肿瘤坏死因子-α可溶性受体对矽肺纤维化的干预研究
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摘要
目的:本研究以大鼠矽肺动物模型为研究对象,通过测定矽肺相关生物活性介质并确定相关介质致纤维化的节点。初步探讨肿瘤坏死因子α(tumor necrosisαfactor,TNF-α)可溶性受体对二氧化硅(silicon dioxide,SiO2)粉尘致大鼠肺纤维化的防治作用以及相关细胞因子表达的影响。
方法:根据随机化原则将大鼠分为3个实验组,即对照组(control group,CL)、染矽尘组(silica-instilled group,SA)、干扰组(intervention group,IN),对照组、染矽尘组每组48只,干扰组10只。对照组大鼠气管内注入生理盐水,染矽尘组大鼠气管内注入矽尘混悬液1ml(50mg/ml),干扰组大鼠气管内注入矽尘混悬液1ml(50mg/ml)后于1、5、8d给予500ug TNF-α可溶性受体皮下注射。气管暴露法建立大鼠矽肺模型,模型建立后,对照组、染矽尘组于1d、3d、7d、14d、21d、28d 6个时间点分别取8只大鼠将其处死。干扰组于7d、14d 2个时间点取5只大鼠处死。HE染色观察大鼠肺组织形态学的变化。血细胞计数仪测定支气管肺泡灌洗液细胞总数。天狼猩红染色法结合偏振光显微镜观察肺组织Ⅰ、Ⅲ型胶原合成。用Image-Pro Plus Version 4.5 for windows TM图象分析系统对图像进行分析。一氧化氮(nitrogen monoxidum,NO)测定采用南京建成生物工程研究所NO试剂盒。酶联免疫吸附法( enzyme-labeledimmunosorbent assay,ELISA)检测对照组、染矽尘组和干扰组各时间点外周血核因子κB(nuclear factorκB,NF-κB)、转化生长因子β1(transforming growth factorβ1,TGF-β1)、白介素(interleukin-1,IL-1β)、TNF-α等4种生物活性介质表达水平。所有数值均用x±s表示,两组间采用t检验,不同组间的比较用单因素方差分析的LSD法,全部数据的统计学处理均采用SPSS15.0 for windows分析软件。
结果: 1 HE染色法证实气管暴露注入SiO2粉尘悬液成功建立矽肺模型。
2 TNF-α可溶性受体对染矽尘大鼠肺脏器系数的影响。与对照组比较,染矽尘组大鼠7d以后各时间点肺脏器系数高于对照组(P<0.05);与染矽尘组比较,干扰组大鼠各时间点肺脏器系数低于染矽尘组,但高于对照组,差异有显著性(P<0.05)。
3 TNF-α可溶性受体对染矽尘大鼠肺泡灌洗液(broncho alveolar lavage fluid,BALF)白细胞总数的影响。与对照组比较,染矽尘组相应时间点BALF白细胞总数均不同程度增高,在14d、21d、28d具有显著性差异(P<0.01);与染矽尘组比较,干扰组各相应时间点BALF白细胞总数均小于染矽尘组,在14d差异有显著性(P<0.05)。
4 TNF-α可溶性受体对染矽尘大鼠Ⅰ、Ⅲ型胶原合成的影响。与对照组比较,染矽尘组7d、14d、21d、28dⅠ型胶原均高于对照组,差异有显著性(P<0.01);与染矽尘组比较,干扰组各时间点Ⅰ胶原低于染矽尘组组,在14d差异有显著性(P<0.05)。与对照组比较,染矽尘组各时间点Ⅲ胶原在21d时上升陡然趋缓,仅在7d、14d、21d时有显著性差异(P<0.01);与染矽尘组比较,干扰组各时间点Ⅲ胶原均低于染矽尘组,但仅在14d差异有显著性(P<0.05)。
5 TNF-α可溶性受体对染矽尘大鼠外周血清NO表达的影响。与对照组比较,染矽尘组各时间点外周血清NO的浓度均高于对照组(P<0.01),在7d、14d、21d、28d具有显著性差异(P<0.05);与染矽尘组比较,干扰组各时间点外周血清NO浓度低于染矽尘组,在14d时差异有显著性(P<0.05)。
6 TNF-α可溶性受体对染矽尘大鼠外周血清IL-1β表达的影响。与对照组比较,染矽尘组各时间点外周血清IL-1β的浓度均高于对照组(P<0.01),但仅在3d、7d时有显著性差异(P<0.05)。与染矽尘组比较,干扰组各时间点外周血清IL-1β浓度低于染矽尘组,在7d时差异有显著性(P<0.01)。
7 TNF-α可溶性受体对染矽尘大鼠外周血清TGF-β表达的影响。与对照组比较,染矽尘组在14d、21d、28d时外周血清TGF-β的浓度高于对照组(P<0.01,P<0.05),其表达高峰在染矽尘后的第21d;与染矽尘组比较,干扰组各时间点外周血清TGF-β浓度低于染矽尘组,在14d时差异有显著性(P<0.05)。
8 TNF-α可溶性受体对染矽尘大鼠外周血清NF-κB表达的影响。与对照组比较,染矽尘组各时间点外周血清NF-κB的浓度均高于对照组(P<0.01,P<0.05),其表达高峰在染矽尘后的第21d;与染矽尘组比较,干扰组各时间点外周血清NF-κB浓度低于染矽尘组,差异有显著性(P<0.05)。
9 TNF-α可溶性受体对染矽尘大鼠外周血清TNF-α表达的影响。染矽尘组与干扰组各时间点外周血清TNF-α的浓度比较无统计学意义;与染矽尘组比较,干扰组各时间点外周血清TNF-α浓度低于染矽尘组,但差异无显著性。
结论:本研究认为:1大鼠支气管内滴入矽尘可引起大鼠肺组织炎性和纤维化性病理变化,并有矽结节形成。2 TNF-α可溶性受体可以缓解矽尘诱导的大鼠肺脏器系数的增加。3 TNF-α可溶性受体对矽尘诱导的大鼠BALF中细胞总数的显著增加有抑制作用。4 TNF-α可溶性受体能够抑制矽尘诱导的大鼠肺组织Ⅰ、Ⅲ型胶原的增加。5 TNF-α可溶性受体能够抑制矽尘诱导的大鼠肺外周血清中NO、IL-1β、TGF-β1、NF-κB、TNF-α的表达水平。
