三七总皂苷防治博莱霉素诱导小鼠肺纤维化的实验研究
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摘要
肺纤维化是一种病因复杂的疾病,以肺上皮细胞的过度凋亡、成纤维细胞过度增殖及胶原蛋白沉积为主要特征。目前临床上也缺乏行之有效的治疗方法,该病的预后不良。因此,研究肺纤维化发病机制,寻找有效的治疗药物具有重大意义。
PNS是从三七中提取的有效活性成份,是三七发挥药理作用的主要成分之一。现代药理研究表明PNS具有广泛的药理作用,如止血、活血化瘀、消肿、补血、调节细胞凋亡等作用。为探讨PNS对肺纤维化小鼠的防治作用,我们以BLM诱导小鼠肺纤维化为模型,从整体与分子水平阐明PNS的作用和作用机制,以期为临床防治肺纤维化提供实验基础。
1 PNS防治肺纤维化作用的观察
1.1方法C57BL/6性小鼠180只,分为模型组；PNS高、中和低剂量三组；阳性药物对照组(醋酸强的松片)；假手术组；共6组,每组30只。除假手术组外其余各组小鼠气管内一次性滴注BLM,假手术组小鼠气管内一次性滴注等体积的生理盐水。造模后第二天开始给药。PNS高、中和低剂量组分别为120、60、30mg/kg/d,醋酸泼尼松组0.56mg/kg/d,假手术组,模型组分别灌服等体积的生理盐水。各组动物于7、14、28d摘眼球取血,分离血清,观察血清中Ⅲ型胶原(Ⅲ-C),Ⅳ型胶原(Ⅳ-C)及层黏连蛋白(LN)和透明质酸(HA)的含量,同时取肺组织进行HE, Mallory染色,检测肺组织羟脯氨酸(HYP)的变化。
1.2结果
PNS可降低肺纤维化小鼠血清中Ⅲ-C、Ⅳ-C型胶原、LN及HA的含量,降低肺纤维化小鼠肺组织HYP的含量,减轻肺组织胶原的增生。因此提示：PNS具有防治BLM诱导的小鼠肺纤维化的作用。
2 PNS防治肺纤维化作用机制的实验研究
2.1 PNS对肺纤维化小鼠肺组织细胞凋亡的影响
通过PNS对肺纤维化小鼠肺组织细胞凋亡影响的研究,探讨PNS防治肺纤维化的作用机制。肺组织来源于实验一。利用TUNEL染色法测定小鼠肺组织中细胞的凋亡情况。结果表明：肺纤维化小鼠肺组织内凋亡细胞明显增加,凋亡的细胞主要为支气管上皮细胞、肺泡上皮细胞和巨噬细胞,还有少量肺间质细胞。PNS中剂量组能显著降低肺纤维化小鼠肺组织上皮细胞的凋亡。因此提示,PNS能通过抑制肺上皮细胞的凋亡而发挥其抗纤维化的作用。
2.2 PNS对肺纤维化小鼠肺组织CatB和CatD的影响
观察PNS对肺纤维化小鼠肺组织CatB和CatD的影响,探讨PNS防治肺纤维化的作用机制。肺组织来源于实验研究一。实验采用免疫组织化学和Westem blotting的方法,研究PNS对肺组织中CatB和CatD的影响。结果表明：PNS中剂量组防治后,各时间点小鼠肺组织中CatB和CatD含量和表达均有一定程度的下降,说明PNS能够从蛋白水平调节CatB和CatD的活性。提示抑制CatB和CatD的表达和活性可能是PNS防治肺纤维化的机制之一
2.3 PNS对肺纤维化小鼠肺组织Bax和Bcl-2的影响
观察PNS对肺纤维化小鼠肺组织Bax和Bcl-2的影响,探讨PNS抗肺纤维化的作用机制。肺组织来源于实验研究一。实验方法采用免疫组织化学法和RT-PCR的方法,研究PNS对肺组织中Bax和Bcl-2的蛋白和基因影响。结果表明：①Bax在肺纤维化小鼠肺组织中的含量明显升高,并且主要表达于肺损伤区的细支气管上皮细胞、肺泡上皮细胞和巨噬细胞,而在肺间质细胞少有表达,因此提示肺内实质细胞是Bax的主要来源之一,Bax在肺纤维化实质细胞的过度凋亡中发挥重要作用；②Bcl-2在肺纤维化小鼠肺组织中的含量亦明显升高,虽然细支气管上皮细胞和肺泡上皮细胞有表达,但在肺损伤区的肺间质细胞表达却明显增多,并且有的已进入细胞核,因此提示增多的Bcl-2主要是由肺间质细胞分泌的,Bcl-2在抑制成纤维细胞凋亡中发挥重要作用；③肺纤维化小鼠肺组织BaxmRNA和Bcl-2mRNA的表达亦明显升高,表明Bax和Bcl-2对肺纤维化小鼠肺组织细胞凋亡的调控至少是在蛋白转录或翻译水平进行的；④结果提示：PNS发挥其抗肺纤维化作用的机制之一在于从蛋白转录和翻译水平调节肺组织中Bax和Bcl-2的活性。
2.4 PNS对肺纤维化小鼠肺组织Fas和FasL的影响
观察PNS对肺纤维化小鼠肺组织Fas和FasL的影响,探讨PNS抗肺纤维化的作用机制。肺组织来源于实验研究一。用免疫组织化学法,研究对肺组织Fas和FasL的表达。结果表明：PNS能降低肺纤维化小鼠肺组织中Fas和FasL的含量。提示：抑制Fas和FasL的表达和活性可能是PNS防治肺纤维化的机制之一
结论
1 PNS可以调节BLM诱导的肺纤维化小鼠细胞外基质的含量,降低肺组织炎症和纤维化的程度,发挥防治肺纤维化的作用。
2 PNS防治肺纤维化的作用机理
2.1抑制肺上皮细胞的凋亡。
2.2抑制肺组织蛋白CatB和CatD的活性.
2.3调节肺组织蛋白Bax和Bcl-2的活性。
2.4抑制肺组织蛋白Fas和FasL的活性。
总之,PNS具有防治肺纤维化的作用,其作用机理可能在于通过抑制肺组织CatB.CatD和Fas/FasL的活性,调节Bax/Bcl-2的活性,抑制肺上皮细胞的凋亡,促进成纤维细胞的凋亡,来实现PNS防治肺纤维化的作用。
The pathogenesis of pulmonary fibrosis is complicated, it is characterized with fibroblast hyperplasia, Epithelial cells apoptosis and deposition of collagen protein. The clinically effective therapy is deficient, the prognosis of this disease is not so better. Therefore, it is important to study the pathogenetic mechanisms and creating new treating scheme.
PNS is one of the effective element extracted from notoginseng. It is one of the major components for notoginseng playing pharmacology.It owes various biological functions, including stop bleeding, remove blood stasis, detumescence, anemia, adjust the cell apoptosis functions and so on. To discuss the preventing and treating effect of PNS on idiopathic pulmonary fibrosis,mice model induced by bleomycin (BLM) was adopted. This thesis describes the effect and mechanisms of PNS on PF from aspects of integral and molecular level which can provides experimental foundation for more exact and scientific therapy. Methods and Results
1 Role of observation on the prevention of PNS on pulmonary fibrosis 1.1 Methods 180 male C57BL/6 were randomly divided into 6 groups(30 mice in each group).Mice in the model control group;high,moderate and low PNS groups were injected. with a single dose of bleomycin by trachea,and mice in sham-model control group with same volume normal saline.1 day after the injection, oral administration of drug daily until they were killed 1 day before.PNS solution of different dosages(120mg,60mg,30mg/kg/d) was respectively given to mice in the high,moderate and low PNS group by gavages, while equal volume of normal saline was given to those in the sham-model control group and model control group, and an equal volume of prednisone(0.56mg·kg-1·d-1) was saline was given to those in positive medicine control group. Each animal in 7,14,28d pick eyeball take blood serum, observation, separationⅢserum collagen type (Ⅲ-C), IV collagen type (Ⅳ-C) and layer ankylosis protein (LN) and hyaluronic acid (HA), and take the content of lung tissue for HE Mallory stain, detection, lung tissue hydroxyproline (HYP) changes.
1.2 Results PNS can modulate the level ofⅢ-collagen,Ⅳ-collagen,laminin and hyaluronic acid in serum compared with those levels in model control group and it can also lessen the hyperplasia of pulmonary fibrosis. It is indicated that PNS can prevent and treat pulmonary fibrosis
2 Experimental study on mechanisms of PNS on pulmonary fibrosis
2.1 The effect of PNS on cell apoptosis in pulmonary tissues of mice
Mechanisms of PNS on pulmonary fibrosis were discussed by the study on the level of cell apoptosis.By the method of TUNEL, observing the apoptosis of the lung. From the results, Pulmonary fibrosis in lung tissue apoptotic cells in mice increased significantly, mainly for the cell apoptosis of bronchial epithelium cells, alveolar epithelial cells, macrophages,and a few interstitial lung cells. In PNS dose group of mice could significantly reduce pulmonary fibrosis apoptosis of epithelial cells of lung tissue. It is suggested that PNS can play the role of the antioxidant fibrosis through inhibiting lung epithelial cell apoptosis.
2.2 The effect of PNS on CatB and CatD in pulmonary tissues of mice
Mechanims of PNS on pulmonary fibrosis were discussed by observing the effect on CatB and CatD.The activition of CatB and CatD in the protein of pulmonary tissues was studied by means of immuno-histochemistry and Western blotting. It is showed that PNS can reduce the content of CatB and CatD in nucleoprotein. which means that one of mechanisms of PNS on pulmonary fibrosis is by inhibiting the activity of CatB and CatD.
2.3 The effect of PNS on Bax and Bcl-2 in pulmonary tissues of mice
The effect of PNS on the lung tissue was investigated by detecting the activity of bax and bcl-2 at the protein and gene transcription level by using immuno-histochemistry and Real-time-PCR methods. The possible mechanism of PNS as anti-fibrosis is fully studied. The lung tissue is originated from experimentⅠ.①The expression of Bax is significantly increas-ed in the lung tissue of pulmonary fibrosis mice, it mainly expressed in the damaged lung bronchial epithelium cells, alveolar epithelial cells, and macrophages. However, the expres-sion of Bax in the interstitial lung cells are less significant, which means that hepatocytes is one of the main sources of Bax, bax plays an important role in the apoptosis of pulmonary fibrosis.②The expression of bcl-2 in the lung tissue of pulmonary fibrosis mice is signi-ficantly enhanced. Although there is expression in the fine bronchial epithelium cells and alveolar epithelial cells, the expression of bcl-2 in the interstitial lung cells is significantly increased, and some already enter the cell nucleus. It shows that bcl-2 are secreted by interstitial lung cells, bcl-2 plays an important role in inhibiting fibroblasts apoptosis.③The mRNA of Bax and bcl-2 significantly increased in the lung tissue of pulmonary fibrosis mice. The result shows that Bax and bcl-2 regulate the apoptosis of lung tissue cells of pulmonary fibrosis mice at least in protein transcription or translation level.④The results shows that the mechanism of PNS as the anti- pulmonary fibrosis is due to regulate the activity of Bax and bcl-2 of the lung tissue at the protein transcription and translation level
2.4 The effect of PNS on Fas and FasL in pulmonary tissues of mice
Mechanims of PNS on pulmonary fibrosis were discussed by observing the effect on Fas/FasL.The activition of CatB and CatD in the protein of pulmonary tissues was studied by means of immuno-histochemistry. It is showed that PNS can reduce the content of Fas/FasL in nucleoprotein. which means that one of mechanisms of PNS on pulmonary fibrosis is by inhibitting the activity of Fas/FasL.
1 PNS can reduce the degree of pulmonary inflammation and fibrosis, and thus prevent and treat pulmonary fibrosis by adjusting the content of extracellular matrix in fibrotic mice by bleomycin-induced.
2 Mechanisms of PNS on IPF lie in such aspects
2.1 PNS can inhibit the activity of CatB and CatD in protein of pulmonary tissues.
2.2 PNS can regulate the activity of Bax and Bcl-2 in protein of pulmonary tissues.
2.3 PNS can inhibit the activity of Fas/FasL in protein of pulmonary tissues.
In conclusion, we can conclude that PNS has a certain effect on the prevention and treatment of pulmonary fibrosis. The possible mechanism is due to inhibit the activity of CatB、CatD and Fas/FasL, regulate the activity of Bax/Bcl-2, inhibit the apoptosis of lung epithelial cells, and induce the apoptosis of fiber cells.
PNS是从三七中提取的有效活性成份,是三七发挥药理作用的主要成分之一。现代药理研究表明PNS具有广泛的药理作用,如止血、活血化瘀、消肿、补血、调节细胞凋亡等作用。为探讨PNS对肺纤维化小鼠的防治作用,我们以BLM诱导小鼠肺纤维化为模型,从整体与分子水平阐明PNS的作用和作用机制,以期为临床防治肺纤维化提供实验基础。
1 PNS防治肺纤维化作用的观察
1.1方法C57BL/6性小鼠180只,分为模型组；PNS高、中和低剂量三组；阳性药物对照组(醋酸强的松片)；假手术组；共6组,每组30只。除假手术组外其余各组小鼠气管内一次性滴注BLM,假手术组小鼠气管内一次性滴注等体积的生理盐水。造模后第二天开始给药。PNS高、中和低剂量组分别为120、60、30mg/kg/d,醋酸泼尼松组0.56mg/kg/d,假手术组,模型组分别灌服等体积的生理盐水。各组动物于7、14、28d摘眼球取血,分离血清,观察血清中Ⅲ型胶原(Ⅲ-C),Ⅳ型胶原(Ⅳ-C)及层黏连蛋白(LN)和透明质酸(HA)的含量,同时取肺组织进行HE, Mallory染色,检测肺组织羟脯氨酸(HYP)的变化。
1.2结果
PNS可降低肺纤维化小鼠血清中Ⅲ-C、Ⅳ-C型胶原、LN及HA的含量,降低肺纤维化小鼠肺组织HYP的含量,减轻肺组织胶原的增生。因此提示：PNS具有防治BLM诱导的小鼠肺纤维化的作用。
2 PNS防治肺纤维化作用机制的实验研究
2.1 PNS对肺纤维化小鼠肺组织细胞凋亡的影响
通过PNS对肺纤维化小鼠肺组织细胞凋亡影响的研究,探讨PNS防治肺纤维化的作用机制。肺组织来源于实验一。利用TUNEL染色法测定小鼠肺组织中细胞的凋亡情况。结果表明：肺纤维化小鼠肺组织内凋亡细胞明显增加,凋亡的细胞主要为支气管上皮细胞、肺泡上皮细胞和巨噬细胞,还有少量肺间质细胞。PNS中剂量组能显著降低肺纤维化小鼠肺组织上皮细胞的凋亡。因此提示,PNS能通过抑制肺上皮细胞的凋亡而发挥其抗纤维化的作用。
2.2 PNS对肺纤维化小鼠肺组织CatB和CatD的影响
观察PNS对肺纤维化小鼠肺组织CatB和CatD的影响,探讨PNS防治肺纤维化的作用机制。肺组织来源于实验研究一。实验采用免疫组织化学和Westem blotting的方法,研究PNS对肺组织中CatB和CatD的影响。结果表明：PNS中剂量组防治后,各时间点小鼠肺组织中CatB和CatD含量和表达均有一定程度的下降,说明PNS能够从蛋白水平调节CatB和CatD的活性。提示抑制CatB和CatD的表达和活性可能是PNS防治肺纤维化的机制之一
2.3 PNS对肺纤维化小鼠肺组织Bax和Bcl-2的影响
观察PNS对肺纤维化小鼠肺组织Bax和Bcl-2的影响,探讨PNS抗肺纤维化的作用机制。肺组织来源于实验研究一。实验方法采用免疫组织化学法和RT-PCR的方法,研究PNS对肺组织中Bax和Bcl-2的蛋白和基因影响。结果表明：①Bax在肺纤维化小鼠肺组织中的含量明显升高,并且主要表达于肺损伤区的细支气管上皮细胞、肺泡上皮细胞和巨噬细胞,而在肺间质细胞少有表达,因此提示肺内实质细胞是Bax的主要来源之一,Bax在肺纤维化实质细胞的过度凋亡中发挥重要作用；②Bcl-2在肺纤维化小鼠肺组织中的含量亦明显升高,虽然细支气管上皮细胞和肺泡上皮细胞有表达,但在肺损伤区的肺间质细胞表达却明显增多,并且有的已进入细胞核,因此提示增多的Bcl-2主要是由肺间质细胞分泌的,Bcl-2在抑制成纤维细胞凋亡中发挥重要作用；③肺纤维化小鼠肺组织BaxmRNA和Bcl-2mRNA的表达亦明显升高,表明Bax和Bcl-2对肺纤维化小鼠肺组织细胞凋亡的调控至少是在蛋白转录或翻译水平进行的；④结果提示：PNS发挥其抗肺纤维化作用的机制之一在于从蛋白转录和翻译水平调节肺组织中Bax和Bcl-2的活性。
2.4 PNS对肺纤维化小鼠肺组织Fas和FasL的影响
观察PNS对肺纤维化小鼠肺组织Fas和FasL的影响,探讨PNS抗肺纤维化的作用机制。肺组织来源于实验研究一。用免疫组织化学法,研究对肺组织Fas和FasL的表达。结果表明：PNS能降低肺纤维化小鼠肺组织中Fas和FasL的含量。提示：抑制Fas和FasL的表达和活性可能是PNS防治肺纤维化的机制之一
结论
1 PNS可以调节BLM诱导的肺纤维化小鼠细胞外基质的含量,降低肺组织炎症和纤维化的程度,发挥防治肺纤维化的作用。
2 PNS防治肺纤维化的作用机理
2.1抑制肺上皮细胞的凋亡。
2.2抑制肺组织蛋白CatB和CatD的活性.
2.3调节肺组织蛋白Bax和Bcl-2的活性。
2.4抑制肺组织蛋白Fas和FasL的活性。
总之,PNS具有防治肺纤维化的作用,其作用机理可能在于通过抑制肺组织CatB.CatD和Fas/FasL的活性,调节Bax/Bcl-2的活性,抑制肺上皮细胞的凋亡,促进成纤维细胞的凋亡,来实现PNS防治肺纤维化的作用。
The pathogenesis of pulmonary fibrosis is complicated, it is characterized with fibroblast hyperplasia, Epithelial cells apoptosis and deposition of collagen protein. The clinically effective therapy is deficient, the prognosis of this disease is not so better. Therefore, it is important to study the pathogenetic mechanisms and creating new treating scheme.
PNS is one of the effective element extracted from notoginseng. It is one of the major components for notoginseng playing pharmacology.It owes various biological functions, including stop bleeding, remove blood stasis, detumescence, anemia, adjust the cell apoptosis functions and so on. To discuss the preventing and treating effect of PNS on idiopathic pulmonary fibrosis,mice model induced by bleomycin (BLM) was adopted. This thesis describes the effect and mechanisms of PNS on PF from aspects of integral and molecular level which can provides experimental foundation for more exact and scientific therapy. Methods and Results
1 Role of observation on the prevention of PNS on pulmonary fibrosis 1.1 Methods 180 male C57BL/6 were randomly divided into 6 groups(30 mice in each group).Mice in the model control group;high,moderate and low PNS groups were injected. with a single dose of bleomycin by trachea,and mice in sham-model control group with same volume normal saline.1 day after the injection, oral administration of drug daily until they were killed 1 day before.PNS solution of different dosages(120mg,60mg,30mg/kg/d) was respectively given to mice in the high,moderate and low PNS group by gavages, while equal volume of normal saline was given to those in the sham-model control group and model control group, and an equal volume of prednisone(0.56mg·kg-1·d-1) was saline was given to those in positive medicine control group. Each animal in 7,14,28d pick eyeball take blood serum, observation, separationⅢserum collagen type (Ⅲ-C), IV collagen type (Ⅳ-C) and layer ankylosis protein (LN) and hyaluronic acid (HA), and take the content of lung tissue for HE Mallory stain, detection, lung tissue hydroxyproline (HYP) changes.
1.2 Results PNS can modulate the level ofⅢ-collagen,Ⅳ-collagen,laminin and hyaluronic acid in serum compared with those levels in model control group and it can also lessen the hyperplasia of pulmonary fibrosis. It is indicated that PNS can prevent and treat pulmonary fibrosis
2 Experimental study on mechanisms of PNS on pulmonary fibrosis
2.1 The effect of PNS on cell apoptosis in pulmonary tissues of mice
Mechanisms of PNS on pulmonary fibrosis were discussed by the study on the level of cell apoptosis.By the method of TUNEL, observing the apoptosis of the lung. From the results, Pulmonary fibrosis in lung tissue apoptotic cells in mice increased significantly, mainly for the cell apoptosis of bronchial epithelium cells, alveolar epithelial cells, macrophages,and a few interstitial lung cells. In PNS dose group of mice could significantly reduce pulmonary fibrosis apoptosis of epithelial cells of lung tissue. It is suggested that PNS can play the role of the antioxidant fibrosis through inhibiting lung epithelial cell apoptosis.
