刺山柑总生物碱对系统性硬皮病小鼠基质金属蛋白酶及其抑制剂的影响(1)
摘要：目的 观察刺山柑总生物碱对系统性硬皮病(SSc)小鼠Ⅳ型胶原(Col-Ⅳ)、基质金属蛋白酶-9(MMP-9)、基质金属蛋白酶抑制剂-1(TIMP-1)和纤溶酶原激活物抑制因子-1(PAI-1)水平的影响，探讨其抗SSc组织纤维化的作用机制。方法 BALB/c小鼠90只随机分为空白对照组、模型组、青霉胺组及刺山柑总生物碱低、中、高剂量组。除空白对照组外，其余各组小鼠背部注射盐酸博莱霉素建立SSc模型。成模后刺山柑总生物碱组小鼠背部外敷不同剂量刺山柑总生物碱乳膏，青霉胺组予青霉胺灌胃，空白对照组、模型组背部外敷不含药基质，每日1次，连续60 d。末次给药后，ELISA检测小鼠皮肤Col-Ⅳ和血清MMP-9、TIMP-1、PAI-1含量。结果 与模型组比较，刺山柑总生物碱中、高剂量组小鼠血清MMP-9含量及MMP-9/TIMP-1比值升高，血清TIMP-1及皮肤Col-Ⅳ含量降低(P<0.05，P<0.01)，但对PAI-1水平无明显影响(P>0.05)。结论 刺山柑总生物碱可通过调节MMP-9/TIMP-1失衡，减少Col-Ⅳ合成，改善SSc组织纤维化。
关键词：刺山柑总生物碱；系统性硬皮病；Ⅳ型胶原；基质金属蛋白酶-9；基质金属蛋白酶抑制剂-1；纤溶酶原激活物抑制因子-1；小鼠
DOI：10.3969/j.issn.1005-5304.2016.03.014
中图分类号：R285.5 文献标识码：A 文章编号：1005-5304(2016)03-0051-03
Abstract： Objective To investigate the effects of capparis spinosa total alkaloid on type Ⅳ collagen (Col-Ⅳ)， matrix metalloproteinase-9 (MMP-9)， tissue inhibitor of metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in bleomycin-induced systemic sclerosis (SSc) mice； To explore the effective mechanism of capparis spinosa total alkaloid on fibrosis of SSc. Methods Totally 90 BALB/c mice were randomly divided into control group， model group， penicillamine group and capparis spinosa total alkaloid low-， medium- and high-dose group. Mice models with SSc were established by repeated local injections of bleomycin in mice back， except for the control group. Mice in medication groups received external application with capparis spinosa total alkaloid cream； mice in penicillamine group were given penicillamine for gavage； mice in the control and model group received external application without substance， one time a day， for 60 days. The contents of MMP-9， TIMP-1 and PAI-1 in serum and Col-Ⅳ in skin tissue were detected respectively by ELISA after the last medication. Results Compared with the model group， the levels of MMP-9 and ratio of MMP-9/TIMP-1 markedly increased and the levels of Col-Ⅳ and TIMP-1 markedly decreased in medium and high- dose of capparis spinosa total alkaloid group (P<0.05， P<0.01). But the level of PAI-1 was not influenced (P>0.05). Conclusion Capparis spinosa total alkaloid is effective in treating fibrosis of SSc by adjusting imbalance of MMP-9/TIMP-1 and decreasing expression of Col-Ⅳ.