Objective: This study was designed to calculate 5 kind of biological activity medium in the blood serum of rats exposed to silica, and speculate the key profibrotic points. Primarily investigate the preventive and therapeutic effect of soluble TNF-αreceptor and the expression of other cytokines
Method: Wistar rats were randomly divided into three experimental groups: control group(n=48), silica group(n=48), and intervention group(n=20). silica-instilled groups were received lightly anesthetized with pentobarbital and received a single intratracheal instillation of silicon suspension of 1ml at the concentration of 50mg/ml. The control group was treated in the same way but injection of 1 ml sterilized saline instead. Rats in drug-treated groups were given soluble TNF-αreceptor (500ug) in the 1, 5, 8 day after operation. At 1d, 3d, 7d, 14d, 21d, 28d after establishment of the animal model, eight rats in control and silica-instilled group were sacrificed. At 7d, 14d after establishment of the animal model, five rats in intervention group were sacrificed. The changes of lung histomorphology of rats were observed by HE staining of histological section. Total cell count and differential cell counts in bronchoalveolar lavage fluid (BALF) were estimated by cytometer. Sirius red polarization microscopy detectsⅠandⅢcollagen. The NO activity was also assayed by spectrophotometer, using the kits purchased from Nanjing Jiancheng Bioengineering Institute. The expression of NF-κB, TGF-β1, IL-1β, TNF-αwas assayed by ELISA kit.
Result: 1 Histochemistry (HE staining) proved that the rat model of silicosis was successfully established by intratracheal infusion of silica dust suspension.
2 Exposure to silica can increased the coefficient of organ to body of rats at each time point, and at 7d, 14d, 21d, 28d this difference was significant(P<0.05). soluble TNF-αreceptor can ameliorated the silica-induced increase in the coefficient of organ to body of rats, this difference was significant at 7d, 14d (P<0.05).
3 Effect of soluble TNF-αreceptor on total white cell count in bronchoalveolar lavage fluid(BALF) of silica-treated rats. Compared with that of control group, total white cell count in BALF of silica goup, silica group at every time points increased, this difference was significant at 14d, 21d, 28d (P<0.01). Compared with that of silica group, total white cell count in BALF of Intervention group at 14d decreased significantly (P<0.05).
