肺痹汤对大鼠肺间质纤维化干预作用的实验研究
|
摘要
本研究探讨了肺痹汤治疗肺间质纤维化的理论依据及其对博莱霉素诱导肺间质纤维化大鼠的影响。
此次实验在文献回顾和导师经验总结的基础上进行了理论研究，认为气虚血瘀，痰热互结，痹阻肺络是本病的主要发病机制。针对肺间质纤维化的病因病机，明确了肺间质纤维化的辨证思路。在临床上制定了益气活血、清热化痰、通络开痹的治疗大法。由于此法针对性强且标本兼治在临床收到满意疗效。
实验研究通过对博莱霉素诱导的7天、14天、28天不同病程的肺间质纤维化大鼠体重、细胞外基质、细胞因子、形态学以及分子生物等不同指标的观察，探讨肺痹汤抗肺间质纤维化可能的作用机制。实验研究采用国际上公认博莱霉素诱发肺纤维化的方法制作肺间质纤维化的模型，选用健康的成年SD大鼠180只，清洁级，体重200—250g。在1.5％戊巴比妥钠(2.5ml·kg~(-1))腹腔注射麻醉条件下，局部消毒后切开大鼠颈部皮肤，采用钝性剥离暴露气管，在肉眼直视下用注射器将博莱霉素A_5缓慢注入大鼠气管内，随后分层缝合并局部消毒。雄性SD大鼠180只，体重200±10g，随机分为博莱霉素(BLM)组(30只)、假手术组(30只)、中药大、中、小剂量组(90只)、阳性药物组(30只)。选用在临床中疗效较好的肺痹汤，根据人与动物剂量进行等效换算。并根据药物浓度的不同分为大、中、小3个剂量组，小剂量：中剂量：大剂量=1：2：4，中药小剂量组给药量为5ml／kg，中药中剂量组给予10ml／kg，中药大剂量组20ml／kg，每周灌胃6天。阳性药物组选用临床常规用药强的松，灌胃给予3.5mg／kg，加水稀释为含生药0.35mg／ml，每周灌胃6天。假手术组及模型组均给予生理盐水2ml灌胃，肺间质纤维化造模成功后第1天各治疗组即开始给药。6组动物同步于实验开始后的第7、14、28天分别随机处死10只。用1.5％戊巴比妥钠腹腔注射麻醉(2.5ml·kg~(-1))后将大鼠固定，腹主动脉取血，分离血清，同时取出肺脏；观察并记录大鼠的体重；采用放免法检测血清中透明质酸、Ⅲ型胶原及白介素-6的含量。采用右肺组织进行病理检测，行HE染色比较肺泡炎及肺纤维化程度。左肺采用免疫组化法检测肺组织中TGF-β1表达；左肺组织匀浆后，采用免疫印迹杂交法(Western blot)检测大鼠肺组织中p38分裂原激活蛋白酶(p38MAPK)表达。
研究结果显示：在各个时间点，肺痹汤各剂量组较模型组可以抑制P38MAPK磷酸化活性和下调Ⅲ型胶原透明质酸和IL-6细胞因子含量，改善肺泡炎及肺纤维化的程度，降低TGF-β_1在肺组织中的表达。其中7d、14d、28d时肺痹汤中剂量的降低作用较为显著，并与大、小剂量组比较具有差异性。说明肺痹汤能显著抑制肺间质纤维化大鼠基质重建的作用。
本课题的创新之处在于用实验研究的方法探讨了肺痹汤对肺间质纤维化干预的作用。肺痹汤治疗肺间质纤维化是通过干预P38MAPK转导通路，抑制P38MAPK磷酸化活性和下调Ⅲ型胶原透明质酸和IL-6细胞因子含量，降低TGF-β_1在肺组织中的表达等作用实现的。同时，以上的创新也为对肺间质纤维化的进一步研究奠定了基础。
The research explored the theory basis of Feibitang on treating the pulmonaryfibrosis and its effects to pulmonary fibrosis rats caused by bleomycin.
On the basis of literature review and tutor clinical practice experiencesummary, got the idea that the main pathogenesis of the disease is theqi-deficiency and blood stasis, the stasis of phlegm and heat, obstruction of thelung collateral. Making clear that the thought of pulmonary fibrosis according tothe pathological factor and pathology. Setting up the treating principle thattonifying qi and promoting blood circulation, clearing heat and removing thephlegm, expel the obstruction from collaterals. It has satisfied effects in clinic forits strong pertinence and both treating the mark and root.
The experimental research observed the height、extracellular matrix、cytokine、morphology and molecular biology of the pulmonary fibrosis rats indifferent course of disease which is 7d、14d、28d induced by bleomycin. Exploringthe probable mechanism of Feibitang in the pulmonary fibrosis treatment.Establishing the pulmonary fibrosis rats mode by the method of bleomycininducement. Choosing 180 SD rats(SPF), height200—250g. Anaesthesia methodwas 1.5% sodium pentobarbital abdominal injection, cutting the neck skin of therats after local sterilization. Blunting peeling off the trachea and injecting thebleomycin A5 into the trachea slowly, then stitch up the wound. 180 SD male rats,height 200±10g, dividing into BLM group(30 rats)、sham operated group(30 rats)、experimental large、middle、small group(90 rats)、positive drugs group(30 rats).Converting the Feibitang dosage between human and animals according to theequivalent dosage. And dividing three different dosage group according to theconcentration, small:middle:large=1:2:4. The concentration of the small dosage group is 5ml/kg, the middle group is 10ml/kg, the large group is 20ml/kg, 6d drugsfor a week. The positive drugs group choosed the common drugs prednisone inclinic, sham operated group and control group were given 2ml normal saline perday. All the group were given the drug after the first day of the success modeestablish of the lung interstitial fibrosis. The six group rats were killed since the 7,14、28 days of the experimental. Getting the serum and the lung of the rats by the1.5% sodium pentobarbital abdominal injection anaesthesia. Observing andrecording the rats height, detecting the amount ofⅢtype collagen, hyaluronicacid and IL-6 in the serum with the method of the radioimmunoassay. Doingpathology detection with the right lung tissue and comparing the degree ofalveolitis and pulmonary fibrosis with the method of HE staining. Observing theexpression of the TGF-β1 in the left lung tissue with the method of immunehistochemistry. Detecting the p38MAPK expression in the lung tissue with themethod of Western blotting.
The result showed that the experimental group can restrain thephosphorylation activity of P38MAPK and down-regulate the amount ofⅢtypecollagen hyaluronic acid and IL-6, improve the degree of alveolitis and pulmonaryfibrosis, decrease the expression of TGF-β1 in the lung tissue compared with themode group at all times. The most obvious decreased function of the Feibitang isthe middle-dosage group at 7 days. 14, 28d, the Feibitang function ofmiddle-dosage group is most significant. It indicated that the Feibitang canrestrain the matrix reconstruction in the lung interstitial fibrosis rats significantly.
The innovation of the project is exploring the function of Feibitang ininterfering the pulmonary fibrosis. By interfering the P38MAPK transductionpassway, restraining the phosphorylation activity of P38MAPK and down-regulating the amount ofⅢtype collagen hyaluronic acid and IL-6,decreasing the expression of TGF-β_1 in the lung tissue. Meanwhile, thisinnovation settled the basis of the further research of the pulmonary fibrosis.
此次实验在文献回顾和导师经验总结的基础上进行了理论研究，认为气虚血瘀，痰热互结，痹阻肺络是本病的主要发病机制。针对肺间质纤维化的病因病机，明确了肺间质纤维化的辨证思路。在临床上制定了益气活血、清热化痰、通络开痹的治疗大法。由于此法针对性强且标本兼治在临床收到满意疗效。
实验研究通过对博莱霉素诱导的7天、14天、28天不同病程的肺间质纤维化大鼠体重、细胞外基质、细胞因子、形态学以及分子生物等不同指标的观察，探讨肺痹汤抗肺间质纤维化可能的作用机制。实验研究采用国际上公认博莱霉素诱发肺纤维化的方法制作肺间质纤维化的模型，选用健康的成年SD大鼠180只，清洁级，体重200—250g。在1.5％戊巴比妥钠(2.5ml·kg~(-1))腹腔注射麻醉条件下，局部消毒后切开大鼠颈部皮肤，采用钝性剥离暴露气管，在肉眼直视下用注射器将博莱霉素A_5缓慢注入大鼠气管内，随后分层缝合并局部消毒。雄性SD大鼠180只，体重200±10g，随机分为博莱霉素(BLM)组(30只)、假手术组(30只)、中药大、中、小剂量组(90只)、阳性药物组(30只)。选用在临床中疗效较好的肺痹汤，根据人与动物剂量进行等效换算。并根据药物浓度的不同分为大、中、小3个剂量组，小剂量：中剂量：大剂量=1：2：4，中药小剂量组给药量为5ml／kg，中药中剂量组给予10ml／kg，中药大剂量组20ml／kg，每周灌胃6天。阳性药物组选用临床常规用药强的松，灌胃给予3.5mg／kg，加水稀释为含生药0.35mg／ml，每周灌胃6天。假手术组及模型组均给予生理盐水2ml灌胃，肺间质纤维化造模成功后第1天各治疗组即开始给药。6组动物同步于实验开始后的第7、14、28天分别随机处死10只。用1.5％戊巴比妥钠腹腔注射麻醉(2.5ml·kg~(-1))后将大鼠固定，腹主动脉取血，分离血清，同时取出肺脏；观察并记录大鼠的体重；采用放免法检测血清中透明质酸、Ⅲ型胶原及白介素-6的含量。采用右肺组织进行病理检测，行HE染色比较肺泡炎及肺纤维化程度。左肺采用免疫组化法检测肺组织中TGF-β1表达；左肺组织匀浆后，采用免疫印迹杂交法(Western blot)检测大鼠肺组织中p38分裂原激活蛋白酶(p38MAPK)表达。
研究结果显示：在各个时间点，肺痹汤各剂量组较模型组可以抑制P38MAPK磷酸化活性和下调Ⅲ型胶原透明质酸和IL-6细胞因子含量，改善肺泡炎及肺纤维化的程度，降低TGF-β_1在肺组织中的表达。其中7d、14d、28d时肺痹汤中剂量的降低作用较为显著，并与大、小剂量组比较具有差异性。说明肺痹汤能显著抑制肺间质纤维化大鼠基质重建的作用。
本课题的创新之处在于用实验研究的方法探讨了肺痹汤对肺间质纤维化干预的作用。肺痹汤治疗肺间质纤维化是通过干预P38MAPK转导通路，抑制P38MAPK磷酸化活性和下调Ⅲ型胶原透明质酸和IL-6细胞因子含量，降低TGF-β_1在肺组织中的表达等作用实现的。同时，以上的创新也为对肺间质纤维化的进一步研究奠定了基础。
The research explored the theory basis of Feibitang on treating the pulmonaryfibrosis and its effects to pulmonary fibrosis rats caused by bleomycin.