Key words： capparis spinosa total alkaloid； systemic sclerosis； type Ⅳ collagen； MMP-9； TIMP-1； PAI-1； mice
系统性硬皮病(systemic sclerosis，SSc)是一种病因不明的慢性多系统疾病，以皮肤组织器官纤维化为特征。基质金属蛋白酶-9(MMP-9)及其抑制剂-1(TIMP-1)和纤溶酶原激活物抑制因子-1(PAI-1)可能在SSc细胞外基质(ECM)的合成中起了重要作用。刺山柑Capparis spinosa L.为白花菜科Capparaceae山柑属Capparis L.植物，系维吾尔医习用药材之一。前期研究表明，刺山柑乙醇提取物可抑制SSc患者成纤维细胞增殖及Ⅰ型胶原的合成[1]；刺山柑鲜果75%乙醇调制的糊膏及刺山柑流浸膏均能显著抑制硬皮病模型小鼠的真皮增厚、胶原沉积[2]。本课题组从刺山柑中提取有效部位刺山柑总生物碱，观察其对SSc小鼠Ⅳ型胶原(Col-Ⅳ)、MMP-9、TIMP-1和PAI-1水平的影响，探讨其抗SSc组织纤维化的作用机制。, 百拇医药(康小龙 刘晶 何承辉 卢军 杨俊玲)
关键词：刺山柑总生物碱；系统性硬皮病；Ⅳ型胶原；基质金属蛋白酶-9；基质金属蛋白酶抑制剂-1；纤溶酶原激活物抑制因子-1；小鼠
DOI：10.3969/j.issn.1005-5304.2016.03.014
中图分类号：R285.5 文献标识码：A 文章编号：1005-5304(2016)03-0051-03
Abstract： Objective To investigate the effects of capparis spinosa total alkaloid on type Ⅳ collagen (Col-Ⅳ)， matrix metalloproteinase-9 (MMP-9)， tissue inhibitor of metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in bleomycin-induced systemic sclerosis (SSc) mice； To explore the effective mechanism of capparis spinosa total alkaloid on fibrosis of SSc. Methods Totally 90 BALB/c mice were randomly divided into control group， model group， penicillamine group and capparis spinosa total alkaloid low-， medium- and high-dose group. Mice models with SSc were established by repeated local injections of bleomycin in mice back， except for the control group. Mice in medication groups received external application with capparis spinosa total alkaloid cream； mice in penicillamine group were given penicillamine for gavage； mice in the control and model group received external application without substance， one time a day， for 60 days. The contents of MMP-9， TIMP-1 and PAI-1 in serum and Col-Ⅳ in skin tissue were detected respectively by ELISA after the last medication. Results Compared with the model group， the levels of MMP-9 and ratio of MMP-9/TIMP-1 markedly increased and the levels of Col-Ⅳ and TIMP-1 markedly decreased in medium and high- dose of capparis spinosa total alkaloid group (P<0.05， P<0.01). But the level of PAI-1 was not influenced (P>0.05). Conclusion Capparis spinosa total alkaloid is effective in treating fibrosis of SSc by adjusting imbalance of MMP-9/TIMP-1 and decreasing expression of Col-Ⅳ.
Key words： capparis spinosa total alkaloid； systemic sclerosis； type Ⅳ collagen； MMP-9； TIMP-1； PAI-1； mice
系统性硬皮病(systemic sclerosis，SSc)是一种病因不明的慢性多系统疾病，以皮肤组织器官纤维化为特征。基质金属蛋白酶-9(MMP-9)及其抑制剂-1(TIMP-1)和纤溶酶原激活物抑制因子-1(PAI-1)可能在SSc细胞外基质(ECM)的合成中起了重要作用。刺山柑Capparis spinosa L.为白花菜科Capparaceae山柑属Capparis L.植物，系维吾尔医习用药材之一。前期研究表明，刺山柑乙醇提取物可抑制SSc患者成纤维细胞增殖及Ⅰ型胶原的合成[1]；刺山柑鲜果75%乙醇调制的糊膏及刺山柑流浸膏均能显著抑制硬皮病模型小鼠的真皮增厚、胶原沉积[2]。本课题组从刺山柑中提取有效部位刺山柑总生物碱，观察其对SSc小鼠Ⅳ型胶原(Col-Ⅳ)、MMP-9、TIMP-1和PAI-1水平的影响，探讨其抗SSc组织纤维化的作用机制。, 百拇医药(康小龙 刘晶 何承辉 卢军 杨俊玲)