,22(6):764-79.
[38]KAMATA Y, ITOH Y, KAJIYA A, et al. Quantification of neutral cysteine protease bleomycin hydrolase and its localization in rat tissues [J]. J Biochem,2007, 141(1):69-76.
[39]张自强,赵东旭,杨新林.羟脯氨酸的研究与开发[J].氨基酸和生物资源,2006,(1)：55-8+62.
[40]胥红,刘蜀凡,沈子华,等.口腔粘膜下纤维性变组织中Ⅰ型和Ⅲ型胶原免疫组化及定量分析[J].实用口腔医学杂志,2000,(1)：52-4.
[41]PHAN S H. Biology of fibroblasts and myofibroblasts [J]. Proc Am Thorac Soc, 2008,5(3):334-7.
[42]WATSKY M A, WEBER K T, SUN Y, et al. New insights into the mechanism of fibroblast to myofibroblast transformation and associated pathologies [J]. Int Rev Cell Mol Biol,2010,282:165-92.
[43]YANJIA H, XINCHUN J. The role of epithelial-mesenchymal transition in oral squamous cell carcinoma and oral submucous fibrosis [J]. Clin Chim Acta,2007, 383(1-2):51-6.
[44]张姗姗,凌天牖.成纤维细胞、肌成纤维细胞与口腔黏膜下纤维性变[J].临床口腔医学杂志,2012,(2)：118-20.
[45]PHAN S H, KUNKEL S L. Lung cytokine production in bleomycin-induced pulmonary fibrosis [J]. Exp Lung Res,1992,18(1):29-43.
[46]RAGHOW B, IRISH P, KANG A H. Coordinate regulation of transforming growth factor beta gene expression and cell proliferation in hamster lungs undergoing bleomycin-induced pulmonary fibrosis [J]. J Clin Invest,1989,84(6):1836-42.
[47]BAECHER-ALLAN C M, BARTH R K. PCR analysis of cytokine induction profiles associated with mouse strain variation in susceptibility to pulmonary fibrosis [J]. Reg Immunol,1993,5(3-4):207-17.
[48]ZHANG K, FLANDERS K C, PHAN S H. Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis [J]. Am J Pathol,1995,147(2):352-61.
[49]高义军,凌天牖,吴汉江,等.口腔粘膜下纤维性变组织中转化生长因子β_1mRNA表达水平[J].华西口腔医学杂志,1996,(1)：20-2+34+77.
[50]邱慧张.干扰素-γ治疗特发性肺纤维化的研究进展[J].国外医学呼吸系统分册,2005,(5)：376-9.
[51]ULLOA L, DOODY J, MASS AGUE J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway [J]. Nature, 1999,397(6721):710-3.
[52]STRIETER R M. Mechanisms of pulmonary fibrosis:conference summary [J]. Chest,2001,120(1 Suppl):77S-85S.
[53]GURUJEYALAKSHMI G, GIRI S N. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression [J]. Exp Lung Res,1995,21(5):791-808.
[54]胥红,彭解英,刘蜀凡,等.口腔粘膜下纤维性变中胶原纤维的超微结构研究[J].临床口腔医学杂志,1998,(3)：172-4.
[55]胥红,刘蜀凡,沈子华,等.口腔粘膜下纤维性变中成纤维细胞的超微结构 观察[J].临床口腔医学杂志,2000,(1)：8-9.
[56]刘蜀藩,彭解英,沈子华,等.口腔粘膜下纤维性变中毛细血管损伤的超微结构研究[J].中华口腔医学杂志,1999,(2)：46.
[57]司静懿,韩日才,李昆,等.口腔粘膜下纤维变病理发生的超微结构研究[J].电子显微学报,1993,(1)：65.
[58]苏葵,刘蜀藩,沈子华,等.肥大细胞与口腔粘膜下纤维性变的超微结构研究[J].湖南医科大学学报,1995,(4)：327-9.
[59]SABARINATH B, SRIRAM G, SARASWATHI T R, et al. Immunohistochemical evaluation of mast cells and vascular endothelial proliferation in oral submucous fibrosis [J]. Indian J Dent Res,2011,22(1):116-21.
[60]GUPTA P C, WARNAKULASURIYA S. Global epidemiology of areca nut usage [J]. Addict Biol,2002,7(1):77-83.