On the basis of literature review and tutor clinical practice experiencesummary, got the idea that the main pathogenesis of the disease is theqi-deficiency and blood stasis, the stasis of phlegm and heat, obstruction of thelung collateral. Making clear that the thought of pulmonary fibrosis according tothe pathological factor and pathology. Setting up the treating principle thattonifying qi and promoting blood circulation, clearing heat and removing thephlegm, expel the obstruction from collaterals. It has satisfied effects in clinic forits strong pertinence and both treating the mark and root.
The experimental research observed the height、extracellular matrix、cytokine、morphology and molecular biology of the pulmonary fibrosis rats indifferent course of disease which is 7d、14d、28d induced by bleomycin. Exploringthe probable mechanism of Feibitang in the pulmonary fibrosis treatment.Establishing the pulmonary fibrosis rats mode by the method of bleomycininducement. Choosing 180 SD rats(SPF), height200—250g. Anaesthesia methodwas 1.5% sodium pentobarbital abdominal injection, cutting the neck skin of therats after local sterilization. Blunting peeling off the trachea and injecting thebleomycin A5 into the trachea slowly, then stitch up the wound. 180 SD male rats,height 200±10g, dividing into BLM group(30 rats)、sham operated group(30 rats)、experimental large、middle、small group(90 rats)、positive drugs group(30 rats).Converting the Feibitang dosage between human and animals according to theequivalent dosage. And dividing three different dosage group according to theconcentration, small:middle:large=1:2:4. The concentration of the small dosage group is 5ml/kg, the middle group is 10ml/kg, the large group is 20ml/kg, 6d drugsfor a week. The positive drugs group choosed the common drugs prednisone inclinic, sham operated group and control group were given 2ml normal saline perday. All the group were given the drug after the first day of the success modeestablish of the lung interstitial fibrosis. The six group rats were killed since the 7,14、28 days of the experimental. Getting the serum and the lung of the rats by the1.5% sodium pentobarbital abdominal injection anaesthesia. Observing andrecording the rats height, detecting the amount ofⅢtype collagen, hyaluronicacid and IL-6 in the serum with the method of the radioimmunoassay. Doingpathology detection with the right lung tissue and comparing the degree ofalveolitis and pulmonary fibrosis with the method of HE staining. Observing theexpression of the TGF-β1 in the left lung tissue with the method of immunehistochemistry. Detecting the p38MAPK expression in the lung tissue with themethod of Western blotting.
The result showed that the experimental group can restrain thephosphorylation activity of P38MAPK and down-regulate the amount ofⅢtypecollagen hyaluronic acid and IL-6, improve the degree of alveolitis and pulmonaryfibrosis, decrease the expression of TGF-β1 in the lung tissue compared with themode group at all times. The most obvious decreased function of the Feibitang isthe middle-dosage group at 7 days. 14, 28d, the Feibitang function ofmiddle-dosage group is most significant. It indicated that the Feibitang canrestrain the matrix reconstruction in the lung interstitial fibrosis rats significantly.
The innovation of the project is exploring the function of Feibitang ininterfering the pulmonary fibrosis. By interfering the P38MAPK transductionpassway, restraining the phosphorylation activity of P38MAPK and down-regulating the amount ofⅢtype collagen hyaluronic acid and IL-6,decreasing the expression of TGF-β_1 in the lung tissue. Meanwhile, thisinnovation settled the basis of the further research of the pulmonary fibrosis.
引文
[1] 翁心植，王辰．呼吸内科专题讲座．郑州大学出版社，2005，165-166．
[2] 李素云，朱佳，吴纪珍．抗纤颗粒治疗弥漫性肺间质纤维化及其对细胞因子的影响[J]．中国中医药信息杂志．2002；9(5)：26-27．
[3] 廖远芳．论肺间质纤维化病名．辽宁中医学院学报，2003，5(3)：225．
[4] 王海彤，武维屏．中医药治疗弥漫性肺间质纤维化信息讨论．中国中医药信息杂志，1996，3(7)：25-26．
[5] 李素云．曹世宏教授治疗肺间质纤维化经验介绍．新中医，2003(35)9期：10-11．
[6] 王玉光，周平安，刘清泉．肺痹证治新诠．中国中医基础医学杂志，2002，8(7)：486-487．
[7] 杨效华、张晓梅、孙海燕．肺间质纤维化的中医药治疗．中国临床医生杂志，2002，3：43-45．
[8] 姜良铎，秦英，杨君等．试论“环境毒”．中国中医基础医学杂志，1999，5(9)：4-6．
[9] 张天嵩．特发性肺纤维化的中医病机探讨．中医函授通讯，1999，18(3)：14-15．
[10] 孔祥文．特发性肺纤维化的中医治疗．现代中西医结合杂志，2003，12(1)：67-68．
[11] 刘伟．弥漫性肺间质纤维化辨治心得．吉林中医药，2003，23(4)：4．
[12] 许振亚，徐振荣．特发性肺间质纤维化的辨治．辽宁中医杂志，1997，24(11)：500．
[13] 龚婕宁，王灿晖．论肺间质纤维化的中医病理学特点．浙江中医杂志，2001，4：139-140．
[14] 王新华等．特发性肺间质纤维化的中西医治疗．贵阳中医学院学报．2000．12；22(4)：3-4．
[15] 陈献亮．虫草汤配合激素治疗特发性肺间质纤维化21例．陕西中医．2002．23(10)：877．
[16] 赵子贤等．补气通肺饮对平阳霉素A5诱发大鼠肺间质纤维化干预作用的试验研究。1999；23(6)：462-469．
[17] 智屹惠．曹世宏教授论治肺间质纤维化．南京中医药大学学报．2001．5；17(3)：185-186．
[18] 蒋宁等．中医络病学说与肺间质纤维化病机关系初探．中国中医基础医学杂志．2003；9(5)：21-23．
[19] 王小平，李晓光，甘丽虹，等．中医治疗特发性肺间质纤维化22例．北京中医药大学学报，2001，24(1)：77．
[20] 赵兰才，武维屏．肺间质纤维化的中医研究进展述评．北京中医药大学学 报，2000，23(4)：70-72．
[21] 李真等．呼吸病诊疗全书．第1版．北京：中国医药科技出版社，2000，404-405．
[22] 张天嵩，韩镭，吴银根．肺纤维化34例辨证分型与CRP计分的关系．辽宁中医杂志，2001，28(11)：646-648．
[23] Liu W M, Xu Q Y, Lin YH, et al. Study of influence of 25% Angelica Injection to Bleomycin-induced pulmonary fibrosis [J].J Wuhan Univ, 2001; 2(4): 326-327.
[24] Krishna G, Liu K, Shigemitju H, et al. PG-490-88, A Deriva-tive Triptolide, Blocks Bleomycin-induced Lung Fibrosis. Am [J]. Pathol. 2001; 158: 997-1004.
[25] Song J P, Li W, Li R Q, et al. Effect of Wu she San on the levels of lamin in and procellgen Ⅲ. in the Bronchio-alvel-lar fluid in rat with pulmonary fibrosis[J].J Inf TraditChin Med. 2001: 8(10):28-31.
[26] 陈建，何冰，刘新民，等．银杏叶制剂治疗肺间质纤维化的实验研究[J]．中国中西医结合杂志，2000；2((6)：441-443．
[27] 洪长福，娄金萍，周华仕，等．桃仁提取物对大鼠实验性矽肺纤维化的影响[J]．浙江省医学科学院学报，2000；、11(1)：7-8．
[28] 刘娟．特发性肺间质纤维化中医治疗方法概况．中国中医药信息志．2000；7(8)：11-12．
[29] Gong J N, Yang J, Zhou K F. Preventing and treating effect on mondel of pulmonary fibrosis by yangfeihuoxue Decoction [J]. Chin J Basic Med Tradit Chin Med. 2001: 7(6):31-33
[30] Xu J, Liu X K. Experimental study on effect of Xuefuzhu-yu Decoction. in Pinyang mycin-induced pulmonary fibrosis[J] Inf Tradit Chin Med. 2000; 1(1): 49-50.
