摘要
目的 观察在不同时期给予留兰香油对博莱霉素引起的小鼠肺纤维化病理改变及肺组织中肿瘤坏死因子-α（TNF-α）、转化生长因子-β1（TGF-β1）、基质金属蛋白酶-9（MMP-9）、金属蛋白酶抑制剂-1（TIMP-1）及α-平滑肌肌动蛋白（α-SMA）表达的影响。方法 ICR小鼠一次性气道内滴入博莱霉素建立肺纤维化模型，实验动物分为留兰香油治疗组和预防组，分别于造模后第8天和第1天开始给予留兰香油灌胃3周和4周。每7 d记录小鼠体重、死亡率；肺组织切片行HE、Masson染色观察气道炎症及纤维化程度，并对病理图片进行形态学测量分析；测定肺组织中羟脯氨酸（hydroxyproline）、TNF-α、TGF-β1、MMP-9及TIMP-1含量；测定肺组织中α-SMA表达水平。结果 留兰香油14、42、140 mg·kg-1预防组能明显减少组织纤维化区域，部分肺泡结构得以保留，肺泡间隔胶原沉积减少；留兰香油14和140 mg·kg-1预防组能够明显降低肺组织中羟脯氨酸、TGF-β1和MMP-9含量；留兰香油14、42、140 mg·kg-1预防组能够明显降低肺内α-SMA表达水平。留兰香油治疗组除14 mg·kg-1组明显减弱α-SMA表达外对其余各项指标均没有明显作用。结论 早期给予留兰香油对博莱霉素引起的小鼠肺纤维化有减轻作用，其机制可能是通过降低肺组织中MMP-9及TGF-β1的含量，减少基底膜断裂，减少成纤维细胞增殖和转化，减少肌成纤维细胞α-SMA表达及细胞外基质的合成，对肺纤维化初期起到干预作用。
Abstract
OBJECTIVE To investigate the effect of spearmint oil given at different period of time on pathological changes and the expression of tumor necrosis factor-α(TNF-α)， transforming growth factor-β1(TGF-β1)， matrix metalloproteinases-9 (MMP-9)， tissue inhibitor of metalloproteinase-1(TIMP-1) and α-smooth muscle actin(α-SMA) in mice with bleomycin-induced pulmonary fibrosis. METHODS Pulmonary fibrosis was induced by intratracheal instillation of bleomycin in ICR mice， then the animals were randomly divided into spearmint oil therapeutic and preventive groups. One day after intratracheal instillation of bleomycin， the mice in preventive group were treated with spearmint oil for 4 weeks; while those in therapeutic groups were given spearmint oil 8 days after administering of bleomycin for 3 weeks. The body weight and mortality were recorded every week; the pathologic changes of lung tissue were observed by HE and Masson staining; the hydroxyproline content was determined; the levels of TNF-α， TGF-β1， MMP-9 and TIMP-1 were measured by ELISA; the expression of α-SMA was observed by immunochemistry. RESULTS In the preventive groups， spearmint oil of 14， 42 and 140 mg·kg-1significantly decreased the fibrosis area and reduced collagen deposition while preserving some alveolar structure; spearmint oil of 14 and 140 mg·kg-1 significantly decreased hydroxyproline， TGF-β1 and MMP-9 content; spearmint oil of 14， 42， 140 mg·kg-1 significantly attenuated the expression of α-SMA. In the therapeutic groups， spearmint oil had no significant effect except that the 14 mg·kg-1 group obviously attenuated the expression of α-SMA. CONCLUSION Spearmint oil given at early period attenuates bleomycin-induced pulmonary fibrosis in mice， the mechanism may include decreasing basemembrane disruption， inhibiting fibroblast， proliferation and transformation， reducing the expression of α-SMA as well as the formation and accumulation of ECM through decreasing the contents of MMP-9 and TGF-β1 in lung tissue.
关键词
留兰香油 /
肺纤维化 /
博莱霉素 /
基质金属蛋白酶-9 /
转化生长因子-β1 /
α-平滑肌肌动蛋白
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Key words
spearmint oil /
pulmonary fibrosis /
bleomycin /
matrix metalloproteinases-9 /
transforming growth factor-β1 /
α-smooth muscle actin
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黄梦珊 刘君波 苏璇 王砚 朱有法 唐法娣.