2.2 The effect of PNS on CatB and CatD in pulmonary tissues of mice
Mechanims of PNS on pulmonary fibrosis were discussed by observing the effect on CatB and CatD.The activition of CatB and CatD in the protein of pulmonary tissues was studied by means of immuno-histochemistry and Western blotting. It is showed that PNS can reduce the content of CatB and CatD in nucleoprotein. which means that one of mechanisms of PNS on pulmonary fibrosis is by inhibiting the activity of CatB and CatD.
2.3 The effect of PNS on Bax and Bcl-2 in pulmonary tissues of mice
The effect of PNS on the lung tissue was investigated by detecting the activity of bax and bcl-2 at the protein and gene transcription level by using immuno-histochemistry and Real-time-PCR methods. The possible mechanism of PNS as anti-fibrosis is fully studied. The lung tissue is originated from experimentⅠ.①The expression of Bax is significantly increas-ed in the lung tissue of pulmonary fibrosis mice, it mainly expressed in the damaged lung bronchial epithelium cells, alveolar epithelial cells, and macrophages. However, the expres-sion of Bax in the interstitial lung cells are less significant, which means that hepatocytes is one of the main sources of Bax, bax plays an important role in the apoptosis of pulmonary fibrosis.②The expression of bcl-2 in the lung tissue of pulmonary fibrosis mice is signi-ficantly enhanced. Although there is expression in the fine bronchial epithelium cells and alveolar epithelial cells, the expression of bcl-2 in the interstitial lung cells is significantly increased, and some already enter the cell nucleus. It shows that bcl-2 are secreted by interstitial lung cells, bcl-2 plays an important role in inhibiting fibroblasts apoptosis.③The mRNA of Bax and bcl-2 significantly increased in the lung tissue of pulmonary fibrosis mice. The result shows that Bax and bcl-2 regulate the apoptosis of lung tissue cells of pulmonary fibrosis mice at least in protein transcription or translation level.④The results shows that the mechanism of PNS as the anti- pulmonary fibrosis is due to regulate the activity of Bax and bcl-2 of the lung tissue at the protein transcription and translation level
2.4 The effect of PNS on Fas and FasL in pulmonary tissues of mice
Mechanims of PNS on pulmonary fibrosis were discussed by observing the effect on Fas/FasL.The activition of CatB and CatD in the protein of pulmonary tissues was studied by means of immuno-histochemistry. It is showed that PNS can reduce the content of Fas/FasL in nucleoprotein. which means that one of mechanisms of PNS on pulmonary fibrosis is by inhibitting the activity of Fas/FasL.
1 PNS can reduce the degree of pulmonary inflammation and fibrosis, and thus prevent and treat pulmonary fibrosis by adjusting the content of extracellular matrix in fibrotic mice by bleomycin-induced.
2 Mechanisms of PNS on IPF lie in such aspects
2.1 PNS can inhibit the activity of CatB and CatD in protein of pulmonary tissues.
2.2 PNS can regulate the activity of Bax and Bcl-2 in protein of pulmonary tissues.
2.3 PNS can inhibit the activity of Fas/FasL in protein of pulmonary tissues.
In conclusion, we can conclude that PNS has a certain effect on the prevention and treatment of pulmonary fibrosis. The possible mechanism is due to inhibit the activity of CatB、CatD and Fas/FasL, regulate the activity of Bax/Bcl-2, inhibit the apoptosis of lung epithelial cells, and induce the apoptosis of fiber cells.
引文
后硬膜外瘢痕组织形成过程中对Ⅰ、Ⅲ型胶原表达及对成纤维细胞凋亡和半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)的影响,结果显示三七透明质酸钠凝胶组Ⅰ型胶原mRNA表达在用药4周时明显低于生理盐水组(P<0.01)；Ⅲ型胶原mRNA表达在用药4周时明显高于生理盐水组(P<0.01)；TUNEL染色结果显示,三七透明质酸钠组在第2、4、8周的细胞凋亡指数显著高于生理盐水组(P<0.01)；原位杂交检测Caspase-3结果显示,实验第2周时三七透明质酸钠组的表达量最高,较生理盐水组有显著性差异(P<0.05),第4周时无统计学差异；第8周时三七透明质酸钠组的表达量显著高于生理盐水组(P<0.01)。提示三七透明质酸钠可明显诱导成纤维细胞的凋亡,减少成纤维细胞合成细胞外基质,其机制可能与促进Caspase-3的表达有关。
王荣国等通过建立椎板切除术大鼠模型,研究分析愈合过程中TGF-β1的表达情况。结果显示三七凝胶组7、14、21d三个时间点TGF-β1的表达均显著低于生理盐水组(P<0.05)。提示三七凝胶早期可以调控硬膜外组织中的炎症反应和胶原纤维合成,其机制可能与PNS的抗炎、抗纤维化有关。6.5 PNS对心肌纤维化的作用
心肌纤维化是指心肌组织中胶原纤维过度沉积,各型胶原比例失调(Ⅰ/Ⅲ型比例增加)以及排列紊乱。随着人口老龄化,心肌纤维化越来越引起人们的重视,但PNS防治其纤维化的研究较少,有待于进一步研究。
程志清等用雄性Balb/c小鼠研究PNS对心肌炎慢性期心肌纤维化的影响,将88只小鼠随机分为正常对照组、模型对照组、PNS高、中、低剂量组,45天后采用免疫组化法及RT-PCR法检测心肌中TGF-β1.PDGF-β的蛋白及mRNA的表达变化。结果显示：PNS治疗组心肌中TGF-β1.PDGF-β的蛋白及mRNA表达水平较模型组下降。提示PNS具有抗病毒性心肌炎慢性期心肌纤维化的作用,可能是与其抑制TGF-β 1.PDGF-β的过度表达有关。
吴柱国等采用背部皮下持续注射异丙肾上腺素诱导心肌肥厚的小鼠模型,随机分为对照组、模型组及3个治疗组(分别为低、中和高剂量组),比较各组小鼠心重指数、左心室重量指数(LVI)、左心室胶原含量、心肌中MMP-2和MMP-9mRNA表达水平的变化。结果模型组小鼠心重指数、LVI.HYP含量及MMP-2、MMP-9的表达明显上调,而PNS中、高剂量组能明显降低心重指数、LVI.HYP含量及MMP-2、MMP-9的表达,与模型组比差别有统计学意义(P<0.01)。说明PNS对改善心肌肥厚有一定作用,其机制至少是部分通过拮抗MMP-2、MMP-9的表达,来抑制心纤维化。7展望
综上所述,PNS是中药三七的主要有效成分,目前在器官纤维化的领域得到了广较多的研究,但主要是在肝脏和肾脏的纤维化研究较多,而对于其他器官的研究较少,因此进行PNS防治其他器官纤维化的研究具有重要作用。 91
[2]中华人民共和国药典委员会编.中华人民共和国药典[S],一部.北京：化学工业出版社,2005：218
[3]鲍建才,刘刚,丛登立,等.三七的化学成分研究进展[J].中成药,2006,28(2)：246-253
[4]冯陆冰,潘西芬,孙泽玲.三七的药理作用研究进展[J].中国药师,2005,11(10)：1185-1186
[5]李冠烈.三七的现代研究与进展(二)[J].世界中西医结合杂志,2008,3(11)：687-691
[6]刘大君,刘汝专,刘佳,等.三七对细胞凋亡的研究进展[J].云南中医中药杂志,2009,30(6)： 62-64
[7]刘剑毅,姚恒,戴霞,等.三七总甙抗纤维化作用的研究进展[J].中国美容医学,2006(15)8：985-986
[8]冯亮,蒋学华,周静,等.三七皂苷R1和人参皂苷Rgl的大鼠在体肠吸收动力学研究[J].中国药学杂志,2006,41(14)：1097-1102
[9]冯亮,胡昌江,余凌英.人参皂苷Rgl及其代谢产物的药代动力学研究[J].药学学报,2010,45(5)：636-640
[10]韩旻,韩丽妹,王青松,等.三七皂苷的口服吸收机制[J].药学学报,2006,41(6)498-505.
[11]王毅,刘铁汉,王巍,等.肠内菌群对人参皂苷Rgl的代谢转化作用的研究[J].中国中药杂志,2001,26(3)：188-190
[12]陈广通,杨敏.三七皂苷R1在大鼠体内的代谢产物分析[J].时珍国医国药,2010,21(2)：485-487
[13]曾聪彦,梅全喜.81例含三七总皂苷类注射剂致不良反应的文献分析[J],中国药房,2007,18(33)：2616-2618
[14]DongTT,CuiXM,SongZH,et al.Chemical assessm ent of roots of Panax notoginsEng in China:regional and seasonal variations in itsactive constituents[J].JA gric Food Chem, 2003,51(16):4617-4623
[15]赵国强,王秀训.三七止血成分的研究[J].中草药,1986,17(6)：34-35
[16]金楠,周莉.三七花中总皂昔对大鼠血液流变学的影响[J].中国药师,2007,10(12)：1193-1195
[17]苏雅,赵益桂,张宗鹏,等.三七三醇皂甙对动物血小板功能及血栓形成的影响[J].中草药,1996,27(11)：666-668
[18]徐皓亮,季勇,饶曼人.三七皂苷Rg1对大鼠实验性血栓形成、血小板聚集率及血小板内游离钙水平的影响[J].中国药理学与毒理学杂志,1998,12(1)：40-42
[19]徐皓亮,刘宛斌,饶曼人.参三七皂苷Rg1对大鼠实验性血栓形成的响及机制探讨[J].药学学报,1997,32(7)：502-505
[20]Lowenstein CJ,Snyder SH.Nitric oxted,anovel biologic messenger[J].Cell,1992,70(5) :705-7
[21]刘刚,刘育辰,鲍建才,等.三七药理作用的研究进展[J].人参研究,2005,3：12-17
[22]郑茵红,高瑞兰,朱大元,等.三七总皂苷及其单体对人骨髓造血祖细胞增殖作用的研究[J].中国中西医结合急救杂志,2003,10(3)：135-137
[23]钱煦岱,高瑞兰,马珂,等.三七皂苷对人骨髓CD34+造血干/祖细胞的增殖分化作用[J].中国实验血液学杂志,2003,1 1(2)：120-123
[24]陈小红,高瑞兰,郑智茵,等.三七皂苷对人骨髓造血细胞凋亡相关蛋白表达的影响[J].中国实验血液学杂志,2006,14(2)：343-346
[25]高瑞兰,徐卫红,陈小红,等.三七皂苷对造血细胞AP-1家族转录调控蛋白NF-E2, c-jun和c-fos的诱导作用[J].中国实验血液学杂志,2004,12(1)：16-19
[26]王一菱,陈迪,吴景兰.三七总皂甙抗炎和镇痛作用及其机理探讨[J].中国中西毯结合杂志,1994,14(1)：35-36
[27]Cicero AF,Vitale G,Savion G,et al.Panax notoginseng(Burk)effects fibrinogen and lipid plasma lever in rats fed on a high-fatdiet[J].PhytotherRes,2003,17(2):174-178
[28]刘文娥,尤昭玲,王若光,等.复方三七成分对恒河猴子宫内膜炎超微结构的影响[J].湖南中医学院学报,2005,25(4)：3-6
[29]崔红晶,安长新,陈东,等.三七总苷对大鼠自身免疫性睾丸炎的拮抗作用[J].解剖学杂志,2008,31(1)：19-21
[30]Hule. A,Navarro S,Smith J R,et al.Panax notoginseng attenuates LPS-induced pro-inflammatory mediators in RAW 2647 cell[J].J Ethnopharmacol,2006,106(1):121-128
[31]贾乙,李晓辉.炎症因素在泡沫细胞形成中的作用及三七皂苷对其影响[J].第三军医大学学报,2005,27(10)：972-974
[32]张翼冠,李晓辉,樊继山,等.三七总皂苷通过抗炎和调血脂作用抑制大鼠动脉粥样硬化形成[J].现代生物医学进展,2007,7(11)：1601-1603
[33]周小玲,李永伟,李逢春,等.三七总皂甙对大鼠免疫功能影响的实验研究[J],广西医科大学学报[J],2001,18(3)：.360-361
[34]孙云,邓阳梅,蔡元培,等.复方三七口服液对小鼠免疫功能和抗氧化功能的影响[J].江苏临床医学杂志,2002,6(6)：518-519
[35]乔萍,杨贵贞.三七皂苷单体Rgl对D-半乳糖模型鼠学习记忆和免疫功能的影响[J].吉林大学学报(医学版),2003,29(3)：267-269
[36]江源,刘翠,陈清彬,等.三七皂苷Rg1对小鼠免疫功能的影响[J].中国现代中药,2006,8(3)：9-10
[37]黄伟,张旋.三七总皂苷对老龄大鼠免疫功能的影响[J].昆明医学院学报,2008,(2)：32-35
[38]蔡辉,姚茹冰,郭郡浩,等.三七总皂苷对佐剂性关节炎大鼠的抗炎及免疫调节作用[J].安徽中医学院学报,2009,28(4)：57-60
[39]姚茹冰,郭郡浩,胡兵,等.三七总苷对大鼠佐剂性关节炎的治疗作用[J].医学研究生学报,2008,21(1)：34-36
[40]姚茹冰,郭郡浩,赵智明,等.三七总皂甙对佐剂性关节炎大鼠腹腔巨噬细胞产生炎性细胞因子的影响[J].中国微循环,2007,11(5)：330-332
[41]丁青,尤昭玲.三七复合有效成分对子宫内膜炎症细胞NF-κ Bp65及TNF-α、IL-1 β变化的影响[J],中国中医药科技,2007,14(2)：113-115
[42]甘雨,徐惠波,孙晓波.三七总皂苷的药理作用研究进展[J].时珍国医国药,2007,18(5)：1251-1252
[43]Han JA,HuWY,Sun ZH.Effect of Panax notoginseng Saponin on Ca2+, CAM in craniocerebral injury[J].Chinese Journalof Integrated Traditional and Western Medicine, 1999,1(9):227
[44]刘建辉,冀风云,王婷,等.三七总皂苷对脑缺血再灌注损伤保护作用的实验研究[J]_中国临床神经科学,2002,10(1)：90
[45]寇幸福,王志方.三七总皂苷对大鼠脑缺血再灌注损伤保护作用及机制的实验研究[11].河南中医学院学报,2008,23(6)：22-23
[46]刘艳娥,刘丽丽,房国涛.三七抗肿瘤的实验研究概况[J].时珍国医国药,2008,19(4)：1015-1016
[47]尚西亮,傅华群,刘佳,等.三七总皂苷对人肝癌细胞的抑制作用[J]_中国临床康复,2006,10(23)：121-123
[48]吴映雅,谭字蕙,钟富有,等.三七总皂苷丹参注射液苦参碱对大鼠肝癌细胞CBRH-791生长的抑制作用[J].辽宁中医杂志,2005,32(10)：1010
‘[49]王志斌,李军祥,朱陵群,等.三七提取物对GES-1细胞及MNNG转化后GES-1细胞增殖的抑制作用[J].中西医结合学报,2004,2(6)：445-449
[50]李军祥,王志斌,朱陵群,等.三七提取物对MNNG转化后GES-1细胞的促凋亡作用[J].中西医结合学报,2005,3(2)：123-127
[51]李军祥,王志斌,朱陵群,等.三七提取物含药血清对MNNG转化后GES-1细胞凋亡相关基因蛋白表达的影响[J].中西医结合学报,2008,6(8)：817-820
[52]李晓红,董作仁,郝洪岭,等.三七皂苷对NB4细胞促凝活性及诱导分化的影响[J].中国中西医结合杂志,2004,24(1)：63-66
[53]徐罗玲,吴琦,高军,等.三七皂苷R诱导HL-60细胞系分化的形态和功能变化[J].中国病理生理杂志,1992,8(1)：55-58
[54]国家中医药管理局《中华本草》编委会.中华本草(上册)[M].上海：上海科学技术出版社,1998：1310
[55]张晓丽,俞惠新,曹国宪,等.P-糖蛋白多药耐药机制及其逆转剂的研究进展[J].中国医学文摘-肿瘤学,2005,19(2)：147
[56]史亦谦,田同德.三七总皂苷体外逆转K562/VCR细胞多药耐药的实验研究[J].中国中医药科技,2005,12(5)：292
[57]史曦凯,张翼军,赵春景,等.人参皂苷单体Rbl对多药耐药细胞系K562/HHT的耐药逆转作用[J].第三军医大学学报,1999,21(11)：825
[58]杨金伟,习杨彦彬,刘佳,等.三七总皂苷对SAM-P/8小鼠海马中衰老相关基因表达的影响[J].解剖科学进展,2007,13(4)：306-313
[59]郑文球,朱敏.三七皂苷R1对HL-60细胞凋亡及survivin、p53表达的影响[J].肿瘤 学杂志,2007,13(3)：198-200
[60]张延斌,周永兰,杨煜,等.三七总皂甙对血管平滑肌细胞凋亡及C-myc基因表达的影响[J].新技术,2007,36(8)：120-121
[61]武凡,康格非.三七皂苷Rg1、Rbl对脂多糖引起的大鼠肝细胞凋亡及相关基因表达的保护作用[J].中国中西医结合杂志,2002,22(3)：165-167
[62]徐正祄,倪世容,王万铁,等.三七总皂苷对肺缺血再灌注损伤时细胞凋亡及Fas/FasL的影响[J].中国病理生理杂志,2005,21(9)：1731-1734
[63]赵玉鑫,王洪,杨述华,等.三七总皂苷对大鼠脊髓损伤后iNOS表达及细胞凋亡的影响[J].实用医药杂志,2006,23(11)：1340-1343
[64]陈彦静,李建东,黄启福.三七总皂苷对Ang Ⅱ秀导心肌细胞凋亡的影响[J].中国中药杂志,2005,30(10)：778-781
[65]张毅,叶启发,明英姿,等.三七总皂苷预处理大鼠供肝对细胞凋亡及TNF-a、 caspase-3表达的影响[J].中国现代医学杂志,2005,15(2)：172-176
[66]李巾伟,朱培纯,司银楚,等.三七总皂苷对脑出血大鼠前脑促凋亡基因caspase-3影响的研究[J].北京中医药大学学报,2003,26(2)：22-25
[67]顾萍,张勇,高飞,等.三七总皂苷对大鼠脑出血模型中神经细胞凋亡、Bcl-2表达的影响[J].中国临床医学,2006,13(4)：527-529
[68]邓志军,郭洁文,杨敏,等.三七总皂苷及其活性单体药代动力学的研究进展[J].药学进展,2009,19(1)：24-27
[69]沈央,方晓玲.三七总皂苷脂质体的药剂学性质及大鼠肺部给药药动学研究[J]_中草药,2004,35(7)：745-749
[70]徐白,沈蕴琪,方晓玲,.等.三七总皂昔复方脂质体凝胶剂的制备及皮肤给药研究[J].中国临床药学杂志,2007,16(3)：144-148
[71]韩旻,付韶,方晓玲.三七总皂苷油包水微乳的处方筛选及体内外评价[J].药学学报,2007,42(7)：780-786
[72]Friedman SI.Hepatic stellate cells Protean, multifunctional and enigmatic cells of the liver[J].PhysiolRev,2008,8:125-172
[73]唐阁,陈文慧,马迪.中药抗脂质过氧化与抗肝纤维化[J].中西医结合肝病杂志,2005,15(6)：379-380
[74]Neuman MG.Cytokines-central factors in alcoholic liver disease[J].Alcohol Res Health,2003,27(4):307-316
[75]Luca M iele,Gary Beale,G illian Patm an,et al.The Kruppel Like factor 6 fenotype is associateed with fibrosis in nonalcoholic fatty liver disease[J].G astroenterology,2008,135 (1):282-291
[76]WangCH,Lee TH,Lu CN,et al.Electroporative alpha-MSH gene transfer attenuates thioacetamide induced murine hepatic fibrosis by MMP and TIMP modulation[J]. JGeneTher,2006,13(13):1000-1009
[77]吕伟红,徐姗,张洪泉.三七总皂苷抗肝纤维化作用机制的研究进展[J].中国野生植物 资源,2009,28(2)：1-3
[78]张荣华.三七总皂苷干预肝纤维化大鼠肝组织Ⅰ型胶原、Ⅲ型胶原、FN、LN表达的研究[c].重庆市中医药学会学术年会论文集,2009,82-85
[79]余万桂,张恒文,晏年春,等.三七总皂甙对肝纤维化小鼠血清酶学及NO的影响[J].中药药理与临床,2005,21(5)：22-23
[80]石小枫,徐曼,刘杞.三七总皂甙对肝纤维化大鼠Ⅰ,Ⅲ型胶原及TGF-β1的影响[J].中药药理与临床,2001,17(2)：7-8
[81]曾文勇,石小枫,刘杞,等.三七总皂苷对肝纤维化大鼠胶原及TGF-β1mRNA表达的影响[J].胃肠病学和肝病学杂志,2010,19(9)：795-798
[82]马岚青,梁兵,柳波,等.人参皂苷Rg1抗肝纤维化的实验研究[J].中国中西医结合消化杂志,2007,15(3)：165
[83]张桂灵,石小枫,冉长清,等.三七总皂甙对抗大鼠免疫性肝纤维化的实验研究[J].第三军医大学学报,2007,29(23)：2212-2213
[84]张荣华,李景怡,陈如泉,等.三七总皂苷对肝纤维化大鼠肝脏超微结构的影响[J].第三军医大学学报,2005,27(24)：2410-2413
[85]王文兵,戴立里,郑元义.三七总皂甙诱导大鼠肝星状细胞凋亡的研究[J].中华肝脏病杂志,2005,13(2)：156-157.