[31] 王海峰．温润养血方治疗特发性肺间质纤维化20例临床观察．浙江中医杂志2003．3：106-107．
[32] 彭玉华．特发性肺间质纤维化中医药治疗思路与方法．中医药学刊．2003．10；21(10)：1774-1775．
[33] 王书臣，崔红，王伟，等．弥漫性肺间质纤维化辨证心得．中医杂志，1998，39(9)：532-533．
[34] 王小平，李晓光，甘丽虹，等．中医治疗特发性肺间质纤维化22例．北京中医药大学学报，2001，24(1)：77．
[35] 侯杰，蔡后荣，戴令娟．川芎和丹参联合泼尼松治疗特发性肺纤维化疗效观察．实用老年医学，2001．04．20；15(2)：99-101．
[36] 董盛等．沈舒文教授从痰瘀辨治难治病验案举隅．陕西中医．2003；24(12)：1107-1108．
[1] 翁心植，王辰．呼吸内科专题讲座．郑州大学出版社，2005，165-166．
[2] American Thoracic Society. Idiopathic pulmonary fibrosis:diagnosis treatment. International consensus statement. Ameri-can Thoracic Society(ATS) and European Respiratory.
[3] Wai KT, et al. Oxalate selectively activates p38 mitogen·activated protein kinase and c—JunN·term Anal kinase signal transduction pathways in renal epithelial ceils. Am J Respir Crit Care Med. 1994; 150:670-675.
[4] Hubbard RS, et al. Increased phosphory lated extrace llulars ignal regulated kinase immuno reactivity associated with proliferative and morphologic tung alterations after chrysotile asbestos inhalation in mice. Lancet. 1996; 347:284-289.
[5] Scott, JI. etal. MontieI—Duarte C. Oses--Prieto JA. el al. p38M APK mediates the regulation of alphal(Ⅰ) procollagen mRNA levels by TNF—alpha and TGF—beta in a cell line of rat hepaticsteIlate cells Br Med J, 1990; 301:1015-1017.
[6] Ward RY, et al. Eduction in pulmonary fibrosis in vivo byhal ofuginone gur Respir J, 1997; 10,2881-2883.
[7] Hubbard RA, et al. Myofibroblast ac-cumulation correlates with the formation of fibrotic tissue in a rat air pouch model J Respir Crit CareMed, 1998; 157:743-747.
[8] 陈灏珠．实用内科学[M]．第11版．北京：人民卫生出版社，2001，1622-1625．
[9] 李芳等．特发性肺间质纤维化的现代治疗进展．国外医学呼吸系统分册2003；23(1)：45-49
[10] Katzenstein ALA, Myers JL. Idiopathic pulmonary fibrosis Clinical relevance of pathological classification. AM J Respir Crit Care Med, 1998,157:1301-1315
[11] Moises S, Talnadge E, King Jr, et al. Idiopathic PulmonaryFibrosis:prevailing and evolving hypotheses about its patho-Genesis and implications for therapy. Ann IntMed, 2001; 134(2):136-151.
[12] 中华医学会呼吸病学分会，2002年4月：特发性肺(间质)纤维化诊断和治疗指南(草案)中华呼吸结核杂志，2002，25(4)：11-18．
[13] Flaherty K R, Travis W D, Colby T V, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Resoi Crit Care Meal, 2001, 164(9): 1722-1727.
[14] AmericanThoracicSociety. ldiopathicpulmonaryfibrosis, diagnoandt reatment. International consensus statemen. American Tracic Society,and the European Respiratory Society ER. Am J Respir Crit Care Med, 2000, 161 (2Pt1) :646.
[15] Robert J, Mason, Marvinl et al. Pharmacological therapy foridio pathic pulmonary fibrosis. Am J Respir Crit Card Med, 1999, 160(5Pt1): 1771-1777.
[16] Coker R K, Laurent G J. Aanticy to kine approaches in pulmonary fibrosis: bring factors into focus. Thorax, 1997, 52(3): 294-296.
[17] Raghu G. Idiopathic pulmonary fibrosis: aneed for treatment with drugs other than cortico steroidsarolefor antifibrotic agents Mayo Clin Proc, 1997, 72(3): 285-287.
[18] Lossos I S, Breuer R, Shrik iM, e tal. Peribronchial lymphocyte activation in bleomycin induced lung injury. Life Sci, 1998, 63(13): 1183-1193.
[19] Undurraga A, Meneses M, Oyarszun M. Evaluation of treatment with cyclosporine in three patients with pulmonary fibrosis. Rev Med Chil, 199, 125(6): 690-695.
[20] Varai G, Earle L, Jimenez S A, et al. A pilot study of intermittent intrare nouscy clophosphumide for the treatmentofsystemics clerosis associated lung disease. JRheumatol, 1998, 25 (7): 1325-1329.
[21] Entzian P, Schlaak M, Seltzer U, et al. Antiinflannatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis. Lung, 1997, 175(1): 41-51.
[22] Douglas W W, Ryu J H, Bjoraker J A, et al. Colchicine versus prednisoneas treatment of usua linterstitial pneumonia. Mayo Clin Proc, 1997, 72(3): 201-209.
[23] Douglas W, Ryu J H, Swensen S J. et al. Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis: a randomized prospective study. Am Respir Crit Care Med, 1998, 158: 220
[24] Coker R K, Laurent G J. Pulmonary fibrosis: cytokines in the balance. Eur RespirJ, 1998, 11 (6): 1218-1221.
[25] 许仁和．特发性肺间质纤维化(IPF)诊治进展．山东医药．2001；41(20)：61-63．
[26] 黄绍光．肺内科新进展．2000．257-276．
[27] 郑建等．特发性肺间质纤维化诊治进展．中国综合临床．2003．12 19(12)：1065-1067．
[28] Iyer SN, Gurujeyalakshmi G, Giri SN. Effect of pirfenidone on transforming growth factor-β gene expression at the transcri-ptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther. 1999; 291: 367-373.
[29] 曹兆龙等．特发性肺间质纤维化诊疗进展．世界药品信息．2002．(4)：14-17．
[30] Raghu G, Johson WC, Lockhart D, et al. Treament of idiopath-ic pulmonary fibrosis with a new antifibrotic agent, pirfeni-done: results if a prospective, open-label Phase Ⅱ study. Am J Respir Crit Care Med. 1999; 291: 367
[31] Thorsell A, Blomqvist AG, Heilig M. Cationlipid mediated delivery and expression in rat: feasibility and limitations. Regulatory Peptides, 1996, 61: 205-211.
[32] Blivet S, Philit F, Sab J M, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respirator failure. Chest, 2001, 120: 209-212.
[33] Stern J B, Herv Mal, Groussard O, et al. Prognosis of patients with Advanced idiopathic pulmonary fibrosis requiring mechanica Ventilation for acute respiratory failure. Chest, 2001, 120: 213-219.
[34] Rosenfeld MA, Siegfried W, Yoshimurak, et al. idenovirus mediated transfer of arecombinantal antiryps ingene to the lung epithelim invivo. Science, 1991, 252: 431-434.
[35] 田欣伦 朱元珏，特发性肺间质纤维化与继发于结缔组织病的肺间质病的临床比较．中华老年医学杂志，2004，23(5)：304-307．
[36] Venkatesan N, Roughley P J, Proteo glycan expression in bleomycin lung fibroblasts: Am J Physiol Lung Cell Mol Physiol, 2002, 283(4): L806-814.
[37] Yamazaki C, Hoshino J, Hori Y, et al. Effect of lecithinized-superoxide dismutase on the interstital pneumonia model induced by bleomycin in mice. Jpn J Pharmacol, 1997, 75(1): 97-100.
[38] Kold M, Galt T, et al. Transient transgene expression of decorin in the lung reduce the fibrotic response to bleomycin. Am J Respir Crit Care Med, 2001, 163(3P t 1): 770-777.
[39] Du Bois R M. Interferon gamma-1b for the treatment of idiopathic pulmonary fibrosis. N Engl J Med, 1999, 341(17): 1302-1304.
[40] 李坚，张德厚，丁明等，无创正压通气在特发性肺纤维化并呼吸衰竭患者中的应用．中国综合临床，2005，21(8)：686-688．
[41] Snell G I, Walters E H, Kotsimbos T C, et al. Idiopathic pulmonary fibrosis: in need of focused and systematic management. Med J Aust, 2001; 174: 137-140.
[42] Meyers B F, Lynch J P, Trulock E P, et al. Singlever susbilateral lung transplantation for idiopathic pulmonary fibrosis: a ten-year in stitution alexperience. JThorac Cardiovasc Surg, 2000; 120: 99-107
[1] 仝润芍．血府逐瘀汤加减治疗弥漫性间质性肺炎46例．河南中医，1999，31(11)：42．
[2] 陶凯，周晓园．肺通口服液治疗间质性肺病20例．北京中医，1997，(2)：13-15．
[3] 周晓园，陶凯，顾振东．肺通治疗放化疗所致肺间质纤维化10例．实用中西医结合杂志，1997，10(19)：1924～1925．
[4] 刘良倚．阳和汤治疗肺系病证验案举隅．山西中医，2000，16(1)：57．
[5] 辛洪涛，等．益气活血法治疗肺间质纤维化临床研究：附18例报告．山东医药，2001，41(24)：9-11．
[6] 张天嵩，赵子贤，马君，欧阳修河．补气通肺汤治疗特发性肺纤维化12例．浙江中医杂志，1999，34(2)：54-55．
[7] 蒋云峰．黄芪桃红汤治疗特发性肺纤维化24例．吉林中医药，2003，23(11)：14．
[8] 王海峰．温润养血方治疗特发性肺间质纤维化20例临床观察．浙江中医杂志．2003．3：106-107．
[9] 田欣伦 朱元珏，特发性肺间质纤维化与继发于结缔组织病的肺间质病的临床比较．中华老年医学杂志，2004，23(5)：304-307．
[10] Blivet S, Philit F, Sab J M, et al. Out come of patients with idiopathic pulmonary fibrosis admitted to the ICU for respirator failure. Chest, 2001, 120: 209-212.