[61]KO Y C, CHIANG T A, CHANG S J, et al. Prevalence of betel quid chewing habit in Taiwan and related sociodemographic factors [J]. J Oral Pathol Med,1992, 21(6):261-4.
[62]LEE C H, KO A M, WARNAKULASURIYA S, et al. Intercountry prevalences and practices of betel-quid use in south, southeast and eastern Asia regions and associated oral preneoplastic disorders:an international collaborative study by Asian betel-quid consortium of south and east Asia [J]. Int J Cancer,2011,129(7):1741-51.
[63]ZHANG S S, LI W H, GAO Y J, et al. Betel-quid and oral submucous fibrosis:a cross-sectional study in Hunan province, China [J]. J Oral Pathol Med,2012,
[64]高义军,彭海艳,尹晓敏,等.湖南省娄底市城区中小学生嚼槟榔情况调查[J].中华口腔医学杂志,2009,44(11)：686-89.
[65]ZHANG X, REICHART P A. A review of betel quid chewing, oral cancer and precancer in Mainland China [J]. Oral Oncol,2007,43(5):424-30.
[66]TILAKARATNE W M, KLINIKOWSKI M F, SAKU T, et al. Oral submucous fibrosis:review on aetiology and pathogenesis [J]. Oral Oncol,2006,42(6):561-8.
[67]GUPTA P C, SINOR P N, BHONSLE R B, et al. Oral submucous fibrosis in India:a new epidemic? [J]. Natl Med J India,1998,11(3):113-6.
[68]LEE C H, KO Y C, HUANG H L, et al. The precancer risk of betel quid chewing, tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan [J]. Br J Cancer,2003,88(3):366-72.
[69]MURTI P R, BHONSLE R B, PINDBORG J J, et al. Malignant transformation rate in oral submucous fibrosis over a 17-year period [J]. Community Dent Oral Epidemiol,1985,13(6):340-1.
[70]PINDBORG J J, POULSEN H E, ZACHARIAH J. Oral epithelial changes in thirty Indians with oral cancer and submucous fibrosis [J]. Cancer,1967,20(7): 1141-6.
[71]吴颖芳,彭解英,阙国鹰,等.中西医结合治疗口腔黏膜下纤维化的疗效[J].中南大学学报(医学版),2011,(4)：358-64.
[72]CHOLE R H, GONDIVKAR S M, GADBAIL A R, et al. Review of drug treatment of oral submucous fibrosis [J]. Oral Oncol,2011,48(5):393-8.
[73]KERR A R, WARNAKULASURIYA S, MIGHELL A J, et al. A systematic review of medical interventions for oral submucous fibrosis and future research opportunities [J]. Oral Dis,2011,17 Suppl 1:42-57.
[74]鲍华英.姜黄素的研究进展[J].国外医学(儿科学分册),2003,(5)：254-6.
[75]STRIMPAKOS A S, SHARMA R A. Curcumin:preventive and therapeutic properties in laboratory studies and clinical trials [J]. Antioxid Redox Signal,2008, 10(3):511-45.
[76]GOEL A, JHURANI S, AGGARWAL B B. Multi-targeted therapy by curcumin: how spicy is it? [J]. Mol Nutr Food Res,2008,52(9):1010-30.
[77]李或,杨丽霞,李亚东,等.姜黄素抗纤维化作用研究进展[J].北京中医药大学学报,2008,(6)：408-11.
[78]刘永刚,陈厚昌,蒋毅萍.姜黄素抗肝纤维化的实验研究[J].时珍国医国药,2002,05)：273-5.
[79]鲍华英,陈荣华,郭梅,等.姜黄素在肾毒血清肾炎中防治作用的初步研究[J].南京医科大学学报(自然科学版),2003,(4)：305-8+2.
[80]鲍华英,陈荣华,郭梅,等.姜黄素对肾毒血清肾炎大鼠肾组织超微结构及细胞增殖的影响[J].江苏医药,2004,(2)：104-6+80.
[81]PUNITHAVATHI D, VENKATESAN N, BABU M. Curcumin inhibition of bleomycin-induced pulmonary fibrosis in rats [J]. Br J Pharmacol,2000,131(2): 169-72.
[82]李银生,牛建昭,王继峰,等.姜黄素对肺纤维化大鼠肺组织胶原沉积及转化生长因子β-1表达的影响[J].中华中医药学刊,2007,(1)：55-7.