4 Effect of soluble TNF-αreceptor on synthesis ofⅠⅢcollogen of silica-treated rats. In comparison to control group,Ⅰcollagen positive area percent of lung in silica-induced group exhibited a sustained significant increase at 7d, 14d, 21d, 28d (P<0.01) , but the increase ofⅢcollagen positive area percent of lung in silica-induced groups began to be small at 21d, this increase was just significant at 7d, 14d, 21d (P<0.01). ForⅠcollagen, such increases were reduced significantly by TNF-αmonoclonal antibody treatment at 14d (P<0.05), and forⅢcollagen significant at 14d too (P<0.05).
5 Effect of soluble TNF-αreceptor on NO content in circumference blood serum of rats exposed to silica. Compared to the control, a relatively increase in the NO content in the serum was observed from silica-exposed rats, this increase was significant at 7d, 14d, 21d, 28d (P<0.05). soluble TNF-αreceptor treatment had obvious effect on the silica-induced increase in this parameter, this reduction was significant at 14d (P<0.05) .
6 Effect of soluble TNF-αreceptor on IL-1βprotein expression in circumference blood serum of rats exposed to silica. Compared to the control, a relatively smaller increase in the IL-1βcontent in the serum was observed from silica-exposed rats, this increase was just significant at 3d, 7d (P<0.05) . soluble TNF-αreceptor treatment had marked effect on the silica-induced increase in this parameter, this reduction was significant at 7d (P<0.05) .
7 Effect of soluble TNF-αreceptor on TGF-β1 protein expression in circumference blood serum of rats exposed to silica. In comparison to the control, there was a significant increase in TGF-β1 content in the serum from silica-exposed group rats at 14d, 21d, 28d (P<0.01, P<0.05), and the highest level of TGF-β1 was found at 21d. Compared with that of silica group, the level of TGF-β1 was significantly decreased at 14d by treatment of soluble TNF-αreceptor.
8 Effect of soluble TNF-αreceptor on NF-κB protein expression in circumference blood serum of rats exposed to silica. Compared to the control, the level of NF-κB increased significantly at at all time points(P<0.01, P<0.05). and it peaked at 3d after rats exposed to silica. such increases were reduced significantly by treatment of soluble TNF-αreceptor at 7d, 14d (P<0.05).
9 Effect of soluble TNF-αreceptor on TNF-αprotein expression in Circumference blood serum of rats exposed to silica. No significant differences were found in serum levels of TNF-αbetween rats received different treatment.
Conclusion: 1 The bronch of the rat instilled silica dust suspension can cause phlegmonosis and fibrosis pathological change in the lung tissues of the rat and form silicotic nodule. 2 soluble TNF-αreceptor can ameliorated the silica-induced increase in the coefficient of organ to body of rats. 3 The increases of the numbers of total cells in BALF in silica-treated rats were significantly suppressed by soluble TNF-αreceptor. 4 The formation ofⅠandⅢcollagen in lung tissues in silica-treated rats can be suppressed by soluble TNF-αreceptor. 5 soluble TNF-αreceptor may plays roles of anti-fiborosis through intervention the key cytokine such as TNF-α、NF-κB、TGF-β1、IL-1βin cytokine network in silicotic process.