[11] Stern J B, Herv Mal, Groussard O, et al. Prognosis of patients with Advanced idiopathic pulmonary fibrosis requiring mechanica Ventilation for acute respiratory failure. Chest, 2001, 120: 213-219
[12] DouglasWW, RyuJH, SchroederDR. Idiopathic pulmonaryfibrosis:Impact of oxygen and colchincine, prednisone, or notherapy on Survival. Am J Respir Crit Care Med. 2000; 161(4) 1172-1178.
[13] 高燕，雍政，黄英，等．百草枯建立肺纤维化动物模型的实验研究．空军总医院学报，2003，19(4)：201-203．
[14] 胡平，张光斌．胺碘酮的肺毒性机理．华西药学杂志，1993，8(3)：173-174．
[15] 刘珊，范桂香．两种小鼠肺纤维化造模方法的比．2004，25(3)：244-246．
[16] Barth RK, Hanchett LA, Baecher Allan CM. Mapping susceptibility genesfortheinductionofpulmonaryfibrosisinmice. Chest, 2002, 121Suppl3-21.
[17] Szapiel SV, Elson N, FulmurJD, et al. Bleomycin induced interstitial pulmonary disease in the nude, athy micmouse. Am Rev Respir Dis, 979, 120: 893-897.
[18] Davis G S, Pfeiffer L M, Hemenway D R. Interferon Cproduction by specific lung lymphocytepheno type sinsilicsis in mice. Am J Respir Cell Mol Biol, 2000, 22: 4912-501.
[19] Robledo R F, Buder Hoffmann S A, Cummins A B, et al. Increased phosphory fated extrace llulars ignal regulated kinase immuno reactivity associated with proliferative and morphologic lung alterations after chrysotile asbestos inha'lation in mice. Am J Pathol, 2000, 156: 1307-1316.
[20] 王健，黄志兰，王涛，等．平阳霉素致肺纤维化动物模型高分辨率CT的评价．第三军医大学学报，1998，20：419-422．
[21] Ekekezie II, Thibeault DW, Rezaeikhaligh MH, et al. Highdose inhaled nitricoxide and hyperoxiai ncreases lungcollagen accumulation inpiglets. Biol Neonate, 2000, 78(3): 198-206.
[22] 姜晓姝，王孝铭，刘晓滨．雾化吸入平阳霉素法致小白鼠肺纤维化的观察．哈尔滨医科大学学报，1995，29(1)：4-5．
[23] YunZhao, Shah DU. Expression of transforming growthfactor B type and type receptor sisalteredinrat lung sunder going bleomycin induced pulmonary fibrosis. Exp Mol Pathol, 2000, 69: 67-68.
[24] 张纾难，韩春生．一种新的肺纤维化造模方法．中日友好医院学报，1997，11(4)：283-285．
[25] 王和枚，瞿文生，余寿忠，等．胺碘酮所致大鼠肺毒性．中国药理学与毒理学杂志，1999，13(4)：301-305．
[26] 王梅，傅强，闵碧荷，等．磷酸羟基哌喹对大鼠放射性肺纤维化的防治作用．中国癌症杂志，2002，12(6)：519-521．
[27] Mclanghlin R F, Tyler W, Canada RO. A study of the subgross pulmonary anatomin various mammals. Am J Anat, 1961, 108(1): 149-165.
[28] 李彦敏，勾宏国，刘意，等．微波热效应对家兔正常肺组织损伤的试验研究．中国医科大学学报，1996，25(2)：189-190．
[29] Snider GI. Chronicinter stitial pulmonary fibrosis produce din hamsters by endotracheol bleomycin. Am Rev Respir Dis, 1978, 117: 1099-1104.
[30] Selman M, Montano M, Montfort, et al. A new model of diffuse interstitial pulmonary fibrosis in the rat .Exp Mol Pathol, 1985, 43(1): 375-387.
[31] 赵洪文，彭璐，吕长俊，等．肺纤维化大鼠BALF中的细胞成分与肺组织病理的动态研究．中国医科大学学报，1997，26(5)：463-466．
[32] Blaisdell RJ, Schiedt M J, Giri SN. Dietary supplementation with taurine and niacinprevents the increase in lung collagen cross links in the multidose bleomycin hamster modeofpulmonary fibrosis. J Biochem Toxicol, 1994, 9 (2): 79-86.
[33] Nagler A, Firman N, Feferman R, et al. Eduction in pulmonary fibrosis in vivo byhal ofuginone.Am J Respir Crit Care Med, 1996, 154(4): 1082-1086.
[34] Rubin P, Johnston CJ, Williams JP, et al. Aperpetual cascade of cytokines postir radiation leads to pulmonary fibrosis, lnt JRadiatnol Biol Phys, 1995, 33 :99-109.
[35] Daba MH, Abdel Aziz AA, Moustafa AM, et al. Effects of Lcarnitine and gink gobilobaextract(EGb761)inexperimentalbleomycininducedlung fibrosis. Pharmacol Res, 2002, 45(6): 461-467.
[36] Mitsuhiro Yoshida, Junko Sakuma Mochizuki, Kinpya Abe, et al. Invivo gene transfer of anextrace llulardomain of platelet derived growth factor breceptor by the HV liposome methoda meliorates bleomycin induced pulmonary fibrosis. Bioche Biophy Res Comm, 1999, 265: 503-508.
[37] Snider G I. Chronicinter stitial pulmonary fibrosis produce din hamsters by endotracheol bleomycin .Am Rev Respir Dis, 1978, 117: 1099-1104.
[38] Gong J N, Yang J, Zhou K F. Preventing and treating effect on mondel of pulmonary fibrosis by yangfeihuoxue Decoction[J]. Chin J Basic Med Tradit Chin Med. 2001: 7(6): 31-33.
[39] Han L. Study on the influence of Buqitongfei Yin in the flui-dity of red blood cell membrane of Bleomycin-induced pulmonary fibrosis in rat [J]. J Shandong Univ Tradit Chin Med. 2001; 19(5): 441-442.
[40] 宋建平，刘方州，李瑞琴，等．栝萎薤白汤、麦门冬汤及肾气丸对平阳霉素所致肺纤维化的影响[J]．国医论坛，2001；16(4)：40-41．
[41] 宫晓燕，王泽玉，张永和．纤克颗粒治疗特发性肺间质纤维化实验研究．长春中医学院学报，2005(1)：70-72．
[42] 朱际平，丁蓉．温润养血颗粒对肺间质纤维化模型大鼠肺泡灌洗液TNF-α浓度的影响．南京中医药大学学报，2003，6：762—764．
[43] 周淼．益阴活血汤对大鼠肺纤维化作用的实验研究用．河南中医学院学报，2004，19(1)：89-92．
[44] 欧阳修河，韩荣庆，张天蒿，等．补气通肺饮对大鼠肺纤维化的作用．中药新药与临床药理，1999，10(2)：93-94．
[45] 张秀芹、解砚英等．肺通口服液对大鼠肺纤维化模型的治疗作用．青岛大学医学院学报，2003，39(1)：39-41．
[46] 刘景艳，修清玉，张铁锋．中药对肺纤维化动物模型细胞因子表达的影响．中国临床医学，2005，12(2)：24-26．
[47] Molteni A, Moulder J E, Cohen E F, et al. Control of radiation induced pneumopathy and lung fibrosis by anziotensin—converting enzyme inhibitors and anangiotensin Ⅱ type 1 receptor blocker, Int J Radiat Biol, 2000; 76: 523-532.
[48] 李楠，何冰，马靖．辛伐他汀对大鼠肺成纤维细胞的影响观察，心肺血管病杂志，2002，21(2)：105-108．
[49] Tan A, Levrey H, Dahm C, et al. Lovastatin induces fibro blastapoptosis in vitro and in vivo. A possible therapy for fibro proliferative disorders. Am J Respir Crit Card Med, 1999, 159(1): 220-227
[50] Morrison C D, Papp A C, Hejmanowski A Q, et al. Increased Dallel frequency of the angiotensin converting enzyme genein pulmonary fibrosis. Human Pathol, 2001, 32 (5): 25-21.
[51] 赵峰，戚好文，赵一玲，吕荣，氟伐他汀对博来霉素A5致大鼠肺纤维化的治疗作用；第四军医大学学报，2002：23(6)：493-496
[1] 翁心植，王辰．呼吸内科专题讲座．郑州大学出版社．2005，168．
[2] 宋雅芳，徐列明，洪嘉禾．转化生长因子β1的c-jun氨基端激酶和p38蛋白激酶通路及其抑制剂与纤维化．[J]．中西医结合学报，2004．2(5)：382—383．
[3] 李素云．曹世宏教授治疗肺间质纤维化经验介绍．新中医，2003(35)9：10—11．
[4] 河南省卫生厅编．河南省老中医经验集锦．河南科学技术出版社．1983：44-46．
[5] 周仲瑛主编．中医内科学．北京：中国中医药出版社，2003，155-158．
[1] 翁心植，王辰．呼吸内科专题讲座．郑州大学出版社，2005，168．
[2] 姜莉，陈佰仪，侯显明，等．肺纤维化大鼠肺泡巨噬细胞细胞因子的研究．中国医科大学学报，1998，27：471-474．
[3] Emura M, NaggiS, TakeuchiM, et al. In vitro production ofB cell growth factor and B cell differentiation factor byperiphral blood mononuclear cells and bronchoalvar lavage Tlymphocytes from patients with idio pathic pulmonary fibrosis. Clin Exp Immunol, 1990, 82: 133-139.