[83]AGGARWAL B B, HARIKUMAR K B. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases [J]. Int J Biochem Cell Biol,2009, 41(1):40-59.
[84]高伟,张东,刘江伟.环氧化酶-2与肺损伤[J].现代生物医学进展,2009,(15)：2992-4.
[85]KHAFIF A, SCHANTZ S P, CHOU T C, et al. Quantitation of chemopreventive synergism between (-)-epigallocatechin-3-gallate and curcumin in normal, premalignant and malignant human oral epithelial cells [J]. Carcinogenesis,1998, 19(3):419-24.
[86]PERKINS S, VERSCHOYLE R D, HILL K, et al. Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+mouse, a model of familial adenomatous polyposis [J]. Cancer Epidemiol Biomarkers Prev,2002,11(6):535-40.
[87]LEV-ARI S, MAIMON Y, STRIER L, et al. Down-regulation of prostaglandin E2 by curcumin is correlated with inhibition of cell growth and induction of apoptosis in human colon carcinoma cell lines [J]. J Soc Integr Oncol,2006,4(1):21-6.
[88]SINGH S, AGGARWAL B B. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected] [J]. J Biol Chem,1995, 270(42):24995-5000.
[89]BIERHAUS A, ZHANG Y, QUEHENBERGER P, et al. The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA and activation of NF-kappa B [J]. Thromb Haemost,1997,77(4): 772-82.
[90]SHISHODIA S, AMIN H M, LAI R, et al. Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma [J]. Biochem Pharmacol,2005,70(5): 700-13.
[91]赵承光,梁广,邵丽丽,等.姜黄素类化合物抗炎和细胞保护作用的构效关系研究进展[J].中草药,2008,(04)：619-22.
[92]JOE B, LOKESH B R. Role of capsaicin, curcumin and dietary n-3 fatty acids in lowering the generation of reactive oxygen species in rat peritoneal macrophages [J]. Biochim Biophys Acta,1994,1224(2):255-63.
[93]S M K, PRIYADARSINI K I, VENKATESAN P, et al. Free radical scavenging ability and antioxidant efficiency of curcumin and its substituted analogue [J]. Biophys Chem,1999,80(2):85-91.
[94]SREEJAYAN N, RAO M N. Free radical scavenging activity of curcuminoids [J]. Arzneimittelforschung,1996,46(2):169-71.
[95]DEROJAS-WALKER T, TAMIR S, JI H, et al. Nitric oxide induces oxidative damage in addition to deamination in macrophage DNA [J]. Chem Res Toxicol,1995, 8(3):473-7.
[96]GRAZIEWICZ M, WINK D A, LAVAL F. Nitric oxide inhibits DNA ligase activity:potential mechanisms for NO-mediated DNA damage [J]. Carcinogenesis, 1996,17(11):2501-5.
[97]BROUET I, OHSHIMA H. Curcumin, an anti-tumour promoter and anti-inflammatory agent, inhibits induction of nitric oxide synthase in activated macrophages [J]. Biochem Biophys Res Commun,1995,206(2):533-40.
[98]CHAN M M, HUANG H I, FENTON M R, et al. In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties [J]. Biochem Pharmacol,1998,55(12):1955-62.
[99]D N. Clinical development plan:curcumin [J]. J Cell Biochem Suppl,1996, 26:72-85.
[100]RAO C V, RIVENSON A, SIMI B, et al. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound [J]. Cancer Res,1995,55(2):259-66.
[101]AGGARWAL B B, SUNG B. Pharmacological basis for the role of curcumin in chronic diseases:an age-old spice with modern targets [J]. Trends Pharmacol Sci, 2009,30(2):85-94.
[102]WOO J H, KIM Y H, CHOI Y J, et al. Molecular mechanisms of curcumin-induced cytotoxicity:induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt [J]. Carcinogenesis,2003,24(7):1199-208.
[103]TAN T W, TSAI H R, LU H F, et al. Curcumin-induced cell cycle arrest and apoptosis in human acute promyelocytic leukemia HL-60 cells via MMP changes and caspase-3 activation [J]. Anticancer Res,2006,26(6B):4361-71.
[104]HUSSAIN A R, AL-RASHEED M, MANOGARAN P S, et al. Curcumin induces apoptosis via inhibition of PI3'-kinase/AKT pathway in acute T cell leukemias [J]. Apoptosis,2006,11(2):245-54.