[86]王怡,薛绍礼,张菁,等.三七总皂甙对传代肝星状细胞增殖的影响[J].淮海医药,2008,26(1)：1-2
[87]薛青,薛绍礼,汪亚松,等.三七总苷对体外培养细胞胶原合成模型的影响[J].医药导报,2008 27(5)：517-518
[88]余万桂,张恒文.三七总皂苷对肝纤维化小鼠TNFa及IL-6活性的影响[J].中药药理与临床,2005,21(4)：31-32
[89]Karl T W.Fibrosis:a common pathway in organ failure:angiotesion Ⅱ and tissure repair [J].Sem Nephro,1997,17(5):467
[90]Eddy AA.Molecular insights into renal interstitial fibrosis[J].AM Soc Nephrol,1996,7 (17):2495-2508
[91]Bohel A,Mackensen Haen S,Vou Gise,et al.The cones quences of tubuloinst Erstitial changes for renal function in glomerulopathies.A morphometric and eytologial analysis[J]. Pathol Res Pract,1990,18(1):135-144
[92]伍红英,金建生,刘静,等.三七总皂苷对腺嘿吟致肾间质纤维化的影响[J].中国新药与临床杂志,2008,27(11)：823-828
[93]刘静,金建生,钟山.三七总皂苷对腺嘌呤致大鼠肾间质纤维化影响的实验研究[J].中国临床药理学杂志,2010,26(4)：287-289
[94]谢纪青,金建生,付次双.三七总皂苷对慢性肾缺血肾间质纤维化的防治作用[J].福建医科大学学报,2010,44(1)：40-44
[95]付次双,金建生,谢纪青.三七总皂苷对大鼠慢性缺血性肾损伤的影响[J].中国新药与临床杂志,2010,29(2)：104-108
[96]赵宗江,张新雪,梁凯峰,等.三七总皂苷对阿霉素肾病大鼠肾组织转化生长因子-β1表达的影响[J].中国中西医结合肾病杂志,2008,9(4)：298-301
[97]赵宗江,梁凯峰,张新雪,等.三七总皂苷对阿霉素肾病大鼠肾组织PDGF及其mRNA表达的影响[J].2008,10(4)：57-59
[98]仇琪,赵宗江,杨美娟.三七总皂苷对阿霉素肾病大鼠肾组织CTGF蛋白及其mRNA表达的影响[J].中华中医药学刊,2008,26(11)：2358-2360
[99]郭兆安,彭书玲,赵鑫,等.三七总皂苷对5/6肾切除大鼠肾脏皮质细胞外基质积聚的影响[J].中国中西医结合肾病杂志,2008,9(12)：1053-1057
[100]许志杰,陶静莉,刘华锋,等.三七总苷对5/6肾切除大鼠肾保护作用的研究[J].中成药,2009,31(10)：1493-1496
[101]谢席胜,冯胜刚,左川,等.三七总皂甙对单侧输尿管梗阻后大鼠肾间质纤维化的作用及机制研究[J].西部医学,2010,22(2)：210-214
[102]冯胜刚,谢席胜,邓尧,等.三七总皂甙对TGF-β/Smads言号通路的作用[J].西部医学,2007,19(4)：526-529
[103]冯胜刚,李光明,樊均明,等.三七总皂甙抗肾小管上皮细胞转分化的实验研究[J].西部医学,2008,20(4)：700-703
[104]赵湘,邱莲女,郭俊华,等.三七总皂苷对大鼠肾小球系膜细胞增殖及细胞周期的影响[J].中华中医药学刊,2008,26(2)：287-289
[105]赵湘,周永烈,郭俊华,等.三七总皂苷对大鼠肾小球系膜细胞结缔组织生长因子表达的影响[J].中国中西医结合肾病杂志,2008,9(2)：149-152
[106]张毅,陈孝文,吴平,等.三七总皂甙对TGF-β1诱导的HK-2细胞总胶原分泌及细胞生长的影响[J].广东医学院学报,2005,23(6)：644-646
[107]刘海燕,陈孝文,刘华锋,等.三七总苷对尿毒血清诱导的人肾小管上皮细胞外基质分泌及降解的影响[J].中草药,2006,.37(2)：245-248
[108]李才.器官纤维化-基础与临床[s].北京：人民卫生出版社,2003：188-189
[109]武慧,冯一中,顾振纶,等.三七总皂甙对博莱霉素所致小鼠肺纤维化的干预作用[J].中国野生植物资源,2007,26(1)：29-32
[110]李学军,崔社怀.三七总皂甙及甲泼尼龙对实验大鼠肺纤维化的干预作用及机制的初步探讨,中华结核和呼吸杂志[J].2002,25(9)：520-523
[111]郑洪,蒋萍,陈佳宁,等.三七总皂甙对大鼠肺纤维化的干预作用及机制探讨[c].第十次全国中西医结合防治呼吸系统疾病学术研讨会论文集,2009,287-290
[112]武慧,冯一中,顾振纶.三七总皂甙对实验性肺纤维化大鼠病理变化和转化生长因子-β1表达的影响[J].苏州大学学报(医学版),2009,29(1)：29-32
[113]李学军,崔社怀.三七总甙对大鼠肺纤维化过程中血浆MIP-1α、MCP-1含量的影响[J].第三军医大学学报,2003,25(6)：522-524
[114]全燕,夏前明,李福祥.三七总皂苷对大鼠肺纤维化及结缔组织生长因子表达的影响[J].西南国防医药,2009,19(1)：23-25
[115]周迎春,王峰,齐彦.三七总甙对博来霉素诱导肺纤维化大鼠肺内结缔组织生长因 子的影响[J].中国现代药物应用2010,4(4)：125
[116]刘剑毅,李世荣,纪淑兴.三七总甙对人增生性瘢痕成纤维细胞增殖及胶原合成的作用[J].第三军医大学学报,2003,25(17)：1562-1563
[117]姚恒,李世荣,刘剑毅.三七总甙对人增生性疲痕成纤维细胞TGF-B和细胞周期的作用[J].中国实用美容整形外科杂志,2005,16(4)：243-245
[118]刘灿,周卫,孔焕宇,等.三七透明质酸钠凝胶对家兔硬膜外瘢痕中成纤维细胞凋亡的影响[J].世界中医药,2010,5(4)：282-284
[119]徐泉,周卫,孔焕宇,等.三七透明质酸钠凝胶对家兔椎板切除术后硬膜外瘢痕中胶原成分的影响[J].中国骨伤,2010,23(4)：278-281
[120]王荣国,周卫,章永东,等.三七凝胶对硬膜外粘连中COX-2、TGF-B1的影响[J].北京中医药大学学报,2010,3(1)：54-57
[121]程志清,徐百鸿,窦丽萍,等.三七总皂甙抗病毒性心肌炎慢性期小鼠心肌纤维化作用及其机制的研究[J].浙江中医药大学学报,2008,32(1)：23-26
[122]程志清,徐百鸿,窦丽萍,等.三七总皂苷对病毒性心肌炎慢性期小鼠心肌纤维化及细胞因子PDGF-B表达的影响[J],中华中医药学刊,2008,26(8)：1618-1621
[123]吴柱国,胡志华.三七总皂苷对小鼠心肌肥厚的抑制作用及机制[J].中国现代医学杂志,2010,20(13)：1943-1947
[1]Turk V, Turk B,Turk D.Lysosomal cysteine proteases:facts and opportunities [J].EM BO J,2001,20(17):4629-4633
[2]HalanW, LerehMM,Bradt-Nedelev B,et al.Role of cathepsin B in Intracelh lar trypsinogen activation and the onset of acute pancreatitis[J].J C lin Invest,2000,106(6):773-81
[3]唐硕,魏强.组织蛋白酶B在非肿瘤疾病中的研究进展[J],西部医学,2008,20(6)：1294-1295
[4]Liaudet CE,Beaujouin M,Derocq D,et al.Cathepsin D:newly discovered functi-Ons of a long standing aspartic protease in cancer and apoptosis[J].Cancer Lett,2006,23(7):167-79
[5]Zaidi N,Maurer A,Kalbacher H.Cathepsin D:a cellular roadmap[J].Biochem Biophys Res Commun,2008,376(1):5-9
[6]Metcalf P,Fusek M.Two crystal structures for cathepsin D:the lysosomal targeting signal and active site[J].EMBO J,1993,1(2):1293-1302
[7]Bossard N, Descotes F, Bremond AG, et al. Keeping data continuous when analyzing the prognostic impact of a tumormarker:an examplewithwith cathepsin D in breast cancer[J].BreastCancerResearch and Treatment,2003,8(2):47-53
[8]陈洋,李舒.组织蛋白酶D与消化道肿瘤的关系[J].咸宁学院学报(医学版),2008,22(6)：546-549
[9]王帅,赵慧颖.组织蛋白酶与动脉硬化的关系[J].中国老年学杂志,2010,30(4)：564-567
[10]Krizaj I,Drobnic-Kosorok M,Brzin J,et al.The primary structure of inhibitor of cystcine proteinases from potato[J].FEBS Lett,1993,33(3):15-20
[11]Berdowska I. Cysteine proteases as disease markers[J].Clin ChimActa,2004,34(2):41-69
[12]Riese RJ,Chapman HA.Cathepsins and compartmentalization in antigen presentation [J].Curr Opin Immunol,2000,1 (2):107-113
[13]Tsukuba T,Okamoto K,Yasuda Y,et al.New functional aspects of cathepsinD and cathepsinE[J].Mol Cells,2000,10(6):601-11
[14]刘玉胜,鹿庆华,蒋卫东,组织蛋白酶与心血管重塑[J].心血管病学进展,2006,27(7)：227-300
[15]Bialek J.Hombach KS,Fiebig B,et al.Lysosomal acid hydrolases of the cathepsin family are novel targets of INSL3 in human thyroid carcinoma cells[J].Ann N Y Acad Sci,2009,11(6):361-366
[16]Khalkhali EZ,Hendrix MJ.Elucidating the function of secreted maspin:inhibitting cathepsin D-mediated matrix degradation[J].CancerRes,2007,67(8):3535-9
[17]Zarzynska J,Gajkowska B,Wojewodzka U,et al.Apoptosis and autophagy in involuting bovine mammary gland is accompanied by up-regulation of TGF-betal and suppression of somatotropicpathway[J].Pol.J.Vet.Sci,2007,10(1):1-9
[18]Lecaille F,Kaleta J,Bromme D.Human and parasitic papain-like cysteine proteases:their role in physiology and pathology and recent developments in inhibitor design[J].Chem Rev,2002,10(2):4459-4488
[19]Demchik LL,Sameni M,Nelson K,et al.Cathepsin B and glioma invasion[J].Int JDevNeurosci,1999,1(7):483-494
[20]蒯小玲,萧树东.组织蛋白酶B与胃肠道肿瘤[J].国外医学：消化系统疾病分册,2002,22(2)：65-67
[21]Koblinski JE,AhramM,Sloane BF.Unraveling the role of proteases in cancer [J].Clin ChimActa,2000,29(1):113-135
[22]Staack A,Koenig F,Daniltchenko D,et al.Cathepsins B,H,and L activities in urine of patientswith transitional cell carcinoma of the bladder[J].Urology,2002,5(9):308-312
[23]Hengartner MO.The biochemistry of apoptosis[J].Nature,2000,407(6805):770-776
[24]陈月桥,王丽,武建华.细胞凋亡信号传导途径研究进展[J].中国实用医药,2007,2(33)：186-187
[25]Chw ie ra lski CE,Welte T,Buhling F.Cathepsin regu lated apoptosis[J].A poptosis,2006,11(2):143-149
[26]Furmanl LM,M aaty W S,Petersen LK,et al.Cysteine protease activation and apoptosis inmurine norovirus infection[J].V irol J,2009,6(9):139-145
[27]A kache B,Grimm D,Shen X,et al.A two hybrid screen identifies cathepsins B and L as uncoating factors for adeno-associated virus 2 and 8[J].MolTher,2007,15(2):330-339
[28]Zhang FT,ZhangYB,Chen YD,et al.Expressional induction of paralichthys olivaceus cathepsin B gene in response to virus,poly I:C and lipopolysaccharide[J].Fish She llfish Immuno,2008,25(5):542-549
[29]Burster T,Giffon T,Dahl ME,et al.Influenza A virus elevates active cathepsin B in primary murine DC[J].Int Immuno,2007,19(5):645-655
[30]Canbay A,Guicciardi M E,H iguchiH,et al.Cathepsin B inactivation attenuates hepatic injury and fibros is during cholestasis[J].J Clin Invest,2003,112(2):152-159
[31]Ben-Ari Z,Mor E,A zarov D,et al.Cathepsin B inactivation attenuates the apoptotic injury induced by ischemia/reperfusion of mouse liver[J].Apoptosis 2005,10(6):1261-1269
[32]Yan BZ,Wang W,Chen LY,et al.Role of cathepsin B mediated apoptosis in fulmin anthepatic failure inmice[J].World J Gastroentero,2009,15(10):1231-1236
[33]Benchoua A,Braudeau J,Reis A,et al.Activation of proinflammatory caspases by cathepsin B in focal cerebral ischem ia[J].J Cereb Blood Flow M etab,2004,24(11):1272-1279
[34]李杰平,何平平,于小华,等.大鼠肺纤维化细胞凋亡及CathePsinB基因变化的关系[J].现代生物医学进展,2007,7(6)：696-698
[35]Yin L,Stearns R,Gonzalez-F lecha B.Lysosom al and m itochondrial pathw ays in H2O2-induced apoptos is of alveolar type Ⅱ cells[J].J Cell Biochem,2005,94(3):433-445
[36]Takuma K,K iriu M,Mori K,et al.Roles of cathepsins in reperfusion-induced apoptos is in cultured astrocytes[J].Neurochem Int,2003,42(2):153-159
[37]张延波,陈溪萍,陶陆阳,等.大鼠脑外伤后溶酶体酶Cathepsin-B和D的表达[J].法医学杂志,2006,22(6)：404-410
[38]PrinceLR,BianchiSM,V aughan KM et al.Subversion of a lysosomal pathway regulating neutrophil apoptosis by a major bacterialtox in, pyocyanin[J].J Immuno,2008,180(5): 3502-3511
[39]Brunk UT.Svensson I[J].Redox Rep,1999,4(2):3-11
[40]Bidere N,Lorenzo HK,Carmona S,et al.Cathepsin D triggers Bax activation, resulting in selective apoptosis inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis[J].J BiolChem,2003,278(33):31401-31411
[41]吴燕婉,刘德瑜.溶酶体的细胞死亡通路[J].解剖学报,2007,38(4)：498-450
[42]Schestkowa O,Geisel D,Jacob R,et al.The catalytically inactive precursor of cathepsin D induces apoptosis in human fibroblasts and HeLa cells[J].J Cell Biochem,2007,10(1): 1558-1566
[43]Trincheri NF,Nicotra G,Follo C,et al.Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D[J].Carcinogenesis, 2007,2(8):922-931
[44]Bestvater F,Dallner C,Spiess E.The C-terminal subunit of artificially truncated human cathepsin B mediates its nuclear targeting, and contributes to cell viability[J].BM C Cell Bio,l 2005,6(1):16-24
[45]李志刚,张智博.溶酶体组织蛋白酶参与细胞凋亡过程的分子机制[J].中国肿瘤生物治疗杂志,2009,16(6)：648-652
[46]Berchem GJ,Glondu M,Gleizes M,et al.Cathepsin-D affect multiple steps of tumor progression:Proliferation,angiogenesis and apoptosis[J].Oncogene,2002,21:5951-5955
[47]Hu L,Roth JM,Brooks P,et al.Thrombin up-regulates cathepsin D which enhancees angiogenesis,growth,and metastasis[J].Cancer Res,2008,68(12):4666-4673
[48]Laurant MV,Maruani HS,Prebois C,et al.Liaudet-Coopman E Catalytically inactive human cathepsin D triggers fibroblast invasive growth[J].J Cell Biol,2005,168(3):489-499
[49]谭业儒,姜浩,甘润良.组蛋白酶D与恶性肿瘤的相关性研究[J],现代生物医学进展,2010,10(14)：2785-2788
[50]Minarowska A,Minarowski L,Karwowska A,et al.Regulatory role of cathepsin D in apoptosis[J].Folia Histochem Cytobiol,2007,45(3):159-163
[51]Roberg K,et al.Relocalization of cathepsin D and cytochrome C early in apoptosis revealed by immunoelectron microscopy[J].Lab Invest,2001,81(2):149-158
[52]Kagedal K,Johansson U,Olinger K,et al.The lysosomal protease casthepsin D mediates apoptosis induced by oxidative stress[J].EMBO J,2001,1(5):1592-1594
[53]王娅兰,林晓.黏液性大肠癌组织蛋白酶B、D表达与肿瘤浸润[J].实用肿瘤学杂志,2003,17(4)：249-251
[54]林晓,王娅兰.大肠癌组织蛋白酶B表达及其与肿瘤微血管密度和生物学行为的关系[J].重庆医科大学学报,2002,27(3)：264-270
[55]Yan S,Sloane BF.Molecular regulation of human cathepsin B:Implication in pathologyies[J].BiolChem,2003,384(6):845-854
[56]李祥春,张开光.组织蛋白酶B与胃癌研究进展[J].安徽医药,2010,14(9)：996-998
[57]Roeby S,Sloane BF,Mo inK.Pericellular cathepsin bandmalig nantprogression[J]. Cancer Metastasis Rew,2003,22(2-3):271-286
[58]SameniM,Dosescu J,Sloane BF.Imaging proteo lysisby living human breast cancer[J].Neoplasis,2000,2(6):496-504
[59]Khan A,Krishna HI,Baker SP,et al.Cathepsin B expression and its correlation with tumor associaled laminin and tumor progression in gastric cancer [J]. Arch patholLah bled,1998, 122(2):172-7
[60]Montuori N,V isconte V,RossiG,et al.Soluble and cleaved forms of the urokinase receptor:degradation products or active molecules[J].Thromb Haemost,2005,93(2):192-198
[61]Rabbani SA,Mazar AP.The role of the plasm inogen activation system in angiog enesis and metastasis[J].Surg Oncol Clin N Am,2001,10(2):393-415
[62]Dem chik LL,SameniM,Nelson K,et al.Cathepsin B and glomainvasion[J].Neur-osci, 1999,17(6):483-494
[63]Sinha AA,Gleason DF,StaleyNA,et al.Cathepsin B in an giogenesis of human prostate an immunohistochem ical and immunoelectron microscopic analysis[J].The Anatomical Record,1995,241(3):353-362
[64]Kostoulas G,Lang A,Nagase H,et al.Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metallopro terinases[J].FEBS Lett,1999,455 (3):286-290
[65]Frohlich E,Sch lagenhauff B,M ohrle M,et al.Activity,expression and transcription rate of the cathepsinsB,D,H,and L in cutaneousm alignantm elanoma[J].Cancer,2001,91(5): 972-982
[66]唐建建,姜曙,毛伯镛.组织蛋白酶B表达与胶质瘤恶性程度和血管生成的关系[J].四川大学学报(医学版),2006,37(2)：212-214
[67]段建敏,左陵君,范文高,等.组织蛋白酶B与膀胱癌恶性度的相关性[J].临床泌尿外科杂志,2003,18(11)：677-679
[68]肖庆,唐深,樊晓晖.组织蛋白酶B及抑制剂与肿瘤[J],现代肿瘤医学,2008,16(4)：674-676
[69]Allayer H,Babic R,Grutzner KU,et al.Tumor associated proteases and inhibittors in gastric cancer Analysis of prognostic impact and individual risk protease pattern[J].Clin Exp Metast,1998,16(1):62
[70]Goishi H,T anaka S,H aruma K,et al.Preditive value of cathepsin D and Ki-67 expression at the deepest penetration site for lymphnode metastases in gastric cancer[J].OncolRep, 2000,7(4):713
[71]Ikeguchi M,Fukuda K,O ka SI,et al.Microlymphnode metasis and its correlation with cathepsin D expression in early gastric cancer[J].Surg O ncol 2001,77:188