方法:根据随机化原则将大鼠分为3个实验组,即对照组(control group,CL)、染矽尘组(silica-instilled group,SA)、干扰组(intervention group,IN),对照组、染矽尘组每组48只,干扰组10只。对照组大鼠气管内注入生理盐水,染矽尘组大鼠气管内注入矽尘混悬液1ml(50mg/ml),干扰组大鼠气管内注入矽尘混悬液1ml(50mg/ml)后于1、5、8d给予500ug TNF-α可溶性受体皮下注射。气管暴露法建立大鼠矽肺模型,模型建立后,对照组、染矽尘组于1d、3d、7d、14d、21d、28d 6个时间点分别取8只大鼠将其处死。干扰组于7d、14d 2个时间点取5只大鼠处死。HE染色观察大鼠肺组织形态学的变化。血细胞计数仪测定支气管肺泡灌洗液细胞总数。天狼猩红染色法结合偏振光显微镜观察肺组织Ⅰ、Ⅲ型胶原合成。用Image-Pro Plus Version 4.5 for windows TM图象分析系统对图像进行分析。一氧化氮(nitrogen monoxidum,NO)测定采用南京建成生物工程研究所NO试剂盒。酶联免疫吸附法( enzyme-labeledimmunosorbent assay,ELISA)检测对照组、染矽尘组和干扰组各时间点外周血核因子κB(nuclear factorκB,NF-κB)、转化生长因子β1(transforming growth factorβ1,TGF-β1)、白介素(interleukin-1,IL-1β)、TNF-α等4种生物活性介质表达水平。所有数值均用x±s表示,两组间采用t检验,不同组间的比较用单因素方差分析的LSD法,全部数据的统计学处理均采用SPSS15.0 for windows分析软件。
结果: 1 HE染色法证实气管暴露注入SiO2粉尘悬液成功建立矽肺模型。
2 TNF-α可溶性受体对染矽尘大鼠肺脏器系数的影响。与对照组比较,染矽尘组大鼠7d以后各时间点肺脏器系数高于对照组(P<0.05);与染矽尘组比较,干扰组大鼠各时间点肺脏器系数低于染矽尘组,但高于对照组,差异有显著性(P<0.05)。
3 TNF-α可溶性受体对染矽尘大鼠肺泡灌洗液(broncho alveolar lavage fluid,BALF)白细胞总数的影响。与对照组比较,染矽尘组相应时间点BALF白细胞总数均不同程度增高,在14d、21d、28d具有显著性差异(P<0.01);与染矽尘组比较,干扰组各相应时间点BALF白细胞总数均小于染矽尘组,在14d差异有显著性(P<0.05)。
4 TNF-α可溶性受体对染矽尘大鼠Ⅰ、Ⅲ型胶原合成的影响。与对照组比较,染矽尘组7d、14d、21d、28dⅠ型胶原均高于对照组,差异有显著性(P<0.01);与染矽尘组比较,干扰组各时间点Ⅰ胶原低于染矽尘组组,在14d差异有显著性(P<0.05)。与对照组比较,染矽尘组各时间点Ⅲ胶原在21d时上升陡然趋缓,仅在7d、14d、21d时有显著性差异(P<0.01);与染矽尘组比较,干扰组各时间点Ⅲ胶原均低于染矽尘组,但仅在14d差异有显著性(P<0.05)。
5 TNF-α可溶性受体对染矽尘大鼠外周血清NO表达的影响。与对照组比较,染矽尘组各时间点外周血清NO的浓度均高于对照组(P<0.01),在7d、14d、21d、28d具有显著性差异(P<0.05);与染矽尘组比较,干扰组各时间点外周血清NO浓度低于染矽尘组,在14d时差异有显著性(P<0.05)。
6 TNF-α可溶性受体对染矽尘大鼠外周血清IL-1β表达的影响。与对照组比较,染矽尘组各时间点外周血清IL-1β的浓度均高于对照组(P<0.01),但仅在3d、7d时有显著性差异(P<0.05)。与染矽尘组比较,干扰组各时间点外周血清IL-1β浓度低于染矽尘组,在7d时差异有显著性(P<0.01)。
7 TNF-α可溶性受体对染矽尘大鼠外周血清TGF-β表达的影响。与对照组比较,染矽尘组在14d、21d、28d时外周血清TGF-β的浓度高于对照组(P<0.01,P<0.05),其表达高峰在染矽尘后的第21d;与染矽尘组比较,干扰组各时间点外周血清TGF-β浓度低于染矽尘组,在14d时差异有显著性(P<0.05)。
8 TNF-α可溶性受体对染矽尘大鼠外周血清NF-κB表达的影响。与对照组比较,染矽尘组各时间点外周血清NF-κB的浓度均高于对照组(P<0.01,P<0.05),其表达高峰在染矽尘后的第21d;与染矽尘组比较,干扰组各时间点外周血清NF-κB浓度低于染矽尘组,差异有显著性(P<0.05)。
9 TNF-α可溶性受体对染矽尘大鼠外周血清TNF-α表达的影响。染矽尘组与干扰组各时间点外周血清TNF-α的浓度比较无统计学意义;与染矽尘组比较,干扰组各时间点外周血清TNF-α浓度低于染矽尘组,但差异无显著性。
结论:本研究认为:1大鼠支气管内滴入矽尘可引起大鼠肺组织炎性和纤维化性病理变化,并有矽结节形成。2 TNF-α可溶性受体可以缓解矽尘诱导的大鼠肺脏器系数的增加。3 TNF-α可溶性受体对矽尘诱导的大鼠BALF中细胞总数的显著增加有抑制作用。4 TNF-α可溶性受体能够抑制矽尘诱导的大鼠肺组织Ⅰ、Ⅲ型胶原的增加。5 TNF-α可溶性受体能够抑制矽尘诱导的大鼠肺外周血清中NO、IL-1β、TGF-β1、NF-κB、TNF-α的表达水平。
Objective: This study was designed to calculate 5 kind of biological activity medium in the blood serum of rats exposed to silica, and speculate the key profibrotic points. Primarily investigate the preventive and therapeutic effect of soluble TNF-αreceptor and the expression of other cytokines