[105]REUTER S, EIFES S, DICATO M, et al. Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells [J]. Biochem Pharmacol,2008,76(11):1340-51.
[106]GURURAJ A E, BELAKAVADI M, VENKATESH D A, et al. Molecular mechanisms of anti-angiogenic effect of curcumin [J]. Biochem Biophys Res Commun,2002,297(4):934-42.
[107]DORAI T, CAO Y C, DORAI B, et al. Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo [J]. Prostate,2001,47(4): 293-303.
[108]SHIM J S, KIM J H, CHO H Y, et al. Irreversible inhibition of CD13/aminopeptidase N by the antiangiogenic agent curcumin [J]. Chem Biol,2003, 10(8):695-704.
[109]HU M, DU Q, VANCUROVA I, et al. Proapoptotic effect of curcumin on human neutrophils:activation of the p38 mitogen-activated protein kinase pathway [J]. Crit Care Med,2005,33(11):2571-8.
[110]CHAN M M. Inhibition of tumor necrosis factor by curcumin, a phytochemical [J]. Biochem Pharmacol,1995,49(11):1551-6.
[111]GAO X, KUO J, JIANG H, et al. Immunomodulatory activity of curcumin: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production in vitro [J]. Biochem Pharmacol,2004,68(1):51-61.
[112]YADAV V S, MISHRA K P, SINGH D P, et al. Immunomodulatory effects of curcumin [J]. Immunopharmacol Immunotoxicol,2005,27(3):485-97.
[113]HAN S S, CHUNG S T, ROBERTSON D A, et al. Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53 [J]. Clin Immunol,1999,93(2):152-61.
[114]JOSHI B H, HOGABOAM C, DOVER P, et al. Role of interleukin-13 in cancer, pulmonary fibrosis, and other T(H)2-type diseases [J]. Vitam Horm,2006, 74:479-504.
[115]JAKUBZICK C, KUNKEL S L, PURI R K, et al. Therapeutic targeting of IL-4-and IL-13-responsive cells in pulmonary fibrosis [J]. Immunol Res,2004,30(3): 339-49.
[116]ELIAS J A, KANG M J, CROTHERS K, et al. State of the art. Mechanistic heterogeneity in chronic obstructive pulmonary disease:insights from transgenic mice [J]. Proc Am Thorac Soc,2006,3(6):494-8.
[117]FULKERSON P C, FISCHETTI C A, HASSMAN L M, et al. Persistent effects induced by IL-13 in the lung [J]. Am J Respir Cell Mol Biol,2006,35(3):337-46.
[118]LANONE S, ZHENG T, ZHU Z, et al. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and-12 in IL-13-induced inflammation and remodeling [J]. J Clin Invest,2002,110(4):463-74.
[119]KAVIRATNE M, HESSE M, LEUSINK M, et al. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent [J]. J Immunol,2004, 173(6):4020-9.
[120]VALKOVA M. Hepatic fibrogenesis [J]. Bratisl Lek Listy,2002,103(2):76-85.
[121]SELMAN M, THANNICKAL V J, PARDO A, et al. Idiopathic pulmonary fibrosis:pathogenesis and therapeutic approaches [J]. Drugs,2004,64(4):405-30.
[122]李霞.细胞因子与口腔粘膜下纤维性变[J].国外医学口腔医学分册,2002,(2)：92-4.
[123]NATHAN C, DING A. Nonresolving inflammation [J]. Cell,2010,140(6): 871-82.
[124]MANTOVANI A, ALLAVENA P, SIC A A, et al. Cancer-related inflammation [J]. Nature,2008,454(7203):436-44.
[125]ZIMMERMAN C M, PADGETT R W. Transforming growth factor beta signaling mediators and modulators [J]. Gene,2000,249(1-2):17-30.
[126]HASHIMOTO S, GON Y, TAKESHITA I, et al. Transforming growth Factor-betal induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway [J]. Am J Respir Crit Care Med,2001,163(1):152-7.
[127]胡永斌,冯德云,彭劲武,等.转化生长因子β1和丝裂原活化激酶通路调控人肺成纤维细胞表型[J].中华劳动卫生职业病杂志,2005,(2)：109-12.
[128]HINZ B, PHAN S H, THANNICKAL V J, et al. The myofibroblast:one function, multiple origins [J]. Am J Pathol,2007,170(6):1807-16.