留兰香油对博莱霉素致小鼠肺纤维化的干预作用及α-平滑肌肌动蛋白表达的影响[J]. 中国药学杂志, 2012, 47(7): 504-511
Effects of Spearmint Oil on Mice with Pulmonary Fibrosis Induced by Bleomycin and Its Impact on the Expression of α-SMA[J]. Chinese Pharmaceutical Journal, 2012, 47(7): 504-511
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参考文献
[1] DU BOIS R M. Strategies for treating idiopathic pulmonary fibrosis[J]. Nat Rev Drug Discov，2010，9(2)：129-140.
[2] SZAPIEL S V， ELSON N A， FULMER J D， et al. Bleomycin-induced interstitial pulmonary disease in the nude， athymic mouse[J]. Am Rev Respir Dis ，1979，120(4)：893-899.
[3] LIU J Y. Effect of Chinese herb on lung tissue pathologic change in bleomycin-induced pulmonary fibrosis in rat[J].Chin Arch Tradit Chin Med（中华中医药学刊）， 2008，26(8) ： 1801-1803.
[4] FUJITA H， SAKAMOTO N， ISHIMATSU Y， et al. Effects of doxycycline on production of growth factors and matrix metalloproteinases in pulmonary fibrosis[J]. Respiration， 2011，81(5)：420-430.
[5] 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)：769-776.
[6] MOELLER A， ASK K， WARBURTON D， et al. The bleomycin animal model： a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? [J]. Int J Biochem Cell Biol， 2008，40(3)：362-382.
[7] ZHAO C Z，WANG Y， TANG F D， et al. Effect of spearmint oil on inflammation， oxidative alteration and Nrf2 expression in lung tissue of COPD rats[ J ]. J Zhejiang Univ (Med Sci)（浙江大学学报：医学版）， 2008， 37(4) ： 357-363.
[8] XIA J F， WANG Y， TANG F D， et al. Effect of spearmint oil on airway inflammation， interleukin-8 and CCR2 expression in lung tissue of COPD rats[J]. Chin Pharm J（中国药学杂志），2010，45(6)：423-428.
[9] LIU J B， WANG Y， TANG F D，et al. Effect of spearmint oil on lipopolysaccharide induced emphysema-like changes and expression of matrix metalloproteinase-9[J].China J Chin Mater Med（中国中药杂志），2011，36(8)：1054-1059.
[10] OIKONOMOU N， HAROKOPOS V， ZALEVSKY J， et al. Soluble TNF mediates the transition from pulmonary inflammation to fibrosis [J]. PLoS ONE，2006，1(2)：1-14.
[11] ALLEN J T， SPITER M A. Growth factors in idiopathic pulmonary fibrosis： relative roles[J]. Respir Res，2002，3(1)：1-9.
[12] BARTRAM U， SPEER C P. The role of transforming growth factor in lung development and disease[J]. Chest， 2004， 125(2)：754-765.
[13] YANG X M ， WANG X S， CUI S H. Origin and role of myofibroblast in pulmonary fibrosis[J]. J Int Pathol Clin Med（国际病理科学与临床杂志），2008，28(1)：54-58.
[14] LAGENTE V， MANOURY B， NENAN S， et al. Role of matrix metalloproteinases in the development of airway inflammation and remodeling[J].Braz J Med Biol Res，2005， 38(10)： 1521-1530.
[15] WINKLER M K， FOWLKES J L. Metalloproteinase and growth factor interactions： do they play a role in pulmonary fibrosis? [J]. Am J Physiol Lung Cell Mol Physiol， 2002，283(1)：1-11.
[16] CORBEL M， CAULET-MAUGENDRE S， GERMAIN N， et al. Inhibition of bleomycin-induced pulmonary fibrosis in mice by the matrix metalloproteinase inhibitor batimastat [J]. J Pathol，2001，193(4)： 538-545.
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脚注
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基金
浙江省中医药重点研究计划资助项目(2008ZA014)
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