Method: Wistar rats were randomly divided into three experimental groups: control group(n=48), silica group(n=48), and intervention group(n=20). silica-instilled groups were received lightly anesthetized with pentobarbital and received a single intratracheal instillation of silicon suspension of 1ml at the concentration of 50mg/ml. The control group was treated in the same way but injection of 1 ml sterilized saline instead. Rats in drug-treated groups were given soluble TNF-αreceptor (500ug) in the 1, 5, 8 day after operation. At 1d, 3d, 7d, 14d, 21d, 28d after establishment of the animal model, eight rats in control and silica-instilled group were sacrificed. At 7d, 14d after establishment of the animal model, five rats in intervention group were sacrificed. The changes of lung histomorphology of rats were observed by HE staining of histological section. Total cell count and differential cell counts in bronchoalveolar lavage fluid (BALF) were estimated by cytometer. Sirius red polarization microscopy detectsⅠandⅢcollagen. The NO activity was also assayed by spectrophotometer, using the kits purchased from Nanjing Jiancheng Bioengineering Institute. The expression of NF-κB, TGF-β1, IL-1β, TNF-αwas assayed by ELISA kit.
Result: 1 Histochemistry (HE staining) proved that the rat model of silicosis was successfully established by intratracheal infusion of silica dust suspension.
2 Exposure to silica can increased the coefficient of organ to body of rats at each time point, and at 7d, 14d, 21d, 28d this difference was significant(P<0.05). soluble TNF-αreceptor can ameliorated the silica-induced increase in the coefficient of organ to body of rats, this difference was significant at 7d, 14d (P<0.05).
3 Effect of soluble TNF-αreceptor on total white cell count in bronchoalveolar lavage fluid(BALF) of silica-treated rats. Compared with that of control group, total white cell count in BALF of silica goup, silica group at every time points increased, this difference was significant at 14d, 21d, 28d (P<0.01). Compared with that of silica group, total white cell count in BALF of Intervention group at 14d decreased significantly (P<0.05).
4 Effect of soluble TNF-αreceptor on synthesis ofⅠⅢcollogen of silica-treated rats. In comparison to control group,Ⅰcollagen positive area percent of lung in silica-induced group exhibited a sustained significant increase at 7d, 14d, 21d, 28d (P<0.01) , but the increase ofⅢcollagen positive area percent of lung in silica-induced groups began to be small at 21d, this increase was just significant at 7d, 14d, 21d (P<0.01). ForⅠcollagen, such increases were reduced significantly by TNF-αmonoclonal antibody treatment at 14d (P<0.05), and forⅢcollagen significant at 14d too (P<0.05).
5 Effect of soluble TNF-αreceptor on NO content in circumference blood serum of rats exposed to silica. Compared to the control, a relatively increase in the NO content in the serum was observed from silica-exposed rats, this increase was significant at 7d, 14d, 21d, 28d (P<0.05). soluble TNF-αreceptor treatment had obvious effect on the silica-induced increase in this parameter, this reduction was significant at 14d (P<0.05) .