[129]WANG R, RAMOS C, JOSHI I, et al. Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides [J]. Am J Physiol,1999,277(6 Pt 1):L1158-64.
[130]WAGHRAY M, CUI Z, HOROWITZ J C, et al. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts [J]. FASEB J,2005,19(7):854-6.
[131]张雁林,赵金垣.血红素加氧酶-1的细胞保护作用研究进展[J].环境与职业医学,2008,(2)：197-202.
[132]NISHINAKA T, ICHIJO Y, ITO M, et al. Curcumin activates human glutathione S-transferase P1 expression through antioxidant response element [J]. Toxicol Lett, 2007,170(3):238-47.
[133]TOURKINA E, GOOZ P, OATES J C, et al. Curcumin-induced apoptosis in scleroderma lung fibroblasts:role of protein kinase cepsilon [J]. Am J Respir Cell Mol Biol,2004,31(1):28-35.
[134JELLEDGE S J. Cell cycle checkpoints:preventing an identity crisis [J]. Science, 1996,274(5293):1664-72.
[135]CHEN A, XU J. Activation of PPAR{gamma} by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR [J]. Am J Physiol Gastrointest Liver Physiol,2005,288(3):G447-56.
[136]PULIYAPPADAMBA V T, CHERIYAN V T, THULASIDASAN A K, et al. Nicotine-induced survival signaling in lung cancer cells is dependent on their p53 status while its down-regulation by curcumin is independent [J]. Mol Cancer,2010, 9:220.
[137]CHOUDHURI T, PAL S, DAS T, et al. Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner [J]. J Biol Chem,2005,280(20):20059-68.
[138]MIYASHITA T, KRAJEWSKI S, KRAJEWSKA M, et al. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo [J]. Oncogene, 1994,9(6):1799-805.
[139]MIYASHITA T, REED J C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene [J]. Cell,1995,80(2):293-9.
[140]PETROS A M, OLEJNICZAK E T, FESIK S W. Structural biology of the Bcl-2 family of proteins [J]. Biochim Biophys Acta,2004,1644(2-3):83-94.
[141]ZINKEL S, GROSS A, YANG E. BCL2 family in DNA damage and cell cycle control [J]. Cell Death Differ,2006,13(8):1351-9.
[142]沃兴德,洪行球,高承贤,等.姜黄素长期毒性试验[J].浙江中医学院学报,2000,(1)：61-5.
[143]DEODHAR S D, SETHI R, SRIMAL R C. Preliminary study on antirheumatic activity of curcumin (diferuloyl methane) [J]. Indian J Med Res,1980,71:632-4.
[144]CHENG A L, HSU C H, LIN J K, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions [J]. Anticancer Res,2001,21(4B):2895-900.
[1]Thompson, L. World Health Organization classification of tumours:pathology and genetics of head and neck tumours. [J] Ear, nose,& throat journal,2006,85(2): 74.
[2]Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis--a collagen metabolic disorder [J]. J Oral Pathol Med.,2005,34(6):321-8.
[3]Angadi PV, Kale AD, Hallikerimath S. Evaluation of myofibroblasts in oral submucous fibrosis:correlation with disease severity [J]. J Oral Pathol Med.,2011 Mar;40(3):208-13.
[4]Wynn TA. Cellular and molecular mechanisms of fibrosis [J].J Pathol.,2008 214(2):199-210
[5]李霞,凌天牖,高义军a-SMA在口腔粘膜下纤维性变成纤维细胞中的表达[J].中国免疫学杂志,2007,23(9)：851-6
[6]宋庆高,石冰.转化生长因子与软组织创面修复的研究进展[J].临床口腔医学杂志,2004,20(2)：126-7.
[7]Zimmerman CM, Padgett RW. Transforming growth factor beta signaling mediators and modulators [J].Gene,2000,249(1-2):17-30.
[8]Hashimoto S, Gon Y, Takeshita I, et al.Transforming growth factor-beta 1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway [J].Am J Respir Crit Care Med, 2001,163(1):152-157.