[4] Moodley YP, Misso NL, Scaffidi AK, et al. Inverse effect s ofinterleukin26 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. Am J Respir Cell Mol Biol, 2003, 29: 490-498.
[5] Ramos C, Montano M, Garcia-Alvarez J, et al, Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue in hibitor of met al oproteinases expression. Am J Respire Cell Mol Biol, 2001, 24(3): 591-598.
[6] Ghosh AK. Factors involved in the regulation of type Ⅰ collagen gene expression: impliction in fibrosis.Exp Biol Med, 2002,227(5):301-314.
[7] NaozumiH, Hhongjin, Bone M. Cderived progenitor cells in pulmonary fibrosis. J ClinInvest 2004, 113(2): 243-252.
[8] 马均．补气通肺汤对肺纤维化大鼠病理及血，BALF中HA，LN的影响．中国中医药信息杂志，1999．6(11)：40．
[9] Bjardahlen A, Onnervik P O, Westergern G, et al. Myofibroblast accumulation correlates with the formation of fibrotic tissue in a rat air pouch model. J Rheumatol, 2002, 29 (8): 1698.
[1] Mclanghlin R F,Tyler W,Canada RO.A study of the subgross pulmonary anatomin various mammals.Am J Anat,1961,108(1):149-165
[2]Szapiel S V, Elson N A, Fulmur J D, et al. Bleomycin induced interstitial pulmonary disease in the nude, athy micmouse. Am Rev Respir Dis, 1979, 120:893 — 897
[3]Ekekezie II,Thibeault DW, Rezaeikhaligh MH,et al. Highdose inhaled nitricoxide and hyperoxiai ncreases lungcollagen accumulation inpiglets. Biol Neonate, 2000, 78 (3) : 198-206.
[4]Snider G I. Chronicinter stitial pulmonary fibrosis produce din hamsters by endotracheol bleomycin. Am Rev Respir Dis,1978 117:1099-1104
[5]Blaisdell R J, Schiedt M J, Giri S N.Dietary supplementation with taurine and niacinprevents the increase in lung collagen cross links in the multidose bleomycin hamster mode of pulmonary fibrosis. J Biochem Toxicol, 1994, 9(2) :79-86.
[6]Beeh K M, Beier J, KornmammO, et al.Neutrophilicin flammation in induced sputum of patients with idiopathic pulmonary fibrosis.Sarcoidosis Vasc DiffuseLung Dis, 2003,20(2):1382.
[1] 翁心植，王辰．呼吸内科专题讲座．郑州大学出版社，2005．165．
[2] 张东伟，王继峰，牛建昭等．复方鳖甲软肝方对肺纤维化大鼠高分辨率CT影响的实验研究．北京中医药大学学报，2003，26(5)：26．
[3] 高春芳，陆伦根．纤维化疾病的基础与临床．上海科技技术出版社．2004．244-245．
[4] Broekelmann, Papp A C, Hejmanowski A Q, et al. Increased Dallel frequency of the angiotensin converting enzyme genein pulmonary fibrosis. Human Pathol, 2001, 32 (5): 25-21.
[5] 李银生，牛建昭，王继峰等．姜黄素对肺间质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．2007，25(1)：55-57．
[1] 曾艳兵，张妮娜，卜平．中药对恶性肿瘤细胞信号转导通路的影响及其作用机理研究的进展．[J]．中国中西医结合杂志，2004．7；24(7)：670—672．
[2] 宋雅芳，徐列明，洪嘉禾．转化生长因子β1的c-jun氨基端激酶和p38蛋白激酶通路及其抑制剂与纤维化．[J]．中西医结合学报，2004．9；2(5)：382—383．
[3] Obata T, Brown GE, Yaffe M B. MAP kinase pathways activa—ted by stress: the p38 MAPK pathway[J]. Crit Care Med, 2000, 28(4 Suppl): N67—N77.
[4] 韩君勇，陈运贞．大鼠心肌细胞缺氧预处理中COX2，iNOS及p38MAPK间信号转导关系的研究．[J]．中国病理生理杂志，2003，19(10)：1407—1410．
[5] 白建文 邓伟吾 丝裂原激活蛋白激酶p38在支气管哮喘小鼠模型肺组织中的表达．[J]．中华结核和呼吸杂志．2004，9(27)9：643-644．
[6] Chaturvedi LS, Koul S, Sekhon A, et al. Oxalate selectively activates p38 mitogen·activated protein kinase and c—JunN·terminal kinase signal transduction pathways in renal epithelial cells. [J] Biol Chem, 2002, 277: 13321-13330.
[7] Hu MC, Wang YP, Mikhail A, et al. Murine p38-delta mitogenactivated proteinkinase, a developmentally regulated protein kinase that is activated by stress andpminflammatOry cytokines. [J]. Biol Chem, 1999, 274: 7095-7102.
[8] Meldrum KK, Meldrum DR, Hile. KL, et al. p38 MAPK mediates renal tubular cell TNF-alpha production and rNF-alpha-dependent apoptosis during simulated ischemia. Am [J]. Physiol Cell Physiol, 2001. 281: C563-C570.
[9] Sengnl S, Zwizinski C, Batuman V. Role of MAPK pathways in light chain-induced cytokine production in human proximal tubule cells. Am [J]. Physiol Renal Physiol, 2003, 284: F1245-F1254.
[10] Kuemmerle JF, Zhou H. Insulin-like growth factor-binding protein-5 (IGFBP-5)stimulates growth and IGF-I secretion in human intestinal smooth muscle by Ras-dependent activation of p38 MAPK kinase and Erk1/2 pathways. [J]. Biol Chem, 2002, 277: 20563-20571.
[11] Fujita H, Omori S, Ishikura K, et al. ERK and p38 mediate HighucOse-induced hypeflrophy and TGF-beta expression in renal tubular cells. Am J. Physiol Renal Physiol, 2004, 286: F120-F126.
[12] SOdhi CP, Batlle D, Sahai A, et al. Osteopo ntin mediates hypoxia-induced proliferation of cultured mesangial cells: role of PKC and p38 MAPK. Kidney Int, 2000, 58: 691-700.
[13] Hashimoto S, Son Y, Takeshita I, et al. Transforming growthfactor-betal induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun—tNH2—terminal ki—nase-dependentpathway[J]. Respir Grit Care Med, 2001, 163(1): 152—157.
[14] Varela Rey M. MontieI—DuarteC. Oses—Prieto JA el al. p38M APK mediates the regulation of alphal(I) procollagen mRNA levels by TNF—alpha and TGF——beta in a cell line of rat hepaticstellate cells(1)[J]. FEBS Lett. 2002. 528(卜3): 133 138.
[15] Dai C, Yang J. Iiu Y. Transforming growth factor—betal potentiates renaI tubular epitheliaI ceII death by a mechanism inde pendent of Smad signaling[J]. J Biol Chem, 2003. 278(14): 12537—12545.
[2] 李素云，朱佳，吴纪珍．抗纤颗粒治疗弥漫性肺间质纤维化及其对细胞因子的影响[J]．中国中医药信息杂志．2002；9(5)：26-27．
[3] 廖远芳．论肺间质纤维化病名．辽宁中医学院学报，2003，5(3)：225．
[4] 王海彤，武维屏．中医药治疗弥漫性肺间质纤维化信息讨论．中国中医药信息杂志，1996，3(7)：25-26．
[5] 李素云．曹世宏教授治疗肺间质纤维化经验介绍．新中医，2003(35)9期：10-11．
[6] 王玉光，周平安，刘清泉．肺痹证治新诠．中国中医基础医学杂志，2002，8(7)：486-487．
[7] 杨效华、张晓梅、孙海燕．肺间质纤维化的中医药治疗．中国临床医生杂志，2002，3：43-45．
[8] 姜良铎，秦英，杨君等．试论“环境毒”．中国中医基础医学杂志，1999，5(9)：4-6．
[9] 张天嵩．特发性肺纤维化的中医病机探讨．中医函授通讯，1999，18(3)：14-15．
[10] 孔祥文．特发性肺纤维化的中医治疗．现代中西医结合杂志，2003，12(1)：67-68．
[11] 刘伟．弥漫性肺间质纤维化辨治心得．吉林中医药，2003，23(4)：4．
[12] 许振亚，徐振荣．特发性肺间质纤维化的辨治．辽宁中医杂志，1997，24(11)：500．
[13] 龚婕宁，王灿晖．论肺间质纤维化的中医病理学特点．浙江中医杂志，2001，4：139-140．
[14] 王新华等．特发性肺间质纤维化的中西医治疗．贵阳中医学院学报．2000．12；22(4)：3-4．
[15] 陈献亮．虫草汤配合激素治疗特发性肺间质纤维化21例．陕西中医．2002．23(10)：877．
[16] 赵子贤等．补气通肺饮对平阳霉素A5诱发大鼠肺间质纤维化干预作用的试验研究。1999；23(6)：462-469．
[17] 智屹惠．曹世宏教授论治肺间质纤维化．南京中医药大学学报．2001．5；17(3)：185-186．
[18] 蒋宁等．中医络病学说与肺间质纤维化病机关系初探．中国中医基础医学杂志．2003；9(5)：21-23．
[19] 王小平，李晓光，甘丽虹，等．中医治疗特发性肺间质纤维化22例．北京中医药大学学报，2001，24(1)：77．
[20] 赵兰才，武维屏．肺间质纤维化的中医研究进展述评．北京中医药大学学 报，2000，23(4)：70-72．
[21] 李真等．呼吸病诊疗全书．第1版．北京：中国医药科技出版社，2000，404-405．
[22] 张天嵩，韩镭，吴银根．肺纤维化34例辨证分型与CRP计分的关系．辽宁中医杂志，2001，28(11)：646-648．
[23] Liu W M, Xu Q Y, Lin YH, et al. Study of influence of 25% Angelica Injection to Bleomycin-induced pulmonary fibrosis [J].J Wuhan Univ, 2001; 2(4): 326-327.