[72]Ikeguchi M,Fukuda K.Clinicopathological significance of cathepsinD expression in gastric adenocarcinom as[J].Oncology,2001,6(1):71
[73]万文徽.肿瘤临床应用与研究进展[M].北京：北京大学医学出版社,2005：226
[74]徐晓艳,范鹏程,马秀梅.E-钙黏附素、组织蛋白酶D与胃癌侵袭转移的关系[J].山西医科大学学报,2008,39(3)：237-240
[75]陈晓艺,张白凌,陈少杰.组织蛋白酶D与基质金属蛋白酶-9在口腔鳞癌的表达[J].福建医科大学学报,2006,40(6)：560-562
[76]吴晶晶,张鹏宇,张明智,等.组织蛋白酶-D和MMP-9在非小细胞肺癌中的表达意 义[J].中国现代药物应用,2010,4(15)：5-6
[77]Szajda SD,Snarska J,Jankowska A,et al.Cathepsin D and carcino-embryonic antigen in serum,urine and tissue of colon adenocarcinoma patients[J]. Hepatogastroenterolo gy,2008, 55(82-83):388-93
[78]Tsukamoto T,Iida J,Dobashi Y,et al.Overexpression in colorectal carcinoma of two lysosome enzymes,CLN2 and CLN1,involved in neuronal ceroid lipofusci-nosis[J]. Cancer,2006,106(7):1489-97
[79]Kaneko I,Tanaka S,Oka S,et al.Immunohistochemical molecular markers as predictors of curability of endoscopically resected submucosal colorectal cancer[J],World J Gastroenterol,2007,13(28):29-35
[80]Dvalishvili I,Charkviani L,Charkviani T,et al.Clinical prognostic factors and expression of cathepsin D in endometrioid adenocarcinoma[J].Deorgian Med News,2005,12(6):27-31
[81]Fernandez AS,Nol JC.Expression of cathepsin D and galectin 3 in tubular carcinomas of the breast[J].APMIS,2008,116(1):33-40
[82]Irawan C,Hukom R,Prayogo N.Factors associated with bone metastasis in breast cancer:a preliminary study in an Indonesian population[J].Acta Med Indone's,2008,40(4):178-180
[83]Abbott DE,Margaryan NV,Jeruss JS,et al.Reevaluating cathepsinD as a biomarker for breast cancer:Serum activity levels versus histopathology[J].CancerBiol Ther,2010, 15(1):31-32
[84]Marki evi M,Petrovi A,Kanjer K,et al.Estrogen-regulated cut off values of PS2 and cathepsin D expression in breast carcinomas[J].Adv Exp Med Biol,2008,61(7):341-348
[85]Ohri SS,Vashishta A,Proctor M,et al.The propetide of cathepsin D prolife Ration, invasion and metastasis of breast cancer cells[J].Int JOncol,2008,32(2):491-498
[86]Brujan I,Mrgritescu C,Simionescu C,et al.Cathepsin-D expression in breast lesion:an immunohistochemical study[J].Rom J Morphol Embryol,2009,50(1):31-39
[87]Leto G,Tumminello FM,Crescimanno M,et al.Cathepsin D expression levels in nongynecological solid tumors:clinical and therapeutic implications[J].Clin Exp Metastasis,2004,21 (2):91-106
[88]Opel D,Poremba C,Simon T,et al.Activation of Akt predicts poor outcome in neuroblastoma[J].Cancer Res,2007,67(2):735-745
[89]Merseburger AS,Hennenlotter J,Simon P,et al.Cathepsin D expression in renal cell cancer clinical implications[J].Eur Urol,2005,48(3):519-526
[90]R.Koslowski, K.Knoch, E.Kuhlisch,et al.Cathepsins in bleomycin induced lung injury in rat[J].CATHEPSINS IN LUNG INJURY,2003,2(2):427-435
[91]郭丽萍,张耀全,袁发焕.部分肾切除大鼠肾组织蛋白酶B的表达与肾脏纤维化的关系[J].重庆医学,2005,34(10)：1447-1449
[92]Reinheckel T,Deussing J,Roth W,et al.Towards specific functions of lysosomal cysteine peptidases:phenotypes of mice deficient for cathepsinB or cathepsin L[J].Biol Chem, 2001,382(5):735-741
[93]A.Kenessey, M. Banay-schwartz, Inerease in cathepsinD aetivity in rat Brain in aging[J].J Neurosci Res,1989,2(3):454-456
[94j Benuck, M.Banay-Sehwartz, Changes in brain Protease aetivety in aging[J].J Neuroe-hem,1996,6(7):2019-2029
[95]Amano T, Nakanishi H, Increasedeexpression of eathepsinsE and D in reaeTive mieroglial cells associated with spongiform degeneration in the brain Stem of seneseenee accelerated mouse[J].Exp Neurol,1995,136(2):171-182
[96]H. Nakanishi, T.Amano.D.F. SastradiPura, Inereased expression of cathepsinE and D in neurons of the aged rat brain an their localization with lipofuscin and carboxy tenminal fragments of Alzheimer amyloid precursor Protein[J].J.Neurochem,1997,6(8):739-749
[97]Podgorski I,L inebaugh BE,Sameni M,et al.Bone microenvironm ent modulates expression and activity of cathepsin B in prostate cancer[J].Neoplasia,2005,7(3):207-223
[98]张智博,刘柳青,龚晓燕,等.大鼠脑缺血再灌注后Cathepsin D和caspase-9表达的动态变化[J].现代生物医学进展,2010,10(5)：851-854
[99]龚晓燕,张智博,刘柳青,等.大鼠脑缺血再灌注后溶酶体组织蛋白酶B表达的动态变化[J].现代生物医学进展,2009,9(10)：1842-1852
[100]Tyynela J,Sohar I,Sleat DE,et al.A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration[J].EMBO J,2000, 19(12):2786-2792
[101]Shin izu T,Hayashi Y,Yamasaki R,et al.Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D deficient mice[J].J Neurochem,2005,94(3):680-690
[102]Myllykangas L,Tyynela J,Page-McCaw A,et al.Cathepsin D deficient D rosophila recapitulate the key features of neuronal ceroid lipofuscinoses[J]. NeurobiolDis,2005, 19(2):194-199
[103]刘凤英,王学峰,李劲梅,等.耐药性癫痫患者脑组织蛋白酶D的表达及意义[J].中国病理生理杂志,2008,24(9)：1757-1761
[104]Handley CJ, Mok MT.CathePsinD eleaves aggreean at unique sites within the interglobular domain and chondroitin sulfate attaehment regions that are Also eleaved when cartiage is maintained at acid PH[J].Matrix Biol,2001,20(8):543-553
[105]Nakase T,Kaneko M,Immununohistochemical detection of cathepsinD,K,and L in the Proeess of endochondral ossification in the human[J].Histochem cell Biol 2000,114(1):21-7
[106]Ariga K, Yonenobu K, et al.Localization of CathepsinsD, k, and L in degenera-ted Human Intervertebral[J].Dises Spin 2001,2(6):2666-2672
[107]赵刚,李双杰,陈瑞珍,等Cathepsin B与扩张型心肌病发病关系的初步探讨[J].复旦学报(医学版),2004,31(6)：556-569
[108]Koblinski JE,Dosescu J,Sameni M,et al.Interaction of human breast fibroblasts with collagen I increase secretion of procathepsin B[J].J Biol Chem,2002,27(7),32220-32227
[109]Varma TH,Liu SQ,West M,et al.Protein kinase C-dependent Phosphory lation and mitochondrial translocation of aldose reduce tase[J].FEBS Lett,2003,53 (4):175-183
[110]于小华,张新刚,王时俊,等.组织蛋白酶B抑制剂CA-074Me对小鼠病毒性心肌炎的干预作用[J].临床儿科杂志,2005,23(1)：52-54
[111]Vanacker GJ,Saluja AK,Bhagat L,et al.cathepsin B inhibition prevents try psinogen activation and reduces pancreatitis severity[J].Am J Physiol Gastrointest Liver Physiol, 2002,283(3):794-800
[112]张慧,冯琴,李红山,等.祛湿化瘀方对非酒精性脂肪性肝炎大鼠组织蛋白酶B和肿瘤坏死因子α表达的影响[J],中西医结合学报.2008,6(9)：928-933
[113]Foghsgaard L,Wissing D,Mauch D,et al.Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor[J].J Cell Biol,2001, 153(5):999-1010
[114]Werneburg N,Guicciardi ME,Yin XM,et al.TNF-alpha mediated lysosomal permeabi lization is FAN and caspase 8/Bid dependent[J] Am J Physiol Gastrointest Liver Physiol, 2004,287(2):436-443
[115]Zegarska J,Paczek L,Pawlowska M,et al.Extracellular matrix proteins, proteolytic enzymes, and TGF-beta1 in the renal. arterial wall of chronically rejectted renal allografts[J].TransplantProc,2003,(6):2193-2195
[1]Fine A,Janssen-Heininger Y,Soultanakis R P,et al.Apoptosis in lung pathoph-ysiology[J].Am J Physiol Lung Cell Mol Physiol,2000,279(3):423-427
[2]Kuwano,K, Kunitake,R,Kawasaki,M,et al.p21 and p53 expression in association with DNA strand breaks in idiopatic pulmonary fibrosis[J].Am J Respir Crit Care Med,1996,154 (2):477-483
[3]Uhal BD Epithelial apoptosis in the initiation of lung fibrosis[J].Eur Respir J Suppl, 2003,9(44):7-9
[4]Khalil N,O'Connor R N,Flanders K C,et al.Regulation of type Ⅱ alveolar epithelial cell proliferation by TGF-beta during bleomycin induced lung injury in rats[J].Am J Physiol,1994,267(5):498-507
[5]Kumar R K,Watkins S G,Lykke A W.Pulmonary responses to bleomycin Induced injury:an immunomorphologic and electron microscopic study[J].Exp Pathol,1985,28(1):33
[6]DosReis G A,Borges V M.Role of Fasligand induced apoptosis in pulmonary infla-mmation and injury[J].Curr Drug Targets Inflamm Allergy,2003,2(2):161
[7]FineA,Janssen-HeiningerY,SoultanakisRP,et al.Apoptosis in lung pathophy siology[J].Am J PhysiolLung Cell MolPhysio,2000,279(3):423-427
[8]Shipley JM,Doyle GA,Fliszar CJ,et al.The structural basis for the elastolytic activity of the 92-KDa and72-KDa gelatinases.Role of the fibronectin type Ⅱ like repeats[J].J Bio Chem,1996,271(8):4335-4341
[9]Xia T,Akers K,Eisen AZ,et al.Comparison of cleavage site specificity of gelatinases A and B using collagenous peptides[J].Biochem Biophys Acta,1996,1293(2):259-266
[10]Nogee LM,DunbarAE,Wert SE,et al.A mutantion in the surfactant protein C gene associated with familial interstitial lung disease[J].N Engl JMed,2001,344(8):537-579
[11]ThomasAQ,LaneK,Pillips J,et al.Heterozygosity for a surfactant- tprotein C gene mutation associated with usual interstitial pneumonitis and celluar nonspecific interstitial pneumonitis in one kindred[J].Am J Respir Crit CareMed,2002,165(9):1322-1328
[12]Plan SH.The myofibroblast in pulmonary fibrosis[J].Chest,2002,122(6):286-289
[13]Zhang K,Rekhter MD,Gordon D,et al.Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis:A combined immunohistochemical and in situ hybridizationstudy[J].Am J Pathol,1994,145(1):114-125
[14]Kuang PP,Lucey E,RishikofDC,et al.Engraftment of neonatal lung fibroblasts into the normal and elastase injured lung[J].Am J Respir Cell MolBio,2005,33(4):371-377
[15]Rehan VK,Wang Y,Patel S,et al.Rosiglitazone,a peroxisome Proliferators activated receptor gamma agonist,prevents hyperoxia induced neonatal rat lung injury in vivo[J].Pediatr Pulmono,2006,41(6):558-569
[16]Rehan VK,Wang Y,Sugano S,et al.Mechanism of nicotine induced pulmonary fibroblast transdifferentiation[J].Am J PhysiolLung Cell MolPhysio,2005,289(4):667-676
[17]BurgessHA,Daugherty LE,ThatcherTH,et al.PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production:Implications for therapy of lung fibrosis[J].Am J Physiol Lung Cell Mol Physio,2005,288(6):1146-1153
[18]Vancheri C,Gili E,Failla M,et al.Bradykinin differentiates human lung fibroblasts to a myofibroblast phenotype via the B2 receptor[J].J Allergy Clin Immunol,2005,116(6): 1242-1248
[19]Phan SH.The myofibroblast in pulmonary fibrosis[J].Chest,2002,122(6):286-289
[20]魏锦锦,李佳鑫.肺间质纤维化中肌成纤维细胞的来源及调控因素[J].新乡医学院学报,2009,26(6)：633-636
[21]WaghrayM,CuiZ,Horowitz JC,et al.Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial celldeath by activated myofibrob lasts[J].FASEB J,2005,19(7): 854-856
[22]Wang R,Ramos C,Joshil,et al.Human lung myofibroblast derived inducers of alveolar epithelial apoptosis identified as angiotension peptides[J].Am Jphysiol,1999,277(l):1158-1164
[23]Wang R,Ibarra Sunga O,Verlinski L,et al.Abrogation of bleomycin induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor[J].Am J physiol Lung Cell Mol physiol,2000,279(1):143-151
[24]Kuwano K,Hagimoto N,Tanaka T,et al.Expression of apoptosis-regulatory genes in epithelial cells in pulmonary fibrosis in mice[J].JPathol,2000,190(2):221-229
[25]Kang HR,Cho SJ,Lee CG,et al.Transforming growth factor (TGF)-β1 stimulates pulmonary fibrosis and inflammation via a Bax-dependent, Bidactivated pathway that involves matrix metalloproteinase-12[J].J Biol Chem,2007,282(10):7723-7732
[26]段斐.复方鳖甲软肝方防治特发性肺纤维化的细胞分子基础[D].北京：北京中医药大学,2005：56
[27]Uhal,BD.Fas and apoptosis in the alveolar epithelium:holes in the dike?[J].Am J Physiol,2001,281 (2),328-335
[28]Kuwano K,Miyazaki H,Hagimoto N,et al.The involvement of Fas-Fas ligand pathway in fibrosing lung diseases[J].Am J Respir Cell Mol Biol,1999,20(l):53-60
[29]Kuwano K,Hagimoto N,Kawasaki M,et al.Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis[J] J Clin Invest,1999,104(1):13-19
[30]Aoshiba K,Yasui S,Tamaoki J,et al.The Fas/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice[J].Am J Respir Crit Care Med, 2000,162(21):695-700
[31]Borge SVM,FalcaoH,LeitejuniorJH,et al.Fas ligand triggers pulmonary Silicosis[J].J Exp Med,2001,194(2):155-164
[32]Moodley YP,Caterina P,Scaffidi AK,et al.Comparison of the morphological and biochemical changes in normal human lung fibroblasts and fibroblasts derived from lungs of patients with idiopathic pulmonary fibrosis during FasL-induced apoptosis[J].J Pathol,2004,202(4):486-495
[33]Moodley YP,Misso NL,Scaffidi AK,et al.Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs[J].Am J Respir Cell Mol Biol,2003,29(4):490-498
[34]B u hling F,Wille A,Rocken C.Altered expression of membrane bound and soluable CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosis[J].Respir Res,2005,6(1):37
[35]段斐,耿德海,许文杰,等.复方鳖甲软肝方防治肺纤维化细胞凋亡的实验研究[J].时珍国医国药,2008,19(5)：1054-1055
[36]许朝霞.化纤汤对博莱霉素致大鼠肺纤维化的干预作用的实验研究[D].武汉：湖北中医学院,2007：20
[37]闫智勇,张天娥,刘明芳,等.化纤方对人胚肺二倍体纤维母细胞的增殖抑制作用[J].华西医学,2005,20(2)：280-281
[38]臧金萍,辛洪涛,王建平,等.芪丹颗粒对博莱霉素致肺损伤大鼠肺组织FasL caspase-3表达的影响[J].山东医药,2008,48(5)：18-20
[39]臧金萍,辛洪涛,王建平,等.芪丹颗粒对博莱霉素致大鼠肺纤维化时FasL、Caspase-3表达的作用[J]_现代诊断与治疗,2010,21(1)：5-8
[40]黄穗山.益气通络解毒方治疗IPF的细胞凋亡机制[D].武汉：湖北中医学院,2009：18
[41]Wang JF,Niu JZ, Lu YS,et al.Experim ental study on protective effects of curcumin on exaggerated ex trace llularm atrix accumulation of pulmonary fibrosis rats[J]. Zhong guo ZhongYao Za Zh,2006,31(7):570-573