[9]胡永斌,冯德云,彭劲武,等.转化生长因子β1和丝裂原活化激酶通路调控人肺成纤维细胞表型[J].中华劳动卫生职业病杂志,2004,23(2)：109-112
[10]高义军,凌天牖,吴汉江,等.转化生长因子β-1在口腔粘膜下纤维性变角朊细胞中的表达[J].中华口腔医学杂志,1996,14(1)：20-2
[11]李霞,凌天牖,高义军,等.槟榔碱对口腔粘膜肌成纤维细胞分化的影响[J].中华口腔医学杂志,2007,42(7)：423-7
[12]余文林,曾东,苑凯华.结缔组织生长因子与器官纤维化[J].中国组织工程研究与临床康复,2007,11(23)：4610-3
[13]Folger PA, Zekaria D, Grotendorst G, et al. Transforming growth factor-beta-stimulated connective tissue growth factor expression during corneal myofibroblast differentiation [J]. Invest Ophthalmol Vis Sci.,2001,42(11): 2534-41.
[14]尹晓敏,高义军.结缔组织生长因子在口腔黏膜下纤维性变组织中的角质形成细胞中的表达[J],中国现代医学杂志,2006,16(10)：1483-1489
[15]Deng YT, Chen HM, Cheng SJ, et al. Arecoline-stimulated connective tissue growth factor production in human buccal mucosal fibroblasts:Modulation by curcumin [J]. Oral Oncol.,2009,45(9):e99-105.
[16]Shahar I, Fireman E, Topilsky M, et al. Effect of endothelin-1 on alpha-smooth muscle actin expression and on alveolar fibroblasts proliferation in interstitial lung diseases [J].Int J Immunpharmacol,1999,21(11):759-75.
[17]Shi-Wen X, Chen YL, Denton CP, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts [J]. Mol Biol Cell,2004,15(6):2707-19.
[18]冯云枝,凌天牖.槟榔提取物对人类口腔黏膜上皮角朊细胞分泌内皮素的影响[J].临床口腔医学杂志,2001,17(3)：215-8
[19]许春姣,彭解英,刘蜀凡.口腔粘膜下纤维性变组织中内皮素1的免疫组织化学和定量研究[J].华西口腔医学杂志,2000,18(6)：394-6
[20]许春姣,彭解英,刘蜀凡,等.口腔粘膜下纤维化组织中内皮素1的免疫电镜研究[J].中华口腔医学杂志,2000,35(3)：215-7
[21]Fraser D, Brunskill N, Ito T, et al. Long-term exposure of proximal tubular epithelial cells to glucose induces transforming growth factor-1 synthesis via an autocrine PDGF Loop [J]. Am J Pathol,2003,163(6):2565-74.
[22]韩为农,彭解英,刘蜀凡.血小板衍生生长因子-BB在口腔粘膜下纤维化中的表达和分布[J].中国病理生理杂志,2002,18(11)：1427-8
[23]韩为农,彭解英,徐锡萍,等.血小板衍生生长因子BB及其受体在口腔粘膜下纤维化的超微结构定位[J].华西口腔医学杂志,2002,20(4)：254-6
[24]吴颖芳,彭解英,韩为农,等.血小板衍生生长因子BB受体在口腔黏膜下纤维化组织中的表达和分布[J].临床口腔医学杂志,2004,20(1)：48-51
[25]Tang WW, Ulich TR, Lacey DL, et al. Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis[J]. Am J Pathol,1996,148 (4):1169-80.
[26]Cui Q, Wang Z, Jiang D, et al. HGF inhibits TGF-β1-induced myofibroblast differentiation and ECM deposition via MMP-2 in Achilles tendon in rat[J]. Eur J Appl Physiol.,2011,111(7):1457-63
[27]张姗姗,凌天牖HGF/c-met在口腔黏膜下纤维化组织中表达的研究[J].实用口腔医学杂志,2012,(1)：110-113
[28]Ramos C, Montano M, Garcia-Alvarez J, et al. Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression [J]. Am J Respir Cell Mol Biol., 2001,24(5):591-8.
[29]Wang R, Ramos C, Joshi I, et al. Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides[J]. Am J Physiol. 1999,277(6 Pt 1):L1158-64.
[30]WaghrayM, Cui Z, Horowitz JC, et al. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts [J].FASEB J,2005,19(7):854-6.
[31]Yanjia H, Xinchun J. The role of epithelial-mesenchymal transition in oral squamous cell carcinoma and oral submucous fibrosis [J]. Clin Chim Acta., 2007,383(1-2):51-6.