[24] Krishna G, Liu K, Shigemitju H, et al. PG-490-88, A Deriva-tive Triptolide, Blocks Bleomycin-induced Lung Fibrosis. Am [J]. Pathol. 2001; 158: 997-1004.
[25] Song J P, Li W, Li R Q, et al. Effect of Wu she San on the levels of lamin in and procellgen Ⅲ. in the Bronchio-alvel-lar fluid in rat with pulmonary fibrosis[J].J Inf TraditChin Med. 2001: 8(10):28-31.
[26] 陈建，何冰，刘新民，等．银杏叶制剂治疗肺间质纤维化的实验研究[J]．中国中西医结合杂志，2000；2((6)：441-443．
[27] 洪长福，娄金萍，周华仕，等．桃仁提取物对大鼠实验性矽肺纤维化的影响[J]．浙江省医学科学院学报，2000；、11(1)：7-8．
[28] 刘娟．特发性肺间质纤维化中医治疗方法概况．中国中医药信息志．2000；7(8)：11-12．
[29] Gong J N, Yang J, Zhou K F. Preventing and treating effect on mondel of pulmonary fibrosis by yangfeihuoxue Decoction [J]. Chin J Basic Med Tradit Chin Med. 2001: 7(6):31-33
[30] Xu J, Liu X K. Experimental study on effect of Xuefuzhu-yu Decoction. in Pinyang mycin-induced pulmonary fibrosis[J] Inf Tradit Chin Med. 2000; 1(1): 49-50.
[31] 王海峰．温润养血方治疗特发性肺间质纤维化20例临床观察．浙江中医杂志2003．3：106-107．
[32] 彭玉华．特发性肺间质纤维化中医药治疗思路与方法．中医药学刊．2003．10；21(10)：1774-1775．
[33] 王书臣，崔红，王伟，等．弥漫性肺间质纤维化辨证心得．中医杂志，1998，39(9)：532-533．
[34] 王小平，李晓光，甘丽虹，等．中医治疗特发性肺间质纤维化22例．北京中医药大学学报，2001，24(1)：77．
[35] 侯杰，蔡后荣，戴令娟．川芎和丹参联合泼尼松治疗特发性肺纤维化疗效观察．实用老年医学，2001．04．20；15(2)：99-101．
[36] 董盛等．沈舒文教授从痰瘀辨治难治病验案举隅．陕西中医．2003；24(12)：1107-1108．
[1] 翁心植，王辰．呼吸内科专题讲座．郑州大学出版社，2005，165-166．
[2] American Thoracic Society. Idiopathic pulmonary fibrosis:diagnosis treatment. International consensus statement. Ameri-can Thoracic Society(ATS) and European Respiratory.
[3] Wai KT, et al. Oxalate selectively activates p38 mitogen·activated protein kinase and c—JunN·term Anal kinase signal transduction pathways in renal epithelial ceils. Am J Respir Crit Care Med. 1994; 150:670-675.
[4] Hubbard RS, et al. Increased phosphory lated extrace llulars ignal regulated kinase immuno reactivity associated with proliferative and morphologic tung alterations after chrysotile asbestos inhalation in mice. Lancet. 1996; 347:284-289.
[5] Scott, JI. etal. MontieI—Duarte C. Oses--Prieto JA. el al. p38M APK mediates the regulation of alphal(Ⅰ) procollagen mRNA levels by TNF—alpha and TGF—beta in a cell line of rat hepaticsteIlate cells Br Med J, 1990; 301:1015-1017.
[6] Ward RY, et al. Eduction in pulmonary fibrosis in vivo byhal ofuginone gur Respir J, 1997; 10,2881-2883.
[7] Hubbard RA, et al. Myofibroblast ac-cumulation correlates with the formation of fibrotic tissue in a rat air pouch model J Respir Crit CareMed, 1998; 157:743-747.
[8] 陈灏珠．实用内科学[M]．第11版．北京：人民卫生出版社，2001，1622-1625．
[9] 李芳等．特发性肺间质纤维化的现代治疗进展．国外医学呼吸系统分册2003；23(1)：45-49
[10] Katzenstein ALA, Myers JL. Idiopathic pulmonary fibrosis Clinical relevance of pathological classification. AM J Respir Crit Care Med, 1998,157:1301-1315
[11] Moises S, Talnadge E, King Jr, et al. Idiopathic PulmonaryFibrosis:prevailing and evolving hypotheses about its patho-Genesis and implications for therapy. Ann IntMed, 2001; 134(2):136-151.
[12] 中华医学会呼吸病学分会，2002年4月：特发性肺(间质)纤维化诊断和治疗指南(草案)中华呼吸结核杂志，2002，25(4)：11-18．
[13] Flaherty K R, Travis W D, Colby T V, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Resoi Crit Care Meal, 2001, 164(9): 1722-1727.
[14] AmericanThoracicSociety. ldiopathicpulmonaryfibrosis, diagnoandt reatment. International consensus statemen. American Tracic Society,and the European Respiratory Society ER. Am J Respir Crit Care Med, 2000, 161 (2Pt1) :646.
[15] Robert J, Mason, Marvinl et al. Pharmacological therapy foridio pathic pulmonary fibrosis. Am J Respir Crit Card Med, 1999, 160(5Pt1): 1771-1777.
[16] Coker R K, Laurent G J. Aanticy to kine approaches in pulmonary fibrosis: bring factors into focus. Thorax, 1997, 52(3): 294-296.
[17] Raghu G. Idiopathic pulmonary fibrosis: aneed for treatment with drugs other than cortico steroidsarolefor antifibrotic agents Mayo Clin Proc, 1997, 72(3): 285-287.
[18] Lossos I S, Breuer R, Shrik iM, e tal. Peribronchial lymphocyte activation in bleomycin induced lung injury. Life Sci, 1998, 63(13): 1183-1193.
[19] Undurraga A, Meneses M, Oyarszun M. Evaluation of treatment with cyclosporine in three patients with pulmonary fibrosis. Rev Med Chil, 199, 125(6): 690-695.
[20] Varai G, Earle L, Jimenez S A, et al. A pilot study of intermittent intrare nouscy clophosphumide for the treatmentofsystemics clerosis associated lung disease. JRheumatol, 1998, 25 (7): 1325-1329.
[21] Entzian P, Schlaak M, Seltzer U, et al. Antiinflannatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis. Lung, 1997, 175(1): 41-51.
[22] Douglas W W, Ryu J H, Bjoraker J A, et al. Colchicine versus prednisoneas treatment of usua linterstitial pneumonia. Mayo Clin Proc, 1997, 72(3): 201-209.
[23] Douglas W, Ryu J H, Swensen S J. et al. Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis: a randomized prospective study. Am Respir Crit Care Med, 1998, 158: 220
[24] Coker R K, Laurent G J. Pulmonary fibrosis: cytokines in the balance. Eur RespirJ, 1998, 11 (6): 1218-1221.
[25] 许仁和．特发性肺间质纤维化(IPF)诊治进展．山东医药．2001；41(20)：61-63．
[26] 黄绍光．肺内科新进展．2000．257-276．
[27] 郑建等．特发性肺间质纤维化诊治进展．中国综合临床．2003．12 19(12)：1065-1067．
[28] Iyer SN, Gurujeyalakshmi G, Giri SN. Effect of pirfenidone on transforming growth factor-β gene expression at the transcri-ptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther. 1999; 291: 367-373.
[29] 曹兆龙等．特发性肺间质纤维化诊疗进展．世界药品信息．2002．(4)：14-17．
[30] Raghu G, Johson WC, Lockhart D, et al. Treament of idiopath-ic pulmonary fibrosis with a new antifibrotic agent, pirfeni-done: results if a prospective, open-label Phase Ⅱ study. Am J Respir Crit Care Med. 1999; 291: 367
[31] Thorsell A, Blomqvist AG, Heilig M. Cationlipid mediated delivery and expression in rat: feasibility and limitations. Regulatory Peptides, 1996, 61: 205-211.
[32] Blivet S, Philit F, Sab J M, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respirator failure. Chest, 2001, 120: 209-212.
[33] Stern J B, Herv Mal, Groussard O, et al. Prognosis of patients with Advanced idiopathic pulmonary fibrosis requiring mechanica Ventilation for acute respiratory failure. Chest, 2001, 120: 213-219.
[34] Rosenfeld MA, Siegfried W, Yoshimurak, et al. idenovirus mediated transfer of arecombinantal antiryps ingene to the lung epithelim invivo. Science, 1991, 252: 431-434.
[35] 田欣伦 朱元珏，特发性肺间质纤维化与继发于结缔组织病的肺间质病的临床比较．中华老年医学杂志，2004，23(5)：304-307．
[36] Venkatesan N, Roughley P J, Proteo glycan expression in bleomycin lung fibroblasts: Am J Physiol Lung Cell Mol Physiol, 2002, 283(4): L806-814.