6 Effect of soluble TNF-αreceptor on IL-1βprotein expression in circumference blood serum of rats exposed to silica. Compared to the control, a relatively smaller increase in the IL-1βcontent in the serum was observed from silica-exposed rats, this increase was just significant at 3d, 7d (P<0.05) . soluble TNF-αreceptor treatment had marked effect on the silica-induced increase in this parameter, this reduction was significant at 7d (P<0.05) .
7 Effect of soluble TNF-αreceptor on TGF-β1 protein expression in circumference blood serum of rats exposed to silica. In comparison to the control, there was a significant increase in TGF-β1 content in the serum from silica-exposed group rats at 14d, 21d, 28d (P<0.01, P<0.05), and the highest level of TGF-β1 was found at 21d. Compared with that of silica group, the level of TGF-β1 was significantly decreased at 14d by treatment of soluble TNF-αreceptor.
8 Effect of soluble TNF-αreceptor on NF-κB protein expression in circumference blood serum of rats exposed to silica. Compared to the control, the level of NF-κB increased significantly at at all time points(P<0.01, P<0.05). and it peaked at 3d after rats exposed to silica. such increases were reduced significantly by treatment of soluble TNF-αreceptor at 7d, 14d (P<0.05).
9 Effect of soluble TNF-αreceptor on TNF-αprotein expression in Circumference blood serum of rats exposed to silica. No significant differences were found in serum levels of TNF-αbetween rats received different treatment.
Conclusion: 1 The bronch of the rat instilled silica dust suspension can cause phlegmonosis and fibrosis pathological change in the lung tissues of the rat and form silicotic nodule. 2 soluble TNF-αreceptor can ameliorated the silica-induced increase in the coefficient of organ to body of rats. 3 The increases of the numbers of total cells in BALF in silica-treated rats were significantly suppressed by soluble TNF-αreceptor. 4 The formation ofⅠandⅢcollagen in lung tissues in silica-treated rats can be suppressed by soluble TNF-αreceptor. 5 soluble TNF-αreceptor may plays roles of anti-fiborosis through intervention the key cytokine such as TNF-α、NF-κB、TGF-β1、IL-1βin cytokine network in silicotic process.
引文
1 卫生部新闻办公室. 2004 年全国职业病报告情况和职业病危害形势
2 Piguet PF, Collart MA, Grau GE, et al. Requirement of tumor necrosis factor for development of silica-induced pulmonary fibrosis. Nature, 1990, 344: 245~247
3 Piguet PF, Vesin C. Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Eur Respir J, 1994, 7:515~518
4 Gosset P, Lassalle P, Vanhee D, et al . Production of tumor necrosis factor-alpha and interleukin-6 by human alveolar macrophages exposed in vitro to coal mine dust. Am J Respir Cell Mol Biol, 1991, 5:431~436
5 Vanhee D, Gosset P, Boitelle A, et al. Cytokines and cytokine network in silicosis and coal workers’ pneumoconiosis. Eur Respir J, 1995, 8:834~842.
6 Sullivan DE, Ferris M, Pociask D. Tumor necrosis factor- alpha induces transforming growth factor-beta1 expression in lung fibroblasts through the extracellular signal regulat- ed kinase pathway. Am J Respir Cell Mol Biol, 2005, 32 (4):342~349
7 冯国贤, 南培宏, 于建军, 等. 早期矽肺患者支气管肺泡灌洗液中生物标志物的研究. 中华劳动卫生职业病杂志,2000, 18:226~228
8 Reichert JM. Monoclonal antibodies in the clinic. NatBiotechnol, 2001, 19:819~822
9 王泊云,李玉松,黄高升,等. 病理学技术. 北京: 人民卫生出版社. 第一版, 2000, 128~130
10 Milita C, Gunilla NF, Prediman KS, et al. Pravastatin treatment increases collagen content and dreasea lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques. Circulation, 2001, 103:926~933
11 刘俊达. L-精氨酸一氧化氮代谢通路的生理功能与致病作用. 国外医学情报, 1995, 16(22):628
12 苗丽娟, 邹吉敏, 吴俊艳, 等. 矽肺患者血清NO、sIL- 2R、IL - 10测定及其意义. 中国煤炭工业医学杂志, 2002, 4:400~402
13 Mayoral P, Criado M, Hidalgo F, et al. Effects of chronic nitric oxide activation or inhibition on early hepatic fibrosis in rats with bile duct ligation. Clin Sci, 1999, 96:297~305.