[1]陈谦明.口腔黏膜病学[M].第三版.北京：人民卫生出版社,2008：122-124
[2]Tilakaratne WM, Klinikowski MF, Saku T, et al. Oral submucous fibrosis:Review on aetiology and pathogenesis[J].Oral Oncol,2006,42(6):561-8,
[3]唐杰清,凌天牖.8例口腔粘膜下纤维性变喉镜检查结果报告[J].口腔医学,1997,17(1)：37-8
[4]International Agency for Research on Cancer. WHO classification of tumors: pathology and genetics of head and neck tumors [M]. Lyon:IARC Press,2005.181.
[5]Lee CH, Ko AM, Warnakulasuriya S, et al. Intercountry prevalences and practices of betel-quid use in south, southeast and eastern asia regions and associated oral preneoplastic disorders:An international collaborative study by asian betel-quid consortium of south and east Asia[J]. Int J Cancer.2011,129(7):1741-51.
[6]Khanna JN, Andrade NN. Oral submucous fibrosis:a new concept in surgical management. Report of 100 cases[J]. Int J Oral Maxillofac Surg.,1995,24(6):433-9.
[7]Maher R, Aga P, Johnson NW, et al. Evaluation of multiple micronutrient supplementation in the management of oral submucous fibrosis in Karachi, Pakistan [J]. Nutr Cance,1997,27(1):41-7.
[8]Lin HJ, Lin JC. Treatment of oral submucous fibrosis by collagenase:Effects on oral opening and eating function [J]. Oral Dis,2007,13(4):407-13.
[9]Rajendran R, Rani V, Shaikh S. Pentoxifylline therapy:A new adjunct in the treatment of oral submucous fibrosis[J]. Indian J Dent Res,2006,17(4):190-8.
[10]李新民,唐杰清.茶色素治疗口腔粘膜下纤维性变的临床观察[J].华西口腔医学杂志,1998,16(1)：50-2.
[11]吴颖芳,彭解英,阙国鹰,等.中西医结合治疗口腔黏膜下纤维化的疗效[J].中南大学学报(医学版),2010,35(4)：358-64.
[12]Gupta S, Reddy MVR, Harinath BC. Role of oxidative stress and antioxidants in aetiopathogenesis and management of oral submucous fibrosis[J]. Indian J Clin Biochem,2004,19(1):138-42.
[13]Kumar A, Bagewadi A, Keluskar V, et al. Efficacy of lycopene in the management of oral submucous fibrosis [J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod,2007,103(2):207-13.
[14]Rao PK. Efficacy of alpha lipoic acid in adjunct with intralesional steroids and hyaluronidase in the management of oral submucous fibrosis [J]. J Cancer Res Ther. 2010,6(4):508-10.
[15]Haque MF, Meghji S, Nazir R, et al. Interferon gamma (IFN-gamma) may reverse oral submucous fibrosis[J]. J Oral Pathol Med.2001,30(1):12-21.
[16]Tai YS, Liu BY, Wang JT, et al. Oral administration of milk from cows immunized with human intestinal bacteria leads to significant improvements of symptoms and signs in patients with oral submucous fibrosis[J]. J Oral Pathol Med, 2001,30(10):618-25.
[17]李新民,唐杰清,凌天牖.高压氧治疗口腔黏膜下纤维性变的临床观察[J].中华口腔医学杂志,1999,34(6)：340-2
[18]Cox S, Zoellner H. Physiotherapeutic treatment improves oral opening in oral submucous fibrosis. J Oral Pathol Med,2009,38(2):220-6.
[19]Chao CK, Chang LC, Liu SY, et al. Histologic examination of pedicled buccal fat pad graft in oral submucous fibrosis[J]. J Oral Maxillofac Surg,2002,60 (10):1131-4.
[20]Wei FC, Chang YM, Kildal M, et al. Bilateral small radial forearm flaps for the reconstruction of buccal mucosa after surgical release of submucosal fibrosis:a new, reliable approach[J]. Plast Reconstr Surg,2001,107(7):1679-1683.
[21]Huang IY, Wu CF, Shen YS, et al. Importance of patient's cooperation in surgical treatment for oral submucous fibrosis[J]. J Oral Maxillofac Surg,2008,66(4):699-703.
[22]Ko EC, Shen YH, Yang CF, et al. Artificial dermis as the substitute for split-thickness skin graft in the treatment of oral submucous fibrosis [J]. J Craniofac Surg,2009,20(2):443-445.