[37] Yamazaki C, Hoshino J, Hori Y, et al. Effect of lecithinized-superoxide dismutase on the interstital pneumonia model induced by bleomycin in mice. Jpn J Pharmacol, 1997, 75(1): 97-100.
[38] Kold M, Galt T, et al. Transient transgene expression of decorin in the lung reduce the fibrotic response to bleomycin. Am J Respir Crit Care Med, 2001, 163(3P t 1): 770-777.
[39] Du Bois R M. Interferon gamma-1b for the treatment of idiopathic pulmonary fibrosis. N Engl J Med, 1999, 341(17): 1302-1304.
[40] 李坚，张德厚，丁明等，无创正压通气在特发性肺纤维化并呼吸衰竭患者中的应用．中国综合临床，2005，21(8)：686-688．
[41] Snell G I, Walters E H, Kotsimbos T C, et al. Idiopathic pulmonary fibrosis: in need of focused and systematic management. Med J Aust, 2001; 174: 137-140.
[42] Meyers B F, Lynch J P, Trulock E P, et al. Singlever susbilateral lung transplantation for idiopathic pulmonary fibrosis: a ten-year in stitution alexperience. JThorac Cardiovasc Surg, 2000; 120: 99-107
[1] 仝润芍．血府逐瘀汤加减治疗弥漫性间质性肺炎46例．河南中医，1999，31(11)：42．
[2] 陶凯，周晓园．肺通口服液治疗间质性肺病20例．北京中医，1997，(2)：13-15．
[3] 周晓园，陶凯，顾振东．肺通治疗放化疗所致肺间质纤维化10例．实用中西医结合杂志，1997，10(19)：1924～1925．
[4] 刘良倚．阳和汤治疗肺系病证验案举隅．山西中医，2000，16(1)：57．
[5] 辛洪涛，等．益气活血法治疗肺间质纤维化临床研究：附18例报告．山东医药，2001，41(24)：9-11．
[6] 张天嵩，赵子贤，马君，欧阳修河．补气通肺汤治疗特发性肺纤维化12例．浙江中医杂志，1999，34(2)：54-55．
[7] 蒋云峰．黄芪桃红汤治疗特发性肺纤维化24例．吉林中医药，2003，23(11)：14．
[8] 王海峰．温润养血方治疗特发性肺间质纤维化20例临床观察．浙江中医杂志．2003．3：106-107．
[9] 田欣伦 朱元珏，特发性肺间质纤维化与继发于结缔组织病的肺间质病的临床比较．中华老年医学杂志，2004，23(5)：304-307．
[10] Blivet S, Philit F, Sab J M, et al. Out come of patients with idiopathic pulmonary fibrosis admitted to the ICU for respirator failure. Chest, 2001, 120: 209-212.
[11] Stern J B, Herv Mal, Groussard O, et al. Prognosis of patients with Advanced idiopathic pulmonary fibrosis requiring mechanica Ventilation for acute respiratory failure. Chest, 2001, 120: 213-219
[12] DouglasWW, RyuJH, SchroederDR. Idiopathic pulmonaryfibrosis:Impact of oxygen and colchincine, prednisone, or notherapy on Survival. Am J Respir Crit Care Med. 2000; 161(4) 1172-1178.
[13] 高燕，雍政，黄英，等．百草枯建立肺纤维化动物模型的实验研究．空军总医院学报，2003，19(4)：201-203．
[14] 胡平，张光斌．胺碘酮的肺毒性机理．华西药学杂志，1993，8(3)：173-174．
[15] 刘珊，范桂香．两种小鼠肺纤维化造模方法的比．2004，25(3)：244-246．
[16] Barth RK, Hanchett LA, Baecher Allan CM. Mapping susceptibility genesfortheinductionofpulmonaryfibrosisinmice. Chest, 2002, 121Suppl3-21.
[17] Szapiel SV, Elson N, FulmurJD, et al. Bleomycin induced interstitial pulmonary disease in the nude, athy micmouse. Am Rev Respir Dis, 979, 120: 893-897.
[18] Davis G S, Pfeiffer L M, Hemenway D R. Interferon Cproduction by specific lung lymphocytepheno type sinsilicsis in mice. Am J Respir Cell Mol Biol, 2000, 22: 4912-501.
[19] Robledo R F, Buder Hoffmann S A, Cummins A B, et al. Increased phosphory fated extrace llulars ignal regulated kinase immuno reactivity associated with proliferative and morphologic lung alterations after chrysotile asbestos inha'lation in mice. Am J Pathol, 2000, 156: 1307-1316.
[20] 王健，黄志兰，王涛，等．平阳霉素致肺纤维化动物模型高分辨率CT的评价．第三军医大学学报，1998，20：419-422．
[21] Ekekezie II, Thibeault DW, Rezaeikhaligh MH, et al. Highdose inhaled nitricoxide and hyperoxiai ncreases lungcollagen accumulation inpiglets. Biol Neonate, 2000, 78(3): 198-206.
[22] 姜晓姝，王孝铭，刘晓滨．雾化吸入平阳霉素法致小白鼠肺纤维化的观察．哈尔滨医科大学学报，1995，29(1)：4-5．
[23] YunZhao, Shah DU. Expression of transforming growthfactor B type and type receptor sisalteredinrat lung sunder going bleomycin induced pulmonary fibrosis. Exp Mol Pathol, 2000, 69: 67-68.
[24] 张纾难，韩春生．一种新的肺纤维化造模方法．中日友好医院学报，1997，11(4)：283-285．
[25] 王和枚，瞿文生，余寿忠，等．胺碘酮所致大鼠肺毒性．中国药理学与毒理学杂志，1999，13(4)：301-305．
[26] 王梅，傅强，闵碧荷，等．磷酸羟基哌喹对大鼠放射性肺纤维化的防治作用．中国癌症杂志，2002，12(6)：519-521．
[27] Mclanghlin R F, Tyler W, Canada RO. A study of the subgross pulmonary anatomin various mammals. Am J Anat, 1961, 108(1): 149-165.
[28] 李彦敏，勾宏国，刘意，等．微波热效应对家兔正常肺组织损伤的试验研究．中国医科大学学报，1996，25(2)：189-190．
[29] Snider GI. Chronicinter stitial pulmonary fibrosis produce din hamsters by endotracheol bleomycin. Am Rev Respir Dis, 1978, 117: 1099-1104.
[30] Selman M, Montano M, Montfort, et al. A new model of diffuse interstitial pulmonary fibrosis in the rat .Exp Mol Pathol, 1985, 43(1): 375-387.
[31] 赵洪文，彭璐，吕长俊，等．肺纤维化大鼠BALF中的细胞成分与肺组织病理的动态研究．中国医科大学学报，1997，26(5)：463-466．
[32] Blaisdell RJ, Schiedt M J, Giri SN. Dietary supplementation with taurine and niacinprevents the increase in lung collagen cross links in the multidose bleomycin hamster modeofpulmonary fibrosis. J Biochem Toxicol, 1994, 9 (2): 79-86.
[33] Nagler A, Firman N, Feferman R, et al. Eduction in pulmonary fibrosis in vivo byhal ofuginone.Am J Respir Crit Care Med, 1996, 154(4): 1082-1086.
[34] Rubin P, Johnston CJ, Williams JP, et al. Aperpetual cascade of cytokines postir radiation leads to pulmonary fibrosis, lnt JRadiatnol Biol Phys, 1995, 33 :99-109.
[35] Daba MH, Abdel Aziz AA, Moustafa AM, et al. Effects of Lcarnitine and gink gobilobaextract(EGb761)inexperimentalbleomycininducedlung fibrosis. Pharmacol Res, 2002, 45(6): 461-467.
[36] Mitsuhiro Yoshida, Junko Sakuma Mochizuki, Kinpya Abe, et al. Invivo gene transfer of anextrace llulardomain of platelet derived growth factor breceptor by the HV liposome methoda meliorates bleomycin induced pulmonary fibrosis. Bioche Biophy Res Comm, 1999, 265: 503-508.
[37] Snider G I. Chronicinter stitial pulmonary fibrosis produce din hamsters by endotracheol bleomycin .Am Rev Respir Dis, 1978, 117: 1099-1104.
[38] Gong J N, Yang J, Zhou K F. Preventing and treating effect on mondel of pulmonary fibrosis by yangfeihuoxue Decoction[J]. Chin J Basic Med Tradit Chin Med. 2001: 7(6): 31-33.
[39] Han L. Study on the influence of Buqitongfei Yin in the flui-dity of red blood cell membrane of Bleomycin-induced pulmonary fibrosis in rat [J]. J Shandong Univ Tradit Chin Med. 2001; 19(5): 441-442.
[40] 宋建平，刘方州，李瑞琴，等．栝萎薤白汤、麦门冬汤及肾气丸对平阳霉素所致肺纤维化的影响[J]．国医论坛，2001；16(4)：40-41．
[41] 宫晓燕，王泽玉，张永和．纤克颗粒治疗特发性肺间质纤维化实验研究．长春中医学院学报，2005(1)：70-72．
[42] 朱际平，丁蓉．温润养血颗粒对肺间质纤维化模型大鼠肺泡灌洗液TNF-α浓度的影响．南京中医药大学学报，2003，6：762—764．
[43] 周淼．益阴活血汤对大鼠肺纤维化作用的实验研究用．河南中医学院学报，2004，19(1)：89-92．
[44] 欧阳修河，韩荣庆，张天蒿，等．补气通肺饮对大鼠肺纤维化的作用．中药新药与临床药理，1999，10(2)：93-94．
[45] 张秀芹、解砚英等．肺通口服液对大鼠肺纤维化模型的治疗作用．青岛大学医学院学报，2003，39(1)：39-41．
[46] 刘景艳，修清玉，张铁锋．中药对肺纤维化动物模型细胞因子表达的影响．中国临床医学，2005，12(2)：24-26．
[47] Molteni A, Moulder J E, Cohen E F, et al. Control of radiation induced pneumopathy and lung fibrosis by anziotensin—converting enzyme inhibitors and anangiotensin Ⅱ type 1 receptor blocker, Int J Radiat Biol, 2000; 76: 523-532.