14 Hayashi T, Stetler-Stevenson W G, Fleming MV, et a1. Immunohischemical study of metalloproteinases and their tissue inhibitors in the lungs of patients with diffuse alveolar damage and idiopathic pulmonary fibrosis. Am J Pathol, 1996, 149(4): 1241~1256
15 Raghow R, Streker LJ, Hudson LD, et a1. Extracellular matrix in normal and fibrotic human lungs. Am Rev Respir Dis, 1985, 131:281~289
16 牟晓燕, 辛洪涛, 靳长俊, 等. 肺纤维化鼠I型前胶原和Ⅲ型前胶原mRNA表达及芪丹颗粒剂的干预效应. 中国组织工程研究与临床康复, 2007, 29:5733~5736
17 郑向鹏, 滑炎卿, 张国桢, 等. Ⅲ型前胶原纤维在实验性特发性肺纤维化早期的动态研究. 上海医学, 2002, 25(4): 205~209
18 Kelley J, Chrin L, Coflesky JT, et a1. Localization of procollagen In the rat lung:biochemical quantitation of type I and Ⅲ procollagen in small airways, vessels, and parenchyma. Lung, 1989, 167:313~322
19 Shahzei S, Mulier B, Crombrugghe B, et a1. Enhanced Ⅲ procollagen gene expression during bleomycin-induced lung fibrosis. Thorax, 1993, 48:622~628
20 柴文戌, 李永春, 刘玉玲, 等. 博莱霉素致肺纤维化大鼠形态学变化的实验研究. 中国实验动物学报, 2003, 11(2): 77~80
21 Driscoll KE, Maurer J K. Cytokine and growth factor release by alveolar macrophages: potential biomarkers of pulmonary toxicity. Toxicol Pathol, 1991, 19:398~405
22 Savici D, He B, Geist LJ, et a1. Silica increases tumor necrosis factor(TNF)production, in part, by upregulating the TNF promoter. Exp Lung Res, 1994, 20:613~625
23 Andrea KH, Cynthia RT, Arti S, et a1. Activation of NF-κB-dependent gene expression by silica in lungs of luciferase reporter mice. Am J Physiol Lung Cell Mol Physiol, 2002, 282:L968~L975
24 XY Zhang, Sanae S, Tohru M, et a1. Antisense oligonucl- eotides to NF-κB improve survival in Bleomycin-inducedPneumopathy of the Mousr Am. J Respir Crit Care Med, 2000, 162:1561~1568
25 Evelyne G, Luis AO, XY Zou, et a1. Silica-induced apoptosis in murine macrophage involvement of tumor necrosis factor and nuclear factor-κB activation. Am J Respir Cell Mol Bio1, 2002, 27: 91~98
26 Kapanci Y, Desmouliere A, Pache JC, et a1. Cytoskeletal protein modulation in pulmonary alveolar myofibroblasts during idiopathic pulmonary fibrosis. Possible role of transforming growth factor beta and tumor necrosis factor alpha. Am J Respir Crit Care Med, 1995, 152, (22):163~ 169
27 Carlo V, MafiaAS, ValerioT, et a1. Diferent expression of TNF-α receptors and prostaglandin E2 production in normal and fibrotic lung fibroblasts potential implications for the evolution of the inflammatory process. Am J Respir Cell Mol Biol, 2000, 22(5):628~634
28 Tomas S, Wilkinson, Susan PP, et aI. Pro- and anti- inflammatory factors cooperate to control hyaluronan synthesis in lung fibroblasts. Am J Respir Cell Mol Biol, 2004, 31:92~99
29 Dionne S, Agata ID, Ruemmele, et al. Tyrosine kinase and MAPK inhibition of TNF-α and EGF-stimulated IEL-6 cell growth. Biochem Res Commum, 1998, 242 (2):146~150
30 Sun Tiezheng, Lu Housan, Yao Libo, et al. Role of proteintyrosine kinase in activation of MAPKs induced by TNF- α in fibroblast-like synoviocytes of rheumatoid arthritis. Chin J Microbiol Immunol, 2001, 21(1):70~74
31 Sime PJ, Marr RA, Gauldie D, et al. Transforming of tumor necrosis factor-α to rat lung induces severe pulmo- nary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-β1 and myofibroblasts. Am J Pathol, 1998, 153(3):825~832