[42]陈伟,欧阳劭,何振华.姜黄素对肺纤维化鼠Bcl-xl表达的影响[J].社区医学杂志,2009,7(19)：1-3
[43]高蔚,张德平,华云峰.姜黄素对大鼠肺成纤维细胞增殖和凋亡的影响[J].实用医学 杂志,2008,24(14)：2393-2396
[44]高蔚,张德平,陈碧.姜黄素诱导人肺成纤维细胞凋亡的相关分子机制的初步研究[J].中国呼吸与危重监护杂志,2009,8(2)：186-189
[45]李杰平.大鼠肺纤维化Cathepsin B的表达及黄芪甲甙的干预[D].衡阳：南华大学,2007：4
[46]柴文戍,翟声平,武素琳,等.灯盏花素对实验性肺纤维化大鼠的干预作用[J].中国药理学通报,2008,24(1)：113-116
[47]徐厚君,张伟,王广增,等.大豆皂甙对矽肺纤维化大鼠肺组织细胞凋亡的影响[J].现代预防医学,2008,35(23)：4681-4683
[48]徐厚君,王志强,苏宇,等.李清钊大豆皂甙对矽肺纤维化大鼠肺组织细胞Fas/FasL系统表达的影响[J].现代预防医学,2010,37(8)：1525-1527
[49]解克芳,王继峰,牛建昭.葛根素对人胚肺成纤维细胞增殖及细胞外基质合成的影响[J].中国中医药信息杂志,2008,15(5)：39-40
[50]许光兰,陈平,梁劲松,等.青蒿琥酯对实验性肺纤维化大鼠治疗作用及其机理研究[J].临床医学工程,2009,16(9)：6
[51]王昌明,张孝飞,黄岚珍,等.青蒿琥酯诱导人胚肺成纤维细胞凋亡的分子机制研究[J].时珍国医国药,2010,21(11)：2837-2838
[52]王昌明,张孝飞,谭宁,等.青蒿琥酯对人胚肺成纤维细胞系HFL-细胞增殖、凋亡的影响及机制[J].山东医药,2010,50(3)：33-35
[53]许朝霞,丁明桥,陈瑞,等.银杏叶提取物干预肺纤维化模型大鼠肺泡Ⅱ型上皮细胞凋亡的变化[J].辽宁中医杂志,2008,35(9)：1312-1314
[54]黄志卫,马忠森,王秀丽,等.刺五加对人胚肺二倍体纤维母细胞生长的影响[J].广西医科大学学报,2004,21(1)：28-30
[55]宋暖.昆布提取物J201抑制人胚肺成纤维细胞增殖的研究[D].青岛：青岛大学,2004：
[1]张玉军.三七总皂苷的药理研究进展[J].广西医学,2009,31(4)：589-591
[2]Szapiel SV,Elson NA,Fulmer JD,et al.Bleomycin-induced interstitial pulmonary disease in the nude,athymic mouse[J].Am Rev Respir Dis,1979,120(4):893-899
[3]戴令娟,侯杰,蔡后荣,等.肺纤维化动物模型肺组织形态定量分析[J].南京铁道医学院学报,1996,15(1)：24-27
[4]Uppaluri R,Hoffman EA.Sonka M,et al.Interstitial lung disease:A quantitative study using the adaptive multiple feature method[J].Am J Respir Crit Care Med,1999,159(2):519-525
[5]王响英,吴淑燕,李苏安等.实验性大鼠肺纤维化病理形态及超微结构观察[J].苏州大学学报(医学版),2005,25(3)：379
[6]Nagao T,Nagai S,Hiramoto Y,et al.Serial evaluation of high-resolution computed tomography findings in patients with idiopathic pulmonary fibrosis in usual interstitial pneumonia[J].Respiration,2002,69(5):413
[7]Donald N.Cook,David M.Brass,et al.A Matrix for New Ideas in Pulmonary Fibr-osis[J]. Am J Respir Cell Mol Biol,2002,27(2):122
[8]White E S,Lazar M H,Thannickal V J.Pathogenetic mechanisms in usual interstitial pneumonia/idiopathic pulmonary fibrosis[J].J Pathol,2003,201(3):343
[9]罗慰慈.现代呼吸病学[M].北京：人民卫生出版社,1997：119
[10]魏茂提,王世鑫,张国辉,等.染矽尘大鼠肺脏系数和肺胶原含量的变化[J].工业卫 生与职业病,2001,27(6)：351-353
[11]Brent E Van Hoozen,Katharine L Grimmer,Gregory P Marelieh.et al.Early Phase collagen synthesis in lungs of rats exposed to bleomyein[J].Toxieology 2000,147 (1):1-13
[12]S N Iyer,G Gurujeyalakshnli,S N Giri.Effeet of pirfenidone on proeollagen gene expression at the transeriptional level in bleomyein hnajster model of lung fibrosis[J].The Journal of Pharmaeology and Experimental Therapeuties,1999,2891:211-218
[13]Van Hoozen BE,Grimmer KL,Marelich GP,et al.Early phase collagen synthesis in lungs of rats exposed to bleomycin[J].Toxicology,2000,147(1):1-13
[14]牛建昭,贲长恩.器官纤维化基础及中医药防治[M].北京：人民卫生出版社,2008：102
[15]Zhao HW,Lu CJ,Yu RJ, Hou XM.An increase in hyaluronan by lung fibroblasts:a biomarker for intensity and activity of interstitial pulmonary fibrosis Respirology[J],1999 ,4(2):131-38
[16]Bensadoun ES,Burke AK,Hogg JC,et al.Proteoglycan deposition in pulmonary fibrosis [J].Am J Respir Crit Care Med,1996,154(6):1819-28
[17]CM,Penno MB,Cowman M,et al.Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages[J].The role of HA size and CD44.J Clin Invest,1996, 98(10):2403-13
[18]Zhu Z,Ma B,Zheng T,Homer RJ,et al.IL-13-induced chemokine responses in the lung: role of CCR2 in the pathogenesis of IL-13-induced inflammation and remodeling[J].J Immunol,2002,168(6):2953-62
[19]Li Y,Rahmanian M,Widstrom C,et al.Irradiation induced expression of hyaluronan (HA) synthase 2 and hyaluronidase 2 genes in rat lung tissue accompanies active turnover of HA and induction of types Ⅰ and Ⅲ collagen gene expression[J]. Am J Respir Cell Mol Biol, 2000,23(3):41118
[20]Ueki N,Taguchi T,Takahashi M,et al.Inhibition of hyaluronan synthesis by vesnarinone in cultured human myofibroblasts[J].Biochim Biophys Acta,2000,1495(2):160
[21]Lappi-Blanco E,Kaarteenaho-Wiik R,Salo S,et al.Laminin-5 gamma2 chain in crypto-genic organizing pneumonia and idiopathic pulmonary fibrosis[J].Am J Respir Crit Care Med,2004,169(1):27-33
[22]Perez-Arellano JL,Pecraz MJ,Fuertes A,et al.Laminin fragment PI is inereased in the lower respiratory raet of Patients with diffuse interstitial lung disease[J]. Chest,1993,104(4): 1163-1169
[23]Singer Ⅱ,Kawka DW,McNally SM,et al.Extensive laminin and basement membrane accumulation occurs at the onset of bleomycin-induced rodent pulmonary fibrosis[J].Am J Pathol,1986,125(2):258-68
[24]Sehoenfeld N,Sehmolke B,et al.Laminin fragment PI in the sera of Patients with Pulmonary sareoidosis[J].Sareoidosis-vase-Diffuse-Lung-Dis,1996,23(2):135-135
[25 ]吴浩,许祖德,张月娥,等.纤维连接蛋白在大鼠肺纤维化中的作用[J].中华结核与呼吸杂志,2001,24(1)：40-42
[26]徐峥嵘.细胞因子及其特异性抑制剂与肺纤维化的治疗[J].中国公共卫生,2005,21(6)： 750-753
[1]孔璐,王继峰,牛建昭.特发性肺纤维化与细胞凋亡[J].中华结核和呼吸杂志,2004,27(6)：368-371
[2]Furmanl LM,M aaty W S,Petersen LK,et al.Cysteine protease activation and apoptosis inmurine norovirus infection[J].V irol J 2009,10(6):139-145
[3]A kache B,Grimm D,Shen X,et al.A two hybrid screen identifies cathepsins B and L as uncoating factors for adeno associated virus 2 and 8[J].MolTher,2007,15(2):330-339
[4]Zhang FT,Zhang YB,Chen YD,et al.Expressional induction of paralichthys olivaceus cathepsin B gene in response to virus, poly I:C and lipopolysaccharide [J].Fish She llfish Immuno,2008,25(5):542-549
[5]Burster T,Giffon T,Dahl ME,et al.Influenza A virus elevates active cathepsin B in primary murine DC[J].Int Immuno,2007,19(5):645-655
[6]Benchoua A,Braudeau J,Reis A,et al.Activation of pro inflammatory caspases by cathepsin B in focal cerebral ischem ia[J].J Cereb Blood Flow M etab,2004,24(11):1272-1279
[7].李杰平,何平平,于小华,等.大鼠肺纤维化细胞凋亡及CathePsinB基因变化的关系[J].现代生物医学进展,2007,7(6)：696-698
[8]Yin L,Stearns R,Gonzalez-F lecha B.Lysosom al and m itochondrial pathw ays in H2O2-induced apoptos is of alveolar type Ⅱ cells[J].J Cell Biochem,2005,94(3):433-445
[9]方肇勤.分子生物学技术在中医药研究中的应用[M].上海：上海科学技术出版社2002：46
[10]贲长恩,李叔庚.组织化学[M].北京：人民卫生出版社,2001：254
[11]RongqiW,Olivia IS,LubaV,et al.Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or a caspase inhibitor[J].Am J Physiol Lung Cell MolPhysio,2000,27(9):143-151
[12]Uhal BD.Apoptosis in Lung Fibrosis and Repair[J].Chest,2002,12(2):293-298
[13]Whitsett JA.Genetic basis of familial interstitial lung disease[J].Am J Respir Crit Care Med,2002,16(5):1201-1202
[14]Barbas-Filho JV,Ferreira MA,SessoA,et al.E vidence of type Ⅱ pncumocyte apoptosis in the pathogenesis idiopathic pulmonary fibrosis/usual interstitial pneumonia(UIP)[J].J Clin Patho,2001,54(2):132-141
[15]Wang LY,Antonini JM,Rojanasakul Y,et al.Potential role of apoptotic macrophages in pulmonary inflammation and fibrosis[J].J Cell Physiol,2002,19(4):215-224
[16]唐硕,魏强.组织蛋白酶B在非肿瘤疾病中的研究进展[J],西部医学,2008,20(6)：1294-1295
[17]陈洋,李舒.组织蛋白酶D与消化道肿瘤的关系[J].咸宁学院学报(医学版),2008,22(6)：546-549
[18]Krizaj I, Drobnic-Kosorok M, Brzin J,et al.The primary structure of inhibitor of cysteine proteinases from potato[J].FEBS Lett,1993,33(3):15-20
[19]Berdowska I.Cysteine proteases as disease markers[J].Clin ChimActa,2004.34(2):41-69
[20]Riese RJ,Chapman HA.Cathepsins and compartmentalization in antigen presentati-on[J].Curr Opin Immunol,2000,1(2):107-113
[21]Tsukuba T,Okamoto K,Yasuda Y,et al.New functional aspects of cathepsin D and cathepsin E[J].Mol Cells,2000,10(6):601-11
[22]刘玉胜,鹿庆华,蒋卫东.组织蛋白酶与心血管重塑[J].心血管病学进展,2006,27(7)：227-300
[23]Liaudet CE,Beaujouin M,Derocq D,et al.Cathepsin D:newl discovered functions of a long-standing aspartic protease in cance and apoptosis[J].Cancer Lett,2006,23(7):167-179
[24]Mctcalf P,Fusek M.Two crystal structures for cathepsin D the lysosomal targeting signal and active site[J].EMBO J,1993,1(2):1293-1302
[25]Bialek J,Hombach KS,Fiebig B,et al.Lysosomal acid hydrolases of the cathepsin family are novel targets of INSL3 in human thyroid carcinoma cells[J]. Ann N Y Acad Sci,2009, 11(6):361-366
[26]Salvesen GS.A. lysosomal protease enters the death scene[J].J Clin Invest,2001, 107(1):21-22
[27]Brunk UT,Neuzil J.Lysosomal involvement in apoptosis[J].Redox Rep,2001,6(2):91-97
[28]Guicciardi ME,Deussing J,Miyoshi H,et al.Cathepsin B contributes to TNF-alpha-mediated hepatocyte by promoting mitochondrial release of cytochrome [J].J Clin Invest,2000,106(9):1127-1137
[29]Brunk UT. Svensson I[J].Redox Rep,1999,4(1):3-11
[30]Bidere N,Lorenzo HK,Carmona S,et al.Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis[J].J Biol Chem,2003,278(33):31401-31411
[31]吴燕婉,刘德瑜.溶酶体的细胞死亡通路[J].解剖学报,2007,38(4)：498-450
[32]Schestkowa O,Geisel D,Jacob R,et al.The catalytically inactive precursor of cathepsin D induces apoptosis in human fibroblasts and HeLa cells[J].J Cell Biochem, 2007,10(1):1558-1566
[33]Trincheri NF,Nicotra G,Follo C,et al.Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D[J].Carcin ogenesis, 2007,2(8):922-931
[34]VANACKER GJ,SALUJA AK,BHAGAT L,et al.CathepsinB inhibition prevents trypsinogen activation and reduces pancreatitis severity [J]. Am J Physiol Gastrointest Liver hysiol,2002,28(3):794-800
[1]Kuwano K,Hagimoto N,Tanaka T,et al.Expression of apoptosis-regulatory genes in epithelial cells in pulmonary fibrosisimice[J].Pathol,2000,190(2):221-229
[2]Kuwano K,Maeyama T,Inoshima I,et al.Increased circulating levels of soluble Fas ligand are correlated with disease activity in patients with fibrosing lung diseases[J]. Respirology,2002,7(1):15-21
[3]Domagala-Kulawik J,Droszcz P,Kraszewska I,et al.Expression of Fas antigen in the cells from bronchalveolar lavage fluid (BALF)[J].Folia Histochem Cytobiol,2000,38(4): 185-188
[4]Yin XM,Oltvai ZN,Veis-Novack DJ,et al.Bcl-2 gene family and the regulation of programmed cell death[J].Cold Spring Harb Symp Quant Biol,1994,59:387-393
[5]Okura T,Igase M,Kitami Y,et al.Platelet-derived growth factor induces apoptosis in vascular smooth muscle cells Roles of the Bcl-2 family[J].Biochim Biophys Acta,1998,1403 (3):245-253
[6]Orrenius S.Mitochondrial regulation of apoptotic cell death[J].Toxicol Lett,2004,149 (1-3):19-23
17] Schindler CK,Shinoda S,Simon RP,et al.Subcellular distribution of Bcl-2 family protei-ns and 14-3-3 within the hippocampus during seizure induced neuronal dealth in the rat[J] .Neurosci Lett,2004,356(3):163-166
[8]Han ming,Zhuo Zhang,Qi feng Zhang,et al.Reactive oxygen species and caspase activation mediate silica induced apoptosis in alveolar macrophages[J].Am J Physiol Lung Cell Mol Physiol,2001,280(1):10-17
[9]Miyashita T,Reed JC.Bcl-2 oneoProtein blocks chemotherapy indueed apoptosis in a human leukemia cell line[J].Blood,1993,81(1):151
[10]Almeida OF,Conde GL,Croehemore C,et al.Subtle shifts in the ratio between Pro and anti-apoptotic molecules after activation of corticosteroid receptors decide neuronal fate[J] .FASEB J,2000,14(5):779-790
[11]Uhal,BD.Fas and apoptosis in the alveolar epithelium:holes in the dike(editorial)[J]. AmJ Physiol,2001,281 (2),326-327
[12]Borge SVM,FalcaoH,LeitejuniorJH,et al.Fas ligand triggers pulmonary Silicosis[J].J Exp Med,2001,194(2):155-164
[13]Kuwano K,Hagimoto N,Kawasaki M,et al.Essential roles of the Fas, Fas ligand pathw ay in the development of pulmonary fibrosis[J].J ClinInvest,1999,104 (1):13-19
王荣国等通过建立椎板切除术大鼠模型,研究分析愈合过程中TGF-β1的表达情况。结果显示三七凝胶组7、14、21d三个时间点TGF-β1的表达均显著低于生理盐水组(P<0.05)。提示三七凝胶早期可以调控硬膜外组织中的炎症反应和胶原纤维合成,其机制可能与PNS的抗炎、抗纤维化有关。6.5 PNS对心肌纤维化的作用
心肌纤维化是指心肌组织中胶原纤维过度沉积,各型胶原比例失调(Ⅰ/Ⅲ型比例增加)以及排列紊乱。随着人口老龄化,心肌纤维化越来越引起人们的重视,但PNS防治其纤维化的研究较少,有待于进一步研究。
程志清等用雄性Balb/c小鼠研究PNS对心肌炎慢性期心肌纤维化的影响,将88只小鼠随机分为正常对照组、模型对照组、PNS高、中、低剂量组,45天后采用免疫组化法及RT-PCR法检测心肌中TGF-β1.PDGF-β的蛋白及mRNA的表达变化。结果显示：PNS治疗组心肌中TGF-β1.PDGF-β的蛋白及mRNA表达水平较模型组下降。提示PNS具有抗病毒性心肌炎慢性期心肌纤维化的作用,可能是与其抑制TGF-β 1.PDGF-β的过度表达有关。
吴柱国等采用背部皮下持续注射异丙肾上腺素诱导心肌肥厚的小鼠模型,随机分为对照组、模型组及3个治疗组(分别为低、中和高剂量组),比较各组小鼠心重指数、左心室重量指数(LVI)、左心室胶原含量、心肌中MMP-2和MMP-9mRNA表达水平的变化。结果模型组小鼠心重指数、LVI.HYP含量及MMP-2、MMP-9的表达明显上调,而PNS中、高剂量组能明显降低心重指数、LVI.HYP含量及MMP-2、MMP-9的表达,与模型组比差别有统计学意义(P<0.01)。说明PNS对改善心肌肥厚有一定作用,其机制至少是部分通过拮抗MMP-2、MMP-9的表达,来抑制心纤维化。7展望
综上所述,PNS是中药三七的主要有效成分,目前在器官纤维化的领域得到了广较多的研究,但主要是在肝脏和肾脏的纤维化研究较多,而对于其他器官的研究较少,因此进行PNS防治其他器官纤维化的研究具有重要作用。 91
[2]中华人民共和国药典委员会编.中华人民共和国药典[S],一部.北京：化学工业出版社,2005：218
[3]鲍建才,刘刚,丛登立,等.三七的化学成分研究进展[J].中成药,2006,28(2)：246-253
[4]冯陆冰,潘西芬,孙泽玲.三七的药理作用研究进展[J].中国药师,2005,11(10)：1185-1186
[5]李冠烈.三七的现代研究与进展(二)[J].世界中西医结合杂志,2008,3(11)：687-691
[6]刘大君,刘汝专,刘佳,等.三七对细胞凋亡的研究进展[J].云南中医中药杂志,2009,30(6)： 62-64
[7]刘剑毅,姚恒,戴霞,等.三七总甙抗纤维化作用的研究进展[J].中国美容医学,2006(15)8：985-986
[8]冯亮,蒋学华,周静,等.三七皂苷R1和人参皂苷Rgl的大鼠在体肠吸收动力学研究[J].中国药学杂志,2006,41(14)：1097-1102
[9]冯亮,胡昌江,余凌英.人参皂苷Rgl及其代谢产物的药代动力学研究[J].药学学报,2010,45(5)：636-640
[10]韩旻,韩丽妹,王青松,等.三七皂苷的口服吸收机制[J].药学学报,2006,41(6)498-505.