[48] 李楠，何冰，马靖．辛伐他汀对大鼠肺成纤维细胞的影响观察，心肺血管病杂志，2002，21(2)：105-108．
[49] Tan A, Levrey H, Dahm C, et al. Lovastatin induces fibro blastapoptosis in vitro and in vivo. A possible therapy for fibro proliferative disorders. Am J Respir Crit Card Med, 1999, 159(1): 220-227
[50] Morrison C D, Papp A C, Hejmanowski A Q, et al. Increased Dallel frequency of the angiotensin converting enzyme genein pulmonary fibrosis. Human Pathol, 2001, 32 (5): 25-21.
[51] 赵峰，戚好文，赵一玲，吕荣，氟伐他汀对博来霉素A5致大鼠肺纤维化的治疗作用；第四军医大学学报，2002：23(6)：493-496
[1] 翁心植，王辰．呼吸内科专题讲座．郑州大学出版社．2005，168．
[2] 宋雅芳，徐列明，洪嘉禾．转化生长因子β1的c-jun氨基端激酶和p38蛋白激酶通路及其抑制剂与纤维化．[J]．中西医结合学报，2004．2(5)：382—383．
[3] 李素云．曹世宏教授治疗肺间质纤维化经验介绍．新中医，2003(35)9：10—11．
[4] 河南省卫生厅编．河南省老中医经验集锦．河南科学技术出版社．1983：44-46．
[5] 周仲瑛主编．中医内科学．北京：中国中医药出版社，2003，155-158．
[1] 翁心植，王辰．呼吸内科专题讲座．郑州大学出版社，2005，168．
[2] 姜莉，陈佰仪，侯显明，等．肺纤维化大鼠肺泡巨噬细胞细胞因子的研究．中国医科大学学报，1998，27：471-474．
[3] Emura M, NaggiS, TakeuchiM, et al. In vitro production ofB cell growth factor and B cell differentiation factor byperiphral blood mononuclear cells and bronchoalvar lavage Tlymphocytes from patients with idio pathic pulmonary fibrosis. Clin Exp Immunol, 1990, 82: 133-139.
[4] Moodley YP, Misso NL, Scaffidi AK, et al. Inverse effect s ofinterleukin26 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. Am J Respir Cell Mol Biol, 2003, 29: 490-498.
[5] Ramos C, Montano M, Garcia-Alvarez J, et al, Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue in hibitor of met al oproteinases expression. Am J Respire Cell Mol Biol, 2001, 24(3): 591-598.
[6] Ghosh AK. Factors involved in the regulation of type Ⅰ collagen gene expression: impliction in fibrosis.Exp Biol Med, 2002,227(5):301-314.
[7] NaozumiH, Hhongjin, Bone M. Cderived progenitor cells in pulmonary fibrosis. J ClinInvest 2004, 113(2): 243-252.
[8] 马均．补气通肺汤对肺纤维化大鼠病理及血，BALF中HA，LN的影响．中国中医药信息杂志，1999．6(11)：40．
[9] Bjardahlen A, Onnervik P O, Westergern G, et al. Myofibroblast accumulation correlates with the formation of fibrotic tissue in a rat air pouch model. J Rheumatol, 2002, 29 (8): 1698.
[1] Mclanghlin R F,Tyler W,Canada RO.A study of the subgross pulmonary anatomin various mammals.Am J Anat,1961,108(1):149-165
[2]Szapiel S V, Elson N A, Fulmur J D, et al. Bleomycin induced interstitial pulmonary disease in the nude, athy micmouse. Am Rev Respir Dis, 1979, 120:893 — 897
[3]Ekekezie II,Thibeault DW, Rezaeikhaligh MH,et al. Highdose inhaled nitricoxide and hyperoxiai ncreases lungcollagen accumulation inpiglets. Biol Neonate, 2000, 78 (3) : 198-206.
[4]Snider G I. Chronicinter stitial pulmonary fibrosis produce din hamsters by endotracheol bleomycin. Am Rev Respir Dis,1978 117:1099-1104
[5]Blaisdell R J, Schiedt M J, Giri S N.Dietary supplementation with taurine and niacinprevents the increase in lung collagen cross links in the multidose bleomycin hamster mode of pulmonary fibrosis. J Biochem Toxicol, 1994, 9(2) :79-86.
[6]Beeh K M, Beier J, KornmammO, et al.Neutrophilicin flammation in induced sputum of patients with idiopathic pulmonary fibrosis.Sarcoidosis Vasc DiffuseLung Dis, 2003,20(2):1382.
[1] 翁心植，王辰．呼吸内科专题讲座．郑州大学出版社，2005．165．
[2] 张东伟，王继峰，牛建昭等．复方鳖甲软肝方对肺纤维化大鼠高分辨率CT影响的实验研究．北京中医药大学学报，2003，26(5)：26．
[3] 高春芳，陆伦根．纤维化疾病的基础与临床．上海科技技术出版社．2004．244-245．
[4] Broekelmann, Papp A C, Hejmanowski A Q, et al. Increased Dallel frequency of the angiotensin converting enzyme genein pulmonary fibrosis. Human Pathol, 2001, 32 (5): 25-21.
[5] 李银生，牛建昭，王继峰等．姜黄素对肺间质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．2007，25(1)：55-57．
[1] 曾艳兵，张妮娜，卜平．中药对恶性肿瘤细胞信号转导通路的影响及其作用机理研究的进展．[J]．中国中西医结合杂志，2004．7；24(7)：670—672．
[2] 宋雅芳，徐列明，洪嘉禾．转化生长因子β1的c-jun氨基端激酶和p38蛋白激酶通路及其抑制剂与纤维化．[J]．中西医结合学报，2004．9；2(5)：382—383．
[3] Obata T, Brown GE, Yaffe M B. MAP kinase pathways activa—ted by stress: the p38 MAPK pathway[J]. Crit Care Med, 2000, 28(4 Suppl): N67—N77.
[4] 韩君勇，陈运贞．大鼠心肌细胞缺氧预处理中COX2，iNOS及p38MAPK间信号转导关系的研究．[J]．中国病理生理杂志，2003，19(10)：1407—1410．
[5] 白建文 邓伟吾 丝裂原激活蛋白激酶p38在支气管哮喘小鼠模型肺组织中的表达．[J]．中华结核和呼吸杂志．2004，9(27)9：643-644．
[6] Chaturvedi LS, Koul S, Sekhon A, et al. Oxalate selectively activates p38 mitogen·activated protein kinase and c—JunN·terminal kinase signal transduction pathways in renal epithelial cells. [J] Biol Chem, 2002, 277: 13321-13330.
[7] Hu MC, Wang YP, Mikhail A, et al. Murine p38-delta mitogenactivated proteinkinase, a developmentally regulated protein kinase that is activated by stress andpminflammatOry cytokines. [J]. Biol Chem, 1999, 274: 7095-7102.
[8] Meldrum KK, Meldrum DR, Hile. KL, et al. p38 MAPK mediates renal tubular cell TNF-alpha production and rNF-alpha-dependent apoptosis during simulated ischemia. Am [J]. Physiol Cell Physiol, 2001. 281: C563-C570.
[9] Sengnl S, Zwizinski C, Batuman V. Role of MAPK pathways in light chain-induced cytokine production in human proximal tubule cells. Am [J]. Physiol Renal Physiol, 2003, 284: F1245-F1254.
[10] Kuemmerle JF, Zhou H. Insulin-like growth factor-binding protein-5 (IGFBP-5)stimulates growth and IGF-I secretion in human intestinal smooth muscle by Ras-dependent activation of p38 MAPK kinase and Erk1/2 pathways. [J]. Biol Chem, 2002, 277: 20563-20571.
[11] Fujita H, Omori S, Ishikura K, et al. ERK and p38 mediate HighucOse-induced hypeflrophy and TGF-beta expression in renal tubular cells. Am J. Physiol Renal Physiol, 2004, 286: F120-F126.
[12] SOdhi CP, Batlle D, Sahai A, et al. Osteopo ntin mediates hypoxia-induced proliferation of cultured mesangial cells: role of PKC and p38 MAPK. Kidney Int, 2000, 58: 691-700.
[13] Hashimoto S, Son Y, Takeshita I, et al. Transforming growthfactor-betal induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun—tNH2—terminal ki—nase-dependentpathway[J]. Respir Grit Care Med, 2001, 163(1): 152—157.
[14] Varela Rey M. MontieI—DuarteC. Oses—Prieto JA el al. p38M APK mediates the regulation of alphal(I) procollagen mRNA levels by TNF—alpha and TGF——beta in a cell line of rat hepaticstellate cells(1)[J]. FEBS Lett. 2002. 528(卜3): 133 138.
[15] Dai C, Yang J. Iiu Y. Transforming growth factor—betal potentiates renaI tubular epitheliaI ceII death by a mechanism inde pendent of Smad signaling[J]. J Biol Chem, 2003. 278(14): 12537—12545.