32 宋明臣, 何冰, 邱忠民, 等. 肺纤维化大鼠肺泡Ⅱ型细胞中细胞因子的表达. 中华结核和呼吸杂志, 1998, 4:08~12
33 Denis M, Cormier Y, Fournier M, et al. Tumor necrosis factor plays an essential role in determining hypersensiti- vity pneumonitis in a mouse model. Am J Respir Cell Mol Biol, 1991, 5(5):477~483
34 Ye Q, Chen B, Tong Z, et al. Thalidomide reduces IL-18, IL-8 and TNF-alpha release from alveolar macrophages in interstitial lung disease. Eur Respir J, 2006, 28: 824~831
35 Kobl M, Margetts PJ, Anthony DC, et a1. Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest, 2001, 107:1529~1536
36 Bartram U, Christian P, The role of transforming growth factor β in lung development and disease. Chest, 2004, 125:754~765
37 蔡后荣, 戴令娟, 郑培德, 等. 博莱霉素致肺纤维化中TGF-β1 表达. 上海免疫学杂志, 2001, 21(2):95~97
38 Yu Y, Sweeney M, Zhan g S, et al. PDGF stimulate pulmonary vascular smooth muscle cell proliferation by upregulating TR PC6 expression. Am J Physiol Cell Physiol, 2003, 284(2):C3 l6~30
39 Schwarts MD, Moore EM, Moore FA, et al. Nuclear factor-JB is activated in alveolar macrophages from patients withacute respiratory distress syndrome. Crit Care Med, 1996, 24:1285~1292
40 Thanos D, Maniatis T. NF-Kappa B a lesson in family value Cell, 1995, 80:529~532
41 曾庆富, 牛海艳. 肺纤维化机制的研究进展. 中华病理学杂志, 2001, 30(5):371~373
42 Hellerbrand C, Jobin C, Limuro Y, et al. Inhibition of NF kappa B in activated rat hepatic stellate cell by proteasome inhibitors and I kappa B super-respressor. Hepatology, 1998, 27:1285~1295
43 齐曼古丽·吾守尔, 程继荣. 喘消雾化液对博莱霉素诱导大鼠肺纤维化模型IL-8、TNF-α水平的影响. 新疆医科大学学报, 2005, 6:499~502
44 陈莉, 姜志明, 刘秋芳, 等. 染石英尘大鼠肺灌洗液中TNF水平. 中华劳动卫生职业病杂志,1995,13(6):358~361
45 Sullivan DE, Ferris M, Pociask D. Tumor necrosis factor-alpha induces transforming growth factor-beta1 expression in lung fibroblasts through the extracellularsignal regulated kinase pathway. Am J Respir Cell Mol Biol, 2005, 32(4):342~349
46 lnayama M, Nishioka Y, Azuma M. A novel Ikappa B kinase-beta inhibitor ameliorates bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med, 2006, 173(9):1016~1022
47 Arnold R, Konig B, Galatti H, et a1. Cytokine (IL-8, IL-6, TNF-alpha) and soluble TNF receptor-I release from human peripheral blood mononuclear cells after respiratory syncytial virus infection. Immunology, 1995, 85(3):364~ 372
48 何凤生,主编. 中华职业医学. 北京:人民卫生出版社, 1999,814~815
49 Coker RK, Laurent GJ. Anticytokine approaches in pulmonary fibrosis: bringing factors into focus. Thorax, 1997, 52: 294~296
1 Baughman RP, Alabi Fo. Nonsteroidal therapy for idiopa- thic pulmonary fibrosis. Curr Opin Pulm Med, 2001, 7: 309~313
2 Kohler G,Milstein C. Continuous cultures of fused cells secretingantibody of predefined specificity. Nature,1975, 256:495~497
3 Chamow SM, Ashkenazi A. Immunoadhesins: principles and applications. Trends Biotechnol, 1996, 14:52~60
4 Arend WP, Malyak M, Guthridge CJ, et al. Inter- leukin-1 receptor antagonist: Role in biology. Annu Rev Immunol, 1998, 16:27~55
5 Bartram U,Christian P.The Role Of Transforming Growth Factor β in Lung Development and Disease. Chest, 