[11]王毅,刘铁汉,王巍,等.肠内菌群对人参皂苷Rgl的代谢转化作用的研究[J].中国中药杂志,2001,26(3)：188-190
[12]陈广通,杨敏.三七皂苷R1在大鼠体内的代谢产物分析[J].时珍国医国药,2010,21(2)：485-487
[13]曾聪彦,梅全喜.81例含三七总皂苷类注射剂致不良反应的文献分析[J],中国药房,2007,18(33)：2616-2618
[14]DongTT,CuiXM,SongZH,et al.Chemical assessm ent of roots of Panax notoginsEng in China:regional and seasonal variations in itsactive constituents[J].JA gric Food Chem, 2003,51(16):4617-4623
[15]赵国强,王秀训.三七止血成分的研究[J].中草药,1986,17(6)：34-35
[16]金楠,周莉.三七花中总皂昔对大鼠血液流变学的影响[J].中国药师,2007,10(12)：1193-1195
[17]苏雅,赵益桂,张宗鹏,等.三七三醇皂甙对动物血小板功能及血栓形成的影响[J].中草药,1996,27(11)：666-668
[18]徐皓亮,季勇,饶曼人.三七皂苷Rg1对大鼠实验性血栓形成、血小板聚集率及血小板内游离钙水平的影响[J].中国药理学与毒理学杂志,1998,12(1)：40-42
[19]徐皓亮,刘宛斌,饶曼人.参三七皂苷Rg1对大鼠实验性血栓形成的响及机制探讨[J].药学学报,1997,32(7)：502-505
[20]Lowenstein CJ,Snyder SH.Nitric oxted,anovel biologic messenger[J].Cell,1992,70(5) :705-7
[21]刘刚,刘育辰,鲍建才,等.三七药理作用的研究进展[J].人参研究,2005,3：12-17
[22]郑茵红,高瑞兰,朱大元,等.三七总皂苷及其单体对人骨髓造血祖细胞增殖作用的研究[J].中国中西医结合急救杂志,2003,10(3)：135-137
[23]钱煦岱,高瑞兰,马珂,等.三七皂苷对人骨髓CD34+造血干/祖细胞的增殖分化作用[J].中国实验血液学杂志,2003,1 1(2)：120-123
[24]陈小红,高瑞兰,郑智茵,等.三七皂苷对人骨髓造血细胞凋亡相关蛋白表达的影响[J].中国实验血液学杂志,2006,14(2)：343-346
[25]高瑞兰,徐卫红,陈小红,等.三七皂苷对造血细胞AP-1家族转录调控蛋白NF-E2, c-jun和c-fos的诱导作用[J].中国实验血液学杂志,2004,12(1)：16-19
[26]王一菱,陈迪,吴景兰.三七总皂甙抗炎和镇痛作用及其机理探讨[J].中国中西毯结合杂志,1994,14(1)：35-36
[27]Cicero AF,Vitale G,Savion G,et al.Panax notoginseng(Burk)effects fibrinogen and lipid plasma lever in rats fed on a high-fatdiet[J].PhytotherRes,2003,17(2):174-178
[28]刘文娥,尤昭玲,王若光,等.复方三七成分对恒河猴子宫内膜炎超微结构的影响[J].湖南中医学院学报,2005,25(4)：3-6
[29]崔红晶,安长新,陈东,等.三七总苷对大鼠自身免疫性睾丸炎的拮抗作用[J].解剖学杂志,2008,31(1)：19-21
[30]Hule. A,Navarro S,Smith J R,et al.Panax notoginseng attenuates LPS-induced pro-inflammatory mediators in RAW 2647 cell[J].J Ethnopharmacol,2006,106(1):121-128
[31]贾乙,李晓辉.炎症因素在泡沫细胞形成中的作用及三七皂苷对其影响[J].第三军医大学学报,2005,27(10)：972-974
[32]张翼冠,李晓辉,樊继山,等.三七总皂苷通过抗炎和调血脂作用抑制大鼠动脉粥样硬化形成[J].现代生物医学进展,2007,7(11)：1601-1603
[33]周小玲,李永伟,李逢春,等.三七总皂甙对大鼠免疫功能影响的实验研究[J],广西医科大学学报[J],2001,18(3)：.360-361
[34]孙云,邓阳梅,蔡元培,等.复方三七口服液对小鼠免疫功能和抗氧化功能的影响[J].江苏临床医学杂志,2002,6(6)：518-519
[35]乔萍,杨贵贞.三七皂苷单体Rgl对D-半乳糖模型鼠学习记忆和免疫功能的影响[J].吉林大学学报(医学版),2003,29(3)：267-269
[36]江源,刘翠,陈清彬,等.三七皂苷Rg1对小鼠免疫功能的影响[J].中国现代中药,2006,8(3)：9-10
[37]黄伟,张旋.三七总皂苷对老龄大鼠免疫功能的影响[J].昆明医学院学报,2008,(2)：32-35
[38]蔡辉,姚茹冰,郭郡浩,等.三七总皂苷对佐剂性关节炎大鼠的抗炎及免疫调节作用[J].安徽中医学院学报,2009,28(4)：57-60
[39]姚茹冰,郭郡浩,胡兵,等.三七总苷对大鼠佐剂性关节炎的治疗作用[J].医学研究生学报,2008,21(1)：34-36
[40]姚茹冰,郭郡浩,赵智明,等.三七总皂甙对佐剂性关节炎大鼠腹腔巨噬细胞产生炎性细胞因子的影响[J].中国微循环,2007,11(5)：330-332
[41]丁青,尤昭玲.三七复合有效成分对子宫内膜炎症细胞NF-κ Bp65及TNF-α、IL-1 β变化的影响[J],中国中医药科技,2007,14(2)：113-115
[42]甘雨,徐惠波,孙晓波.三七总皂苷的药理作用研究进展[J].时珍国医国药,2007,18(5)：1251-1252
[43]Han JA,HuWY,Sun ZH.Effect of Panax notoginseng Saponin on Ca2+, CAM in craniocerebral injury[J].Chinese Journalof Integrated Traditional and Western Medicine, 1999,1(9):227
[44]刘建辉,冀风云,王婷,等.三七总皂苷对脑缺血再灌注损伤保护作用的实验研究[J]_中国临床神经科学,2002,10(1)：90
[45]寇幸福,王志方.三七总皂苷对大鼠脑缺血再灌注损伤保护作用及机制的实验研究[11].河南中医学院学报,2008,23(6)：22-23
[46]刘艳娥,刘丽丽,房国涛.三七抗肿瘤的实验研究概况[J].时珍国医国药,2008,19(4)：1015-1016
[47]尚西亮,傅华群,刘佳,等.三七总皂苷对人肝癌细胞的抑制作用[J]_中国临床康复,2006,10(23)：121-123
[48]吴映雅,谭字蕙,钟富有,等.三七总皂苷丹参注射液苦参碱对大鼠肝癌细胞CBRH-791生长的抑制作用[J].辽宁中医杂志,2005,32(10)：1010
‘[49]王志斌,李军祥,朱陵群,等.三七提取物对GES-1细胞及MNNG转化后GES-1细胞增殖的抑制作用[J].中西医结合学报,2004,2(6)：445-449
[50]李军祥,王志斌,朱陵群,等.三七提取物对MNNG转化后GES-1细胞的促凋亡作用[J].中西医结合学报,2005,3(2)：123-127
[51]李军祥,王志斌,朱陵群,等.三七提取物含药血清对MNNG转化后GES-1细胞凋亡相关基因蛋白表达的影响[J].中西医结合学报,2008,6(8)：817-820
[52]李晓红,董作仁,郝洪岭,等.三七皂苷对NB4细胞促凝活性及诱导分化的影响[J].中国中西医结合杂志,2004,24(1)：63-66
[53]徐罗玲,吴琦,高军,等.三七皂苷R诱导HL-60细胞系分化的形态和功能变化[J].中国病理生理杂志,1992,8(1)：55-58
[54]国家中医药管理局《中华本草》编委会.中华本草(上册)[M].上海：上海科学技术出版社,1998：1310
[55]张晓丽,俞惠新,曹国宪,等.P-糖蛋白多药耐药机制及其逆转剂的研究进展[J].中国医学文摘-肿瘤学,2005,19(2)：147
[56]史亦谦,田同德.三七总皂苷体外逆转K562/VCR细胞多药耐药的实验研究[J].中国中医药科技,2005,12(5)：292
[57]史曦凯,张翼军,赵春景,等.人参皂苷单体Rbl对多药耐药细胞系K562/HHT的耐药逆转作用[J].第三军医大学学报,1999,21(11)：825
[58]杨金伟,习杨彦彬,刘佳,等.三七总皂苷对SAM-P/8小鼠海马中衰老相关基因表达的影响[J].解剖科学进展,2007,13(4)：306-313
[59]郑文球,朱敏.三七皂苷R1对HL-60细胞凋亡及survivin、p53表达的影响[J].肿瘤 学杂志,2007,13(3)：198-200
[60]张延斌,周永兰,杨煜,等.三七总皂甙对血管平滑肌细胞凋亡及C-myc基因表达的影响[J].新技术,2007,36(8)：120-121
[61]武凡,康格非.三七皂苷Rg1、Rbl对脂多糖引起的大鼠肝细胞凋亡及相关基因表达的保护作用[J].中国中西医结合杂志,2002,22(3)：165-167
[62]徐正祄,倪世容,王万铁,等.三七总皂苷对肺缺血再灌注损伤时细胞凋亡及Fas/FasL的影响[J].中国病理生理杂志,2005,21(9)：1731-1734
[63]赵玉鑫,王洪,杨述华,等.三七总皂苷对大鼠脊髓损伤后iNOS表达及细胞凋亡的影响[J].实用医药杂志,2006,23(11)：1340-1343
[64]陈彦静,李建东,黄启福.三七总皂苷对Ang Ⅱ秀导心肌细胞凋亡的影响[J].中国中药杂志,2005,30(10)：778-781
[65]张毅,叶启发,明英姿,等.三七总皂苷预处理大鼠供肝对细胞凋亡及TNF-a、 caspase-3表达的影响[J].中国现代医学杂志,2005,15(2)：172-176
[66]李巾伟,朱培纯,司银楚,等.三七总皂苷对脑出血大鼠前脑促凋亡基因caspase-3影响的研究[J].北京中医药大学学报,2003,26(2)：22-25
[67]顾萍,张勇,高飞,等.三七总皂苷对大鼠脑出血模型中神经细胞凋亡、Bcl-2表达的影响[J].中国临床医学,2006,13(4)：527-529
[68]邓志军,郭洁文,杨敏,等.三七总皂苷及其活性单体药代动力学的研究进展[J].药学进展,2009,19(1)：24-27
[69]沈央,方晓玲.三七总皂苷脂质体的药剂学性质及大鼠肺部给药药动学研究[J]_中草药,2004,35(7)：745-749
[70]徐白,沈蕴琪,方晓玲,.等.三七总皂昔复方脂质体凝胶剂的制备及皮肤给药研究[J].中国临床药学杂志,2007,16(3)：144-148
[71]韩旻,付韶,方晓玲.三七总皂苷油包水微乳的处方筛选及体内外评价[J].药学学报,2007,42(7)：780-786
[72]Friedman SI.Hepatic stellate cells Protean, multifunctional and enigmatic cells of the liver[J].PhysiolRev,2008,8:125-172
[73]唐阁,陈文慧,马迪.中药抗脂质过氧化与抗肝纤维化[J].中西医结合肝病杂志,2005,15(6)：379-380
[74]Neuman MG.Cytokines-central factors in alcoholic liver disease[J].Alcohol Res Health,2003,27(4):307-316
[75]Luca M iele,Gary Beale,G illian Patm an,et al.The Kruppel Like factor 6 fenotype is associateed with fibrosis in nonalcoholic fatty liver disease[J].G astroenterology,2008,135 (1):282-291
[76]WangCH,Lee TH,Lu CN,et al.Electroporative alpha-MSH gene transfer attenuates thioacetamide induced murine hepatic fibrosis by MMP and TIMP modulation[J]. JGeneTher,2006,13(13):1000-1009
[77]吕伟红,徐姗,张洪泉.三七总皂苷抗肝纤维化作用机制的研究进展[J].中国野生植物 资源,2009,28(2)：1-3
[78]张荣华.三七总皂苷干预肝纤维化大鼠肝组织Ⅰ型胶原、Ⅲ型胶原、FN、LN表达的研究[c].重庆市中医药学会学术年会论文集,2009,82-85
[79]余万桂,张恒文,晏年春,等.三七总皂甙对肝纤维化小鼠血清酶学及NO的影响[J].中药药理与临床,2005,21(5)：22-23
[80]石小枫,徐曼,刘杞.三七总皂甙对肝纤维化大鼠Ⅰ,Ⅲ型胶原及TGF-β1的影响[J].中药药理与临床,2001,17(2)：7-8
[81]曾文勇,石小枫,刘杞,等.三七总皂苷对肝纤维化大鼠胶原及TGF-β1mRNA表达的影响[J].胃肠病学和肝病学杂志,2010,19(9)：795-798
[82]马岚青,梁兵,柳波,等.人参皂苷Rg1抗肝纤维化的实验研究[J].中国中西医结合消化杂志,2007,15(3)：165
[83]张桂灵,石小枫,冉长清,等.三七总皂甙对抗大鼠免疫性肝纤维化的实验研究[J].第三军医大学学报,2007,29(23)：2212-2213
[84]张荣华,李景怡,陈如泉,等.三七总皂苷对肝纤维化大鼠肝脏超微结构的影响[J].第三军医大学学报,2005,27(24)：2410-2413
[85]王文兵,戴立里,郑元义.三七总皂甙诱导大鼠肝星状细胞凋亡的研究[J].中华肝脏病杂志,2005,13(2)：156-157.
[86]王怡,薛绍礼,张菁,等.三七总皂甙对传代肝星状细胞增殖的影响[J].淮海医药,2008,26(1)：1-2
[87]薛青,薛绍礼,汪亚松,等.三七总苷对体外培养细胞胶原合成模型的影响[J].医药导报,2008 27(5)：517-518
[88]余万桂,张恒文.三七总皂苷对肝纤维化小鼠TNFa及IL-6活性的影响[J].中药药理与临床,2005,21(4)：31-32
[89]Karl T W.Fibrosis:a common pathway in organ failure:angiotesion Ⅱ and tissure repair [J].Sem Nephro,1997,17(5):467
[90]Eddy AA.Molecular insights into renal interstitial fibrosis[J].AM Soc Nephrol,1996,7 (17):2495-2508
[91]Bohel A,Mackensen Haen S,Vou Gise,et al.The cones quences of tubuloinst Erstitial changes for renal function in glomerulopathies.A morphometric and eytologial analysis[J]. Pathol Res Pract,1990,18(1):135-144
[92]伍红英,金建生,刘静,等.三七总皂苷对腺嘿吟致肾间质纤维化的影响[J].中国新药与临床杂志,2008,27(11)：823-828
[93]刘静,金建生,钟山.三七总皂苷对腺嘌呤致大鼠肾间质纤维化影响的实验研究[J].中国临床药理学杂志,2010,26(4)：287-289
[94]谢纪青,金建生,付次双.三七总皂苷对慢性肾缺血肾间质纤维化的防治作用[J].福建医科大学学报,2010,44(1)：40-44
[95]付次双,金建生,谢纪青.三七总皂苷对大鼠慢性缺血性肾损伤的影响[J].中国新药与临床杂志,2010,29(2)：104-108
[96]赵宗江,张新雪,梁凯峰,等.三七总皂苷对阿霉素肾病大鼠肾组织转化生长因子-β1表达的影响[J].中国中西医结合肾病杂志,2008,9(4)：298-301
[97]赵宗江,梁凯峰,张新雪,等.三七总皂苷对阿霉素肾病大鼠肾组织PDGF及其mRNA表达的影响[J].2008,10(4)：57-59
[98]仇琪,赵宗江,杨美娟.三七总皂苷对阿霉素肾病大鼠肾组织CTGF蛋白及其mRNA表达的影响[J].中华中医药学刊,2008,26(11)：2358-2360
[99]郭兆安,彭书玲,赵鑫,等.三七总皂苷对5/6肾切除大鼠肾脏皮质细胞外基质积聚的影响[J].中国中西医结合肾病杂志,2008,9(12)：1053-1057
[100]许志杰,陶静莉,刘华锋,等.三七总苷对5/6肾切除大鼠肾保护作用的研究[J].中成药,2009,31(10)：1493-1496
[101]谢席胜,冯胜刚,左川,等.三七总皂甙对单侧输尿管梗阻后大鼠肾间质纤维化的作用及机制研究[J].西部医学,2010,22(2)：210-214
[102]冯胜刚,谢席胜,邓尧,等.三七总皂甙对TGF-β/Smads言号通路的作用[J].西部医学,2007,19(4)：526-529
[103]冯胜刚,李光明,樊均明,等.三七总皂甙抗肾小管上皮细胞转分化的实验研究[J].西部医学,2008,20(4)：700-703
[104]赵湘,邱莲女,郭俊华,等.三七总皂苷对大鼠肾小球系膜细胞增殖及细胞周期的影响[J].中华中医药学刊,2008,26(2)：287-289
[105]赵湘,周永烈,郭俊华,等.三七总皂苷对大鼠肾小球系膜细胞结缔组织生长因子表达的影响[J].中国中西医结合肾病杂志,2008,9(2)：149-152
[106]张毅,陈孝文,吴平,等.三七总皂甙对TGF-β1诱导的HK-2细胞总胶原分泌及细胞生长的影响[J].广东医学院学报,2005,23(6)：644-646
[107]刘海燕,陈孝文,刘华锋,等.三七总苷对尿毒血清诱导的人肾小管上皮细胞外基质分泌及降解的影响[J].中草药,2006,.37(2)：245-248
[108]李才.器官纤维化-基础与临床[s].北京：人民卫生出版社,2003：188-189
[109]武慧,冯一中,顾振纶,等.三七总皂甙对博莱霉素所致小鼠肺纤维化的干预作用[J].中国野生植物资源,2007,26(1)：29-32
[110]李学军,崔社怀.三七总皂甙及甲泼尼龙对实验大鼠肺纤维化的干预作用及机制的初步探讨,中华结核和呼吸杂志[J].2002,25(9)：520-523
[111]郑洪,蒋萍,陈佳宁,等.三七总皂甙对大鼠肺纤维化的干预作用及机制探讨[c].第十次全国中西医结合防治呼吸系统疾病学术研讨会论文集,2009,287-290
[112]武慧,冯一中,顾振纶.三七总皂甙对实验性肺纤维化大鼠病理变化和转化生长因子-β1表达的影响[J].苏州大学学报(医学版),2009,29(1)：29-32
[113]李学军,崔社怀.三七总甙对大鼠肺纤维化过程中血浆MIP-1α、MCP-1含量的影响[J].第三军医大学学报,2003,25(6)：522-524
[114]全燕,夏前明,李福祥.三七总皂苷对大鼠肺纤维化及结缔组织生长因子表达的影响[J].西南国防医药,2009,19(1)：23-25
[115]周迎春,王峰,齐彦.三七总甙对博来霉素诱导肺纤维化大鼠肺内结缔组织生长因 子的影响[J].中国现代药物应用2010,4(4)：125
[116]刘剑毅,李世荣,纪淑兴.三七总甙对人增生性瘢痕成纤维细胞增殖及胶原合成的作用[J].第三军医大学学报,2003,25(17)：1562-1563
[117]姚恒,李世荣,刘剑毅.三七总甙对人增生性疲痕成纤维细胞TGF-B和细胞周期的作用[J].中国实用美容整形外科杂志,2005,16(4)：243-245
[118]刘灿,周卫,孔焕宇,等.三七透明质酸钠凝胶对家兔硬膜外瘢痕中成纤维细胞凋亡的影响[J].世界中医药,2010,5(4)：282-284
[119]徐泉,周卫,孔焕宇,等.三七透明质酸钠凝胶对家兔椎板切除术后硬膜外瘢痕中胶原成分的影响[J].中国骨伤,2010,23(4)：278-281
[120]王荣国,周卫,章永东,等.三七凝胶对硬膜外粘连中COX-2、TGF-B1的影响[J].北京中医药大学学报,2010,3(1)：54-57
[121]程志清,徐百鸿,窦丽萍,等.三七总皂甙抗病毒性心肌炎慢性期小鼠心肌纤维化作用及其机制的研究[J].浙江中医药大学学报,2008,32(1)：23-26
[122]程志清,徐百鸿,窦丽萍,等.三七总皂苷对病毒性心肌炎慢性期小鼠心肌纤维化及细胞因子PDGF-B表达的影响[J],中华中医药学刊,2008,26(8)：1618-1621
[123]吴柱国,胡志华.三七总皂苷对小鼠心肌肥厚的抑制作用及机制[J].中国现代医学杂志,2010,20(13)：1943-1947
[1]Turk V, Turk B,Turk D.Lysosomal cysteine proteases:facts and opportunities [J].EM BO J,2001,20(17):4629-4633
[2]HalanW, LerehMM,Bradt-Nedelev B,et al.Role of cathepsin B in Intracelh lar trypsinogen activation and the onset of acute pancreatitis[J].J C lin Invest,2000,106(6):773-81
[3]唐硕,魏强.组织蛋白酶B在非肿瘤疾病中的研究进展[J],西部医学,2008,20(6)：1294-1295
[4]Liaudet CE,Beaujouin M,Derocq D,et al.Cathepsin D:newly discovered functi-Ons of a long standing aspartic protease in cancer and apoptosis[J].Cancer Lett,2006,23(7):167-79
[5]Zaidi N,Maurer A,Kalbacher H.Cathepsin D:a cellular roadmap[J].Biochem Biophys Res Commun,2008,376(1):5-9
[6]Metcalf P,Fusek M.Two crystal structures for cathepsin D:the lysosomal targeting signal and active site[J].EMBO J,1993,1(2):1293-1302
[7]Bossard N, Descotes F, Bremond AG, et al. Keeping data continuous when analyzing the prognostic impact of a tumormarker:an examplewithwith cathepsin D in breast cancer[J].BreastCancerResearch and Treatment,2003,8(2):47-53
[8]陈洋,李舒.组织蛋白酶D与消化道肿瘤的关系[J].咸宁学院学报(医学版),2008,22(6)：546-549
[9]王帅,赵慧颖.组织蛋白酶与动脉硬化的关系[J].中国老年学杂志,2010,30(4)：564-567
[10]Krizaj I,Drobnic-Kosorok M,Brzin J,et al.The primary structure of inhibitor of cystcine proteinases from potato[J].FEBS Lett,1993,33(3):15-20
[11]Berdowska I. Cysteine proteases as disease markers[J].Clin ChimActa,2004,34(2):41-69
[12]Riese RJ,Chapman HA.Cathepsins and compartmentalization in antigen presentation [J].Curr Opin Immunol,2000,1 (2):107-113
[13]Tsukuba T,Okamoto K,Yasuda Y,et al.New functional aspects of cathepsinD and cathepsinE[J].Mol Cells,2000,10(6):601-11
[14]刘玉胜,鹿庆华,蒋卫东,组织蛋白酶与心血管重塑[J].心血管病学进展,2006,27(7)：227-300
[15]Bialek J.Hombach KS,Fiebig B,et al.Lysosomal acid hydrolases of the cathepsin family are novel targets of INSL3 in human thyroid carcinoma cells[J].Ann N Y Acad Sci,2009,11(6):361-366
[16]Khalkhali EZ,Hendrix MJ.Elucidating the function of secreted maspin:inhibitting cathepsin D-mediated matrix degradation[J].CancerRes,2007,67(8):3535-9
[17]Zarzynska J,Gajkowska B,Wojewodzka U,et al.Apoptosis and autophagy in involuting bovine mammary gland is accompanied by up-regulation of TGF-betal and suppression of somatotropicpathway[J].Pol.J.Vet.Sci,2007,10(1):1-9
[18]Lecaille F,Kaleta J,Bromme D.Human and parasitic papain-like cysteine proteases:their role in physiology and pathology and recent developments in inhibitor design[J].Chem Rev,2002,10(2):4459-4488
[19]Demchik LL,Sameni M,Nelson K,et al.Cathepsin B and glioma invasion[J].Int JDevNeurosci,1999,1(7):483-494
[20]蒯小玲,萧树东.组织蛋白酶B与胃肠道肿瘤[J].国外医学：消化系统疾病分册,2002,22(2)：65-67
[21]Koblinski JE,AhramM,Sloane BF.Unraveling the role of proteases in cancer [J].Clin ChimActa,2000,29(1):113-135
[22]Staack A,Koenig F,Daniltchenko D,et al.Cathepsins B,H,and L activities in urine of patientswith transitional cell carcinoma of the bladder[J].Urology,2002,5(9):308-312
[23]Hengartner MO.The biochemistry of apoptosis[J].Nature,2000,407(6805):770-776
[24]陈月桥,王丽,武建华.细胞凋亡信号传导途径研究进展[J].中国实用医药,2007,2(33)：186-187
[25]Chw ie ra lski CE,Welte T,Buhling F.Cathepsin regu lated apoptosis[J].A poptosis,2006,11(2):143-149
[26]Furmanl LM,M aaty W S,Petersen LK,et al.Cysteine protease activation and apoptosis inmurine norovirus infection[J].V irol J,2009,6(9):139-145
[27]A kache B,Grimm D,Shen X,et al.A two hybrid screen identifies cathepsins B and L as uncoating factors for adeno-associated virus 2 and 8[J].MolTher,2007,15(2):330-339
[28]Zhang FT,ZhangYB,Chen YD,et al.Expressional induction of paralichthys olivaceus cathepsin B gene in response to virus,poly I:C and lipopolysaccharide[J].Fish She llfish Immuno,2008,25(5):542-549
[29]Burster T,Giffon T,Dahl ME,et al.Influenza A virus elevates active cathepsin B in primary murine DC[J].Int Immuno,2007,19(5):645-655
[30]Canbay A,Guicciardi M E,H iguchiH,et al.Cathepsin B inactivation attenuates hepatic injury and fibros is during cholestasis[J].J Clin Invest,2003,112(2):152-159
[31]Ben-Ari Z,Mor E,A zarov D,et al.Cathepsin B inactivation attenuates the apoptotic injury induced by ischemia/reperfusion of mouse liver[J].Apoptosis 2005,10(6):1261-1269
[32]Yan BZ,Wang W,Chen LY,et al.Role of cathepsin B mediated apoptosis in fulmin anthepatic failure inmice[J].World J Gastroentero,2009,15(10):1231-1236
[33]Benchoua A,Braudeau J,Reis A,et al.Activation of proinflammatory caspases by cathepsin B in focal cerebral ischem ia[J].J Cereb Blood Flow M etab,2004,24(11):1272-1279
[34]李杰平,何平平,于小华,等.大鼠肺纤维化细胞凋亡及CathePsinB基因变化的关系[J].现代生物医学进展,2007,7(6)：696-698
[35]Yin L,Stearns R,Gonzalez-F lecha B.Lysosom al and m itochondrial pathw ays in H2O2-induced apoptos is of alveolar type Ⅱ cells[J].J Cell Biochem,2005,94(3):433-445
[36]Takuma K,K iriu M,Mori K,et al.Roles of cathepsins in reperfusion-induced apoptos is in cultured astrocytes[J].Neurochem Int,2003,42(2):153-159
[37]张延波,陈溪萍,陶陆阳,等.大鼠脑外伤后溶酶体酶Cathepsin-B和D的表达[J].法医学杂志,2006,22(6)：404-410
[38]PrinceLR,BianchiSM,V aughan KM et al.Subversion of a lysosomal pathway regulating neutrophil apoptosis by a major bacterialtox in, pyocyanin[J].J Immuno,2008,180(5): 3502-3511
[39]Brunk UT.Svensson I[J].Redox Rep,1999,4(2):3-11
[40]Bidere N,Lorenzo HK,Carmona S,et al.Cathepsin D triggers Bax activation, resulting in selective apoptosis inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis[J].J BiolChem,2003,278(33):31401-31411
[41]吴燕婉,刘德瑜.溶酶体的细胞死亡通路[J].解剖学报,2007,38(4)：498-450
[42]Schestkowa O,Geisel D,Jacob R,et al.The catalytically inactive precursor of cathepsin D induces apoptosis in human fibroblasts and HeLa cells[J].J Cell Biochem,2007,10(1): 1558-1566
[43]Trincheri NF,Nicotra G,Follo C,et al.Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D[J].Carcinogenesis, 2007,2(8):922-931
[44]Bestvater F,Dallner C,Spiess E.The C-terminal subunit of artificially truncated human cathepsin B mediates its nuclear targeting, and contributes to cell viability[J].BM C Cell Bio,l 2005,6(1):16-24
[45]李志刚,张智博.溶酶体组织蛋白酶参与细胞凋亡过程的分子机制[J].中国肿瘤生物治疗杂志,2009,16(6)：648-652
[46]Berchem GJ,Glondu M,Gleizes M,et al.Cathepsin-D affect multiple steps of tumor progression:Proliferation,angiogenesis and apoptosis[J].Oncogene,2002,21:5951-5955
[47]Hu L,Roth JM,Brooks P,et al.Thrombin up-regulates cathepsin D which enhancees angiogenesis,growth,and metastasis[J].Cancer Res,2008,68(12):4666-4673
[48]Laurant MV,Maruani HS,Prebois C,et al.Liaudet-Coopman E Catalytically inactive human cathepsin D triggers fibroblast invasive growth[J].J Cell Biol,2005,168(3):489-499
[49]谭业儒,姜浩,甘润良.组蛋白酶D与恶性肿瘤的相关性研究[J],现代生物医学进展,2010,10(14)：2785-2788
[50]Minarowska A,Minarowski L,Karwowska A,et al.Regulatory role of cathepsin D in apoptosis[J].Folia Histochem Cytobiol,2007,45(3):159-163
[51]Roberg K,et al.Relocalization of cathepsin D and cytochrome C early in apoptosis revealed by immunoelectron microscopy[J].Lab Invest,2001,81(2):149-158
[52]Kagedal K,Johansson U,Olinger K,et al.The lysosomal protease casthepsin D mediates apoptosis induced by oxidative stress[J].EMBO J,2001,1(5):1592-1594
[53]王娅兰,林晓.黏液性大肠癌组织蛋白酶B、D表达与肿瘤浸润[J].实用肿瘤学杂志,2003,17(4)：249-251
[54]林晓,王娅兰.大肠癌组织蛋白酶B表达及其与肿瘤微血管密度和生物学行为的关系[J].重庆医科大学学报,2002,27(3)：264-270
[55]Yan S,Sloane BF.Molecular regulation of human cathepsin B:Implication in pathologyies[J].BiolChem,2003,384(6):845-854
[56]李祥春,张开光.组织蛋白酶B与胃癌研究进展[J].安徽医药,2010,14(9)：996-998
[57]Roeby S,Sloane BF,Mo inK.Pericellular cathepsin bandmalig nantprogression[J]. Cancer Metastasis Rew,2003,22(2-3):271-286
[58]SameniM,Dosescu J,Sloane BF.Imaging proteo lysisby living human breast cancer[J].Neoplasis,2000,2(6):496-504
[59]Khan A,Krishna HI,Baker SP,et al.Cathepsin B expression and its correlation with tumor associaled laminin and tumor progression in gastric cancer [J]. Arch patholLah bled,1998, 122(2):172-7
[60]Montuori N,V isconte V,RossiG,et al.Soluble and cleaved forms of the urokinase receptor:degradation products or active molecules[J].Thromb Haemost,2005,93(2):192-198
[61]Rabbani SA,Mazar AP.The role of the plasm inogen activation system in angiog enesis and metastasis[J].Surg Oncol Clin N Am,2001,10(2):393-415
[62]Dem chik LL,SameniM,Nelson K,et al.Cathepsin B and glomainvasion[J].Neur-osci, 1999,17(6):483-494
[63]Sinha AA,Gleason DF,StaleyNA,et al.Cathepsin B in an giogenesis of human prostate an immunohistochem ical and immunoelectron microscopic analysis[J].The Anatomical Record,1995,241(3):353-362
[64]Kostoulas G,Lang A,Nagase H,et al.Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metallopro terinases[J].FEBS Lett,1999,455 (3):286-290
[65]Frohlich E,Sch lagenhauff B,M ohrle M,et al.Activity,expression and transcription rate of the cathepsinsB,D,H,and L in cutaneousm alignantm elanoma[J].Cancer,2001,91(5): 972-982
[66]唐建建,姜曙,毛伯镛.组织蛋白酶B表达与胶质瘤恶性程度和血管生成的关系[J].四川大学学报(医学版),2006,37(2)：212-214
[67]段建敏,左陵君,范文高,等.组织蛋白酶B与膀胱癌恶性度的相关性[J].临床泌尿外科杂志,2003,18(11)：677-679
[68]肖庆,唐深,樊晓晖.组织蛋白酶B及抑制剂与肿瘤[J],现代肿瘤医学,2008,16(4)：674-676
[69]Allayer H,Babic R,Grutzner KU,et al.Tumor associated proteases and inhibittors in gastric cancer Analysis of prognostic impact and individual risk protease pattern[J].Clin Exp Metast,1998,16(1):62
[70]Goishi H,T anaka S,H aruma K,et al.Preditive value of cathepsin D and Ki-67 expression at the deepest penetration site for lymphnode metastases in gastric cancer[J].OncolRep, 2000,7(4):713
[71]Ikeguchi M,Fukuda K,O ka SI,et al.Microlymphnode metasis and its correlation with cathepsin D expression in early gastric cancer[J].Surg O ncol 2001,77:188
[72]Ikeguchi M,Fukuda K.Clinicopathological significance of cathepsinD expression in gastric adenocarcinom as[J].Oncology,2001,6(1):71
[73]万文徽.肿瘤临床应用与研究进展[M].北京：北京大学医学出版社,2005：226
[74]徐晓艳,范鹏程,马秀梅.E-钙黏附素、组织蛋白酶D与胃癌侵袭转移的关系[J].山西医科大学学报,2008,39(3)：237-240
[75]陈晓艺,张白凌,陈少杰.组织蛋白酶D与基质金属蛋白酶-9在口腔鳞癌的表达[J].福建医科大学学报,2006,40(6)：560-562
[76]吴晶晶,张鹏宇,张明智,等.组织蛋白酶-D和MMP-9在非小细胞肺癌中的表达意 义[J].中国现代药物应用,2010,4(15)：5-6
[77]Szajda SD,Snarska J,Jankowska A,et al.Cathepsin D and carcino-embryonic antigen in serum,urine and tissue of colon adenocarcinoma patients[J]. Hepatogastroenterolo gy,2008, 55(82-83):388-93
[78]Tsukamoto T,Iida J,Dobashi Y,et al.Overexpression in colorectal carcinoma of two lysosome enzymes,CLN2 and CLN1,involved in neuronal ceroid lipofusci-nosis[J]. Cancer,2006,106(7):1489-97
[79]Kaneko I,Tanaka S,Oka S,et al.Immunohistochemical molecular markers as predictors of curability of endoscopically resected submucosal colorectal cancer[J],World J Gastroenterol,2007,13(28):29-35
[80]Dvalishvili I,Charkviani L,Charkviani T,et al.Clinical prognostic factors and expression of cathepsin D in endometrioid adenocarcinoma[J].Deorgian Med News,2005,12(6):27-31
[81]Fernandez AS,Nol JC.Expression of cathepsin D and galectin 3 in tubular carcinomas of the breast[J].APMIS,2008,116(1):33-40
[82]Irawan C,Hukom R,Prayogo N.Factors associated with bone metastasis in breast cancer:a preliminary study in an Indonesian population[J].Acta Med Indone's,2008,40(4):178-180
[83]Abbott DE,Margaryan NV,Jeruss JS,et al.Reevaluating cathepsinD as a biomarker for breast cancer:Serum activity levels versus histopathology[J].CancerBiol Ther,2010, 15(1):31-32
[84]Marki evi M,Petrovi A,Kanjer K,et al.Estrogen-regulated cut off values of PS2 and cathepsin D expression in breast carcinomas[J].Adv Exp Med Biol,2008,61(7):341-348
[85]Ohri SS,Vashishta A,Proctor M,et al.The propetide of cathepsin D prolife Ration, invasion and metastasis of breast cancer cells[J].Int JOncol,2008,32(2):491-498
[86]Brujan I,Mrgritescu C,Simionescu C,et al.Cathepsin-D expression in breast lesion:an immunohistochemical study[J].Rom J Morphol Embryol,2009,50(1):31-39
[87]Leto G,Tumminello FM,Crescimanno M,et al.Cathepsin D expression levels in nongynecological solid tumors:clinical and therapeutic implications[J].Clin Exp Metastasis,2004,21 (2):91-106
[88]Opel D,Poremba C,Simon T,et al.Activation of Akt predicts poor outcome in neuroblastoma[J].Cancer Res,2007,67(2):735-745
[89]Merseburger AS,Hennenlotter J,Simon P,et al.Cathepsin D expression in renal cell cancer clinical implications[J].Eur Urol,2005,48(3):519-526
[90]R.Koslowski, K.Knoch, E.Kuhlisch,et al.Cathepsins in bleomycin induced lung injury in rat[J].CATHEPSINS IN LUNG INJURY,2003,2(2):427-435
[91]郭丽萍,张耀全,袁发焕.部分肾切除大鼠肾组织蛋白酶B的表达与肾脏纤维化的关系[J].重庆医学,2005,34(10)：1447-1449
[92]Reinheckel T,Deussing J,Roth W,et al.Towards specific functions of lysosomal cysteine peptidases:phenotypes of mice deficient for cathepsinB or cathepsin L[J].Biol Chem, 2001,382(5):735-741
[93]A.Kenessey, M. Banay-schwartz, Inerease in cathepsinD aetivity in rat Brain in aging[J].J Neurosci Res,1989,2(3):454-456
[94j Benuck, M.Banay-Sehwartz, Changes in brain Protease aetivety in aging[J].J Neuroe-hem,1996,6(7):2019-2029
[95]Amano T, Nakanishi H, Increasedeexpression of eathepsinsE and D in reaeTive mieroglial cells associated with spongiform degeneration in the brain Stem of seneseenee accelerated mouse[J].Exp Neurol,1995,136(2):171-182
[96]H. Nakanishi, T.Amano.D.F. SastradiPura, Inereased expression of cathepsinE and D in neurons of the aged rat brain an their localization with lipofuscin and carboxy tenminal fragments of Alzheimer amyloid precursor Protein[J].J.Neurochem,1997,6(8):739-749
[97]Podgorski I,L inebaugh BE,Sameni M,et al.Bone microenvironm ent modulates expression and activity of cathepsin B in prostate cancer[J].Neoplasia,2005,7(3):207-223
[98]张智博,刘柳青,龚晓燕,等.大鼠脑缺血再灌注后Cathepsin D和caspase-9表达的动态变化[J].现代生物医学进展,2010,10(5)：851-854
[99]龚晓燕,张智博,刘柳青,等.大鼠脑缺血再灌注后溶酶体组织蛋白酶B表达的动态变化[J].现代生物医学进展,2009,9(10)：1842-1852
[100]Tyynela J,Sohar I,Sleat DE,et al.A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration[J].EMBO J,2000, 19(12):2786-2792
[101]Shin izu T,Hayashi Y,Yamasaki R,et al.Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D deficient mice[J].J Neurochem,2005,94(3):680-690
[102]Myllykangas L,Tyynela J,Page-McCaw A,et al.Cathepsin D deficient D rosophila recapitulate the key features of neuronal ceroid lipofuscinoses[J]. NeurobiolDis,2005, 19(2):194-199
[103]刘凤英,王学峰,李劲梅,等.耐药性癫痫患者脑组织蛋白酶D的表达及意义[J].中国病理生理杂志,2008,24(9)：1757-1761
[104]Handley CJ, Mok MT.CathePsinD eleaves aggreean at unique sites within the interglobular domain and chondroitin sulfate attaehment regions that are Also eleaved when cartiage is maintained at acid PH[J].Matrix Biol,2001,20(8):543-553
[105]Nakase T,Kaneko M,Immununohistochemical detection of cathepsinD,K,and L in the Proeess of endochondral ossification in the human[J].Histochem cell Biol 2000,114(1):21-7
[106]Ariga K, Yonenobu K, et al.Localization of CathepsinsD, k, and L in degenera-ted Human Intervertebral[J].Dises Spin 2001,2(6):2666-2672
[107]赵刚,李双杰,陈瑞珍,等Cathepsin B与扩张型心肌病发病关系的初步探讨[J].复旦学报(医学版),2004,31(6)：556-569
[108]Koblinski JE,Dosescu J,Sameni M,et al.Interaction of human breast fibroblasts with collagen I increase secretion of procathepsin B[J].J Biol Chem,2002,27(7),32220-32227
[109]Varma TH,Liu SQ,West M,et al.Protein kinase C-dependent Phosphory lation and mitochondrial translocation of aldose reduce tase[J].FEBS Lett,2003,53 (4):175-183
[110]于小华,张新刚,王时俊,等.组织蛋白酶B抑制剂CA-074Me对小鼠病毒性心肌炎的干预作用[J].临床儿科杂志,2005,23(1)：52-54
[111]Vanacker GJ,Saluja AK,Bhagat L,et al.cathepsin B inhibition prevents try psinogen activation and reduces pancreatitis severity[J].Am J Physiol Gastrointest Liver Physiol, 2002,283(3):794-800
[112]张慧,冯琴,李红山,等.祛湿化瘀方对非酒精性脂肪性肝炎大鼠组织蛋白酶B和肿瘤坏死因子α表达的影响[J],中西医结合学报.2008,6(9)：928-933
[113]Foghsgaard L,Wissing D,Mauch D,et al.Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor[J].J Cell Biol,2001, 153(5):999-1010
[114]Werneburg N,Guicciardi ME,Yin XM,et al.TNF-alpha mediated lysosomal permeabi lization is FAN and caspase 8/Bid dependent[J] Am J Physiol Gastrointest Liver Physiol, 2004,287(2):436-443
[115]Zegarska J,Paczek L,Pawlowska M,et al.Extracellular matrix proteins, proteolytic enzymes, and TGF-beta1 in the renal. arterial wall of chronically rejectted renal allografts[J].TransplantProc,2003,(6):2193-2195
[1]Fine A,Janssen-Heininger Y,Soultanakis R P,et al.Apoptosis in lung pathoph-ysiology[J].Am J Physiol Lung Cell Mol Physiol,2000,279(3):423-427
[2]Kuwano,K, Kunitake,R,Kawasaki,M,et al.p21 and p53 expression in association with DNA strand breaks in idiopatic pulmonary fibrosis[J].Am J Respir Crit Care Med,1996,154 (2):477-483
[3]Uhal BD Epithelial apoptosis in the initiation of lung fibrosis[J].Eur Respir J Suppl, 2003,9(44):7-9
[4]Khalil N,O'Connor R N,Flanders K C,et al.Regulation of type Ⅱ alveolar epithelial cell proliferation by TGF-beta during bleomycin induced lung injury in rats[J].Am J Physiol,1994,267(5):498-507
[5]Kumar R K,Watkins S G,Lykke A W.Pulmonary responses to bleomycin Induced injury:an immunomorphologic and electron microscopic study[J].Exp Pathol,1985,28(1):33
[6]DosReis G A,Borges V M.Role of Fasligand induced apoptosis in pulmonary infla-mmation and injury[J].Curr Drug Targets Inflamm Allergy,2003,2(2):161
[7]FineA,Janssen-HeiningerY,SoultanakisRP,et al.Apoptosis in lung pathophy siology[J].Am J PhysiolLung Cell MolPhysio,2000,279(3):423-427
[8]Shipley JM,Doyle GA,Fliszar CJ,et al.The structural basis for the elastolytic activity of the 92-KDa and72-KDa gelatinases.Role of the fibronectin type Ⅱ like repeats[J].J Bio Chem,1996,271(8):4335-4341
[9]Xia T,Akers K,Eisen AZ,et al.Comparison of cleavage site specificity of gelatinases A and B using collagenous peptides[J].Biochem Biophys Acta,1996,1293(2):259-266
[10]Nogee LM,DunbarAE,Wert SE,et al.A mutantion in the surfactant protein C gene associated with familial interstitial lung disease[J].N Engl JMed,2001,344(8):537-579
[11]ThomasAQ,LaneK,Pillips J,et al.Heterozygosity for a surfactant- tprotein C gene mutation associated with usual interstitial pneumonitis and celluar nonspecific interstitial pneumonitis in one kindred[J].Am J Respir Crit CareMed,2002,165(9):1322-1328
[12]Plan SH.The myofibroblast in pulmonary fibrosis[J].Chest,2002,122(6):286-289
[13]Zhang K,Rekhter MD,Gordon D,et al.Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis:A combined immunohistochemical and in situ hybridizationstudy[J].Am J Pathol,1994,145(1):114-125
[14]Kuang PP,Lucey E,RishikofDC,et al.Engraftment of neonatal lung fibroblasts into the normal and elastase injured lung[J].Am J Respir Cell MolBio,2005,33(4):371-377
[15]Rehan VK,Wang Y,Patel S,et al.Rosiglitazone,a peroxisome Proliferators activated receptor gamma agonist,prevents hyperoxia induced neonatal rat lung injury in vivo[J].Pediatr Pulmono,2006,41(6):558-569
[16]Rehan VK,Wang Y,Sugano S,et al.Mechanism of nicotine induced pulmonary fibroblast transdifferentiation[J].Am J PhysiolLung Cell MolPhysio,2005,289(4):667-676
[17]BurgessHA,Daugherty LE,ThatcherTH,et al.PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production:Implications for therapy of lung fibrosis[J].Am J Physiol Lung Cell Mol Physio,2005,288(6):1146-1153
[18]Vancheri C,Gili E,Failla M,et al.Bradykinin differentiates human lung fibroblasts to a myofibroblast phenotype via the B2 receptor[J].J Allergy Clin Immunol,2005,116(6): 1242-1248
[19]Phan SH.The myofibroblast in pulmonary fibrosis[J].Chest,2002,122(6):286-289
[20]魏锦锦,李佳鑫.肺间质纤维化中肌成纤维细胞的来源及调控因素[J].新乡医学院学报,2009,26(6)：633-636
[21]WaghrayM,CuiZ,Horowitz JC,et al.Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial celldeath by activated myofibrob lasts[J].FASEB J,2005,19(7): 854-856
[22]Wang R,Ramos C,Joshil,et al.Human lung myofibroblast derived inducers of alveolar epithelial apoptosis identified as angiotension peptides[J].Am Jphysiol,1999,277(l):1158-1164
[23]Wang R,Ibarra Sunga O,Verlinski L,et al.Abrogation of bleomycin induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor[J].Am J physiol Lung Cell Mol physiol,2000,279(1):143-151
[24]Kuwano K,Hagimoto N,Tanaka T,et al.Expression of apoptosis-regulatory genes in epithelial cells in pulmonary fibrosis in mice[J].JPathol,2000,190(2):221-229
[25]Kang HR,Cho SJ,Lee CG,et al.Transforming growth factor (TGF)-β1 stimulates pulmonary fibrosis and inflammation via a Bax-dependent, Bidactivated pathway that involves matrix metalloproteinase-12[J].J Biol Chem,2007,282(10):7723-7732
[26]段斐.复方鳖甲软肝方防治特发性肺纤维化的细胞分子基础[D].北京：北京中医药大学,2005：56
[27]Uhal,BD.Fas and apoptosis in the alveolar epithelium:holes in the dike?[J].Am J Physiol,2001,281 (2),328-335
[28]Kuwano K,Miyazaki H,Hagimoto N,et al.The involvement of Fas-Fas ligand pathway in fibrosing lung diseases[J].Am J Respir Cell Mol Biol,1999,20(l):53-60
[29]Kuwano K,Hagimoto N,Kawasaki M,et al.Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis[J] J Clin Invest,1999,104(1):13-19
[30]Aoshiba K,Yasui S,Tamaoki J,et al.The Fas/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice[J].Am J Respir Crit Care Med, 2000,162(21):695-700
[31]Borge SVM,FalcaoH,LeitejuniorJH,et al.Fas ligand triggers pulmonary Silicosis[J].J Exp Med,2001,194(2):155-164
[32]Moodley YP,Caterina P,Scaffidi AK,et al.Comparison of the morphological and biochemical changes in normal human lung fibroblasts and fibroblasts derived from lungs of patients with idiopathic pulmonary fibrosis during FasL-induced apoptosis[J].J Pathol,2004,202(4):486-495
[33]Moodley YP,Misso NL,Scaffidi AK,et al.Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs[J].Am J Respir Cell Mol Biol,2003,29(4):490-498
[34]B u hling F,Wille A,Rocken C.Altered expression of membrane bound and soluable CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosis[J].Respir Res,2005,6(1):37
[35]段斐,耿德海,许文杰,等.复方鳖甲软肝方防治肺纤维化细胞凋亡的实验研究[J].时珍国医国药,2008,19(5)：1054-1055
[36]许朝霞.化纤汤对博莱霉素致大鼠肺纤维化的干预作用的实验研究[D].武汉：湖北中医学院,2007：20
[37]闫智勇,张天娥,刘明芳,等.化纤方对人胚肺二倍体纤维母细胞的增殖抑制作用[J].华西医学,2005,20(2)：280-281
[38]臧金萍,辛洪涛,王建平,等.芪丹颗粒对博莱霉素致肺损伤大鼠肺组织FasL caspase-3表达的影响[J].山东医药,2008,48(5)：18-20
[39]臧金萍,辛洪涛,王建平,等.芪丹颗粒对博莱霉素致大鼠肺纤维化时FasL、Caspase-3表达的作用[J]_现代诊断与治疗,2010,21(1)：5-8
[40]黄穗山.益气通络解毒方治疗IPF的细胞凋亡机制[D].武汉：湖北中医学院,2009：18
[41]Wang JF,Niu JZ, Lu YS,et al.Experim ental study on protective effects of curcumin on exaggerated ex trace llularm atrix accumulation of pulmonary fibrosis rats[J]. Zhong guo ZhongYao Za Zh,2006,31(7):570-573
[42]陈伟,欧阳劭,何振华.姜黄素对肺纤维化鼠Bcl-xl表达的影响[J].社区医学杂志,2009,7(19)：1-3
[43]高蔚,张德平,华云峰.姜黄素对大鼠肺成纤维细胞增殖和凋亡的影响[J].实用医学 杂志,2008,24(14)：2393-2396
[44]高蔚,张德平,陈碧.姜黄素诱导人肺成纤维细胞凋亡的相关分子机制的初步研究[J].中国呼吸与危重监护杂志,2009,8(2)：186-189
[45]李杰平.大鼠肺纤维化Cathepsin B的表达及黄芪甲甙的干预[D].衡阳：南华大学,2007：4
[46]柴文戍,翟声平,武素琳,等.灯盏花素对实验性肺纤维化大鼠的干预作用[J].中国药理学通报,2008,24(1)：113-116
[47]徐厚君,张伟,王广增,等.大豆皂甙对矽肺纤维化大鼠肺组织细胞凋亡的影响[J].现代预防医学,2008,35(23)：4681-4683
[48]徐厚君,王志强,苏宇,等.李清钊大豆皂甙对矽肺纤维化大鼠肺组织细胞Fas/FasL系统表达的影响[J].现代预防医学,2010,37(8)：1525-1527
[49]解克芳,王继峰,牛建昭.葛根素对人胚肺成纤维细胞增殖及细胞外基质合成的影响[J].中国中医药信息杂志,2008,15(5)：39-40
[50]许光兰,陈平,梁劲松,等.青蒿琥酯对实验性肺纤维化大鼠治疗作用及其机理研究[J].临床医学工程,2009,16(9)：6
[51]王昌明,张孝飞,黄岚珍,等.青蒿琥酯诱导人胚肺成纤维细胞凋亡的分子机制研究[J].时珍国医国药,2010,21(11)：2837-2838
[52]王昌明,张孝飞,谭宁,等.青蒿琥酯对人胚肺成纤维细胞系HFL-细胞增殖、凋亡的影响及机制[J].山东医药,2010,50(3)：33-35
[53]许朝霞,丁明桥,陈瑞,等.银杏叶提取物干预肺纤维化模型大鼠肺泡Ⅱ型上皮细胞凋亡的变化[J].辽宁中医杂志,2008,35(9)：1312-1314
[54]黄志卫,马忠森,王秀丽,等.刺五加对人胚肺二倍体纤维母细胞生长的影响[J].广西医科大学学报,2004,21(1)：28-30
[55]宋暖.昆布提取物J201抑制人胚肺成纤维细胞增殖的研究[D].青岛：青岛大学,2004：
[1]张玉军.三七总皂苷的药理研究进展[J].广西医学,2009,31(4)：589-591
[2]Szapiel SV,Elson NA,Fulmer JD,et al.Bleomycin-induced interstitial pulmonary disease in the nude,athymic mouse[J].Am Rev Respir Dis,1979,120(4):893-899
[3]戴令娟,侯杰,蔡后荣,等.肺纤维化动物模型肺组织形态定量分析[J].南京铁道医学院学报,1996,15(1)：24-27
[4]Uppaluri R,Hoffman EA.Sonka M,et al.Interstitial lung disease:A quantitative study using the adaptive multiple feature method[J].Am J Respir Crit Care Med,1999,159(2):519-525
[5]王响英,吴淑燕,李苏安等.实验性大鼠肺纤维化病理形态及超微结构观察[J].苏州大学学报(医学版),2005,25(3)：379
[6]Nagao T,Nagai S,Hiramoto Y,et al.Serial evaluation of high-resolution computed tomography findings in patients with idiopathic pulmonary fibrosis in usual interstitial pneumonia[J].Respiration,2002,69(5):413
[7]Donald N.Cook,David M.Brass,et al.A Matrix for New Ideas in Pulmonary Fibr-osis[J]. Am J Respir Cell Mol Biol,2002,27(2):122
[8]White E S,Lazar M H,Thannickal V J.Pathogenetic mechanisms in usual interstitial pneumonia/idiopathic pulmonary fibrosis[J].J Pathol,2003,201(3):343
[9]罗慰慈.现代呼吸病学[M].北京：人民卫生出版社,1997：119
[10]魏茂提,王世鑫,张国辉,等.染矽尘大鼠肺脏系数和肺胶原含量的变化[J].工业卫 生与职业病,2001,27(6)：351-353
[11]Brent E Van Hoozen,Katharine L Grimmer,Gregory P Marelieh.et al.Early Phase collagen synthesis in lungs of rats exposed to bleomyein[J].Toxieology 2000,147 (1):1-13
[12]S N Iyer,G Gurujeyalakshnli,S N Giri.Effeet of pirfenidone on proeollagen gene expression at the transeriptional level in bleomyein hnajster model of lung fibrosis[J].The Journal of Pharmaeology and Experimental Therapeuties,1999,2891:211-218
[13]Van Hoozen BE,Grimmer KL,Marelich GP,et al.Early phase collagen synthesis in lungs of rats exposed to bleomycin[J].Toxicology,2000,147(1):1-13
[14]牛建昭,贲长恩.器官纤维化基础及中医药防治[M].北京：人民卫生出版社,2008：102
[15]Zhao HW,Lu CJ,Yu RJ, Hou XM.An increase in hyaluronan by lung fibroblasts:a biomarker for intensity and activity of interstitial pulmonary fibrosis Respirology[J],1999 ,4(2):131-38
[16]Bensadoun ES,Burke AK,Hogg JC,et al.Proteoglycan deposition in pulmonary fibrosis [J].Am J Respir Crit Care Med,1996,154(6):1819-28
[17]CM,Penno MB,Cowman M,et al.Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages[J].The role of HA size and CD44.J Clin Invest,1996, 98(10):2403-13
[18]Zhu Z,Ma B,Zheng T,Homer RJ,et al.IL-13-induced chemokine responses in the lung: role of CCR2 in the pathogenesis of IL-13-induced inflammation and remodeling[J].J Immunol,2002,168(6):2953-62
[19]Li Y,Rahmanian M,Widstrom C,et al.Irradiation induced expression of hyaluronan (HA) synthase 2 and hyaluronidase 2 genes in rat lung tissue accompanies active turnover of HA and induction of types Ⅰ and Ⅲ collagen gene expression[J]. Am J Respir Cell Mol Biol, 2000,23(3):41118
[20]Ueki N,Taguchi T,Takahashi M,et al.Inhibition of hyaluronan synthesis by vesnarinone in cultured human myofibroblasts[J].Biochim Biophys Acta,2000,1495(2):160
[21]Lappi-Blanco E,Kaarteenaho-Wiik R,Salo S,et al.Laminin-5 gamma2 chain in crypto-genic organizing pneumonia and idiopathic pulmonary fibrosis[J].Am J Respir Crit Care Med,2004,169(1):27-33
[22]Perez-Arellano JL,Pecraz MJ,Fuertes A,et al.Laminin fragment PI is inereased in the lower respiratory raet of Patients with diffuse interstitial lung disease[J]. Chest,1993,104(4): 1163-1169
[23]Singer Ⅱ,Kawka DW,McNally SM,et al.Extensive laminin and basement membrane accumulation occurs at the onset of bleomycin-induced rodent pulmonary fibrosis[J].Am J Pathol,1986,125(2):258-68
[24]Sehoenfeld N,Sehmolke B,et al.Laminin fragment PI in the sera of Patients with Pulmonary sareoidosis[J].Sareoidosis-vase-Diffuse-Lung-Dis,1996,23(2):135-135
[25 ]吴浩,许祖德,张月娥,等.纤维连接蛋白在大鼠肺纤维化中的作用[J].中华结核与呼吸杂志,2001,24(1)：40-42
[26]徐峥嵘.细胞因子及其特异性抑制剂与肺纤维化的治疗[J].中国公共卫生,2005,21(6)： 750-753
[1]孔璐,王继峰,牛建昭.特发性肺纤维化与细胞凋亡[J].中华结核和呼吸杂志,2004,27(6)：368-371
[2]Furmanl LM,M aaty W S,Petersen LK,et al.Cysteine protease activation and apoptosis inmurine norovirus infection[J].V irol J 2009,10(6):139-145
[3]A kache B,Grimm D,Shen X,et al.A two hybrid screen identifies cathepsins B and L as uncoating factors for adeno associated virus 2 and 8[J].MolTher,2007,15(2):330-339
[4]Zhang FT,Zhang YB,Chen YD,et al.Expressional induction of paralichthys olivaceus cathepsin B gene in response to virus, poly I:C and lipopolysaccharide [J].Fish She llfish Immuno,2008,25(5):542-549
[5]Burster T,Giffon T,Dahl ME,et al.Influenza A virus elevates active cathepsin B in primary murine DC[J].Int Immuno,2007,19(5):645-655
[6]Benchoua A,Braudeau J,Reis A,et al.Activation of pro inflammatory caspases by cathepsin B in focal cerebral ischem ia[J].J Cereb Blood Flow M etab,2004,24(11):1272-1279
[7].李杰平,何平平,于小华,等.大鼠肺纤维化细胞凋亡及CathePsinB基因变化的关系[J].现代生物医学进展,2007,7(6)：696-698
[8]Yin L,Stearns R,Gonzalez-F lecha B.Lysosom al and m itochondrial pathw ays in H2O2-induced apoptos is of alveolar type Ⅱ cells[J].J Cell Biochem,2005,94(3):433-445
[9]方肇勤.分子生物学技术在中医药研究中的应用[M].上海：上海科学技术出版社2002：46
[10]贲长恩,李叔庚.组织化学[M].北京：人民卫生出版社,2001：254
[11]RongqiW,Olivia IS,LubaV,et al.Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or a caspase inhibitor[J].Am J Physiol Lung Cell MolPhysio,2000,27(9):143-151
[12]Uhal BD.Apoptosis in Lung Fibrosis and Repair[J].Chest,2002,12(2):293-298
[13]Whitsett JA.Genetic basis of familial interstitial lung disease[J].Am J Respir Crit Care Med,2002,16(5):1201-1202
[14]Barbas-Filho JV,Ferreira MA,SessoA,et al.E vidence of type Ⅱ pncumocyte apoptosis in the pathogenesis idiopathic pulmonary fibrosis/usual interstitial pneumonia(UIP)[J].J Clin Patho,2001,54(2):132-141
[15]Wang LY,Antonini JM,Rojanasakul Y,et al.Potential role of apoptotic macrophages in pulmonary inflammation and fibrosis[J].J Cell Physiol,2002,19(4):215-224
[16]唐硕,魏强.组织蛋白酶B在非肿瘤疾病中的研究进展[J],西部医学,2008,20(6)：1294-1295
[17]陈洋,李舒.组织蛋白酶D与消化道肿瘤的关系[J].咸宁学院学报(医学版),2008,22(6)：546-549
[18]Krizaj I, Drobnic-Kosorok M, Brzin J,et al.The primary structure of inhibitor of cysteine proteinases from potato[J].FEBS Lett,1993,33(3):15-20
[19]Berdowska I.Cysteine proteases as disease markers[J].Clin ChimActa,2004.34(2):41-69
[20]Riese RJ,Chapman HA.Cathepsins and compartmentalization in antigen presentati-on[J].Curr Opin Immunol,2000,1(2):107-113
[21]Tsukuba T,Okamoto K,Yasuda Y,et al.New functional aspects of cathepsin D and cathepsin E[J].Mol Cells,2000,10(6):601-11
[22]刘玉胜,鹿庆华,蒋卫东.组织蛋白酶与心血管重塑[J].心血管病学进展,2006,27(7)：227-300
[23]Liaudet CE,Beaujouin M,Derocq D,et al.Cathepsin D:newl discovered functions of a long-standing aspartic protease in cance and apoptosis[J].Cancer Lett,2006,23(7):167-179
[24]Mctcalf P,Fusek M.Two crystal structures for cathepsin D the lysosomal targeting signal and active site[J].EMBO J,1993,1(2):1293-1302
[25]Bialek J,Hombach KS,Fiebig B,et al.Lysosomal acid hydrolases of the cathepsin family are novel targets of INSL3 in human thyroid carcinoma cells[J]. Ann N Y Acad Sci,2009, 11(6):361-366
[26]Salvesen GS.A. lysosomal protease enters the death scene[J].J Clin Invest,2001, 107(1):21-22
[27]Brunk UT,Neuzil J.Lysosomal involvement in apoptosis[J].Redox Rep,2001,6(2):91-97
[28]Guicciardi ME,Deussing J,Miyoshi H,et al.Cathepsin B contributes to TNF-alpha-mediated hepatocyte by promoting mitochondrial release of cytochrome [J].J Clin Invest,2000,106(9):1127-1137
[29]Brunk UT. Svensson I[J].Redox Rep,1999,4(1):3-11
[30]Bidere N,Lorenzo HK,Carmona S,et al.Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis[J].J Biol Chem,2003,278(33):31401-31411
[31]吴燕婉,刘德瑜.溶酶体的细胞死亡通路[J].解剖学报,2007,38(4)：498-450
[32]Schestkowa O,Geisel D,Jacob R,et al.The catalytically inactive precursor of cathepsin D induces apoptosis in human fibroblasts and HeLa cells[J].J Cell Biochem, 2007,10(1):1558-1566
[33]Trincheri NF,Nicotra G,Follo C,et al.Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D[J].Carcin ogenesis, 2007,2(8):922-931
[34]VANACKER GJ,SALUJA AK,BHAGAT L,et al.CathepsinB inhibition prevents trypsinogen activation and reduces pancreatitis severity [J]. Am J Physiol Gastrointest Liver hysiol,2002,28(3):794-800
[1]Kuwano K,Hagimoto N,Tanaka T,et al.Expression of apoptosis-regulatory genes in epithelial cells in pulmonary fibrosisimice[J].Pathol,2000,190(2):221-229
[2]Kuwano K,Maeyama T,Inoshima I,et al.Increased circulating levels of soluble Fas ligand are correlated with disease activity in patients with fibrosing lung diseases[J]. Respirology,2002,7(1):15-21
[3]Domagala-Kulawik J,Droszcz P,Kraszewska I,et al.Expression of Fas antigen in the cells from bronchalveolar lavage fluid (BALF)[J].Folia Histochem Cytobiol,2000,38(4): 185-188
[4]Yin XM,Oltvai ZN,Veis-Novack DJ,et al.Bcl-2 gene family and the regulation of programmed cell death[J].Cold Spring Harb Symp Quant Biol,1994,59:387-393
[5]Okura T,Igase M,Kitami Y,et al.Platelet-derived growth factor induces apoptosis in vascular smooth muscle cells Roles of the Bcl-2 family[J].Biochim Biophys Acta,1998,1403 (3):245-253
[6]Orrenius S.Mitochondrial regulation of apoptotic cell death[J].Toxicol Lett,2004,149 (1-3):19-23
17] Schindler CK,Shinoda S,Simon RP,et al.Subcellular distribution of Bcl-2 family protei-ns and 14-3-3 within the hippocampus during seizure induced neuronal dealth in the rat[J] .Neurosci Lett,2004,356(3):163-166
[8]Han ming,Zhuo Zhang,Qi feng Zhang,et al.Reactive oxygen species and caspase activation mediate silica induced apoptosis in alveolar macrophages[J].Am J Physiol Lung Cell Mol Physiol,2001,280(1):10-17
[9]Miyashita T,Reed JC.Bcl-2 oneoProtein blocks chemotherapy indueed apoptosis in a human leukemia cell line[J].Blood,1993,81(1):151
[10]Almeida OF,Conde GL,Croehemore C,et al.Subtle shifts in the ratio between Pro and anti-apoptotic molecules after activation of corticosteroid receptors decide neuronal fate[J] .FASEB J,2000,14(5):779-790
[11]Uhal,BD.Fas and apoptosis in the alveolar epithelium:holes in the dike(editorial)[J]. AmJ Physiol,2001,281 (2),326-327
[12]Borge SVM,FalcaoH,LeitejuniorJH,et al.Fas ligand triggers pulmonary Silicosis[J].J Exp Med,2001,194(2):155-164
[13]Kuwano K,Hagimoto N,Kawasaki M,et al.Essential roles of the Fas, Fas ligand pathw ay in the development of pulmonary fibrosis[J].J ClinInvest,1999,104 (1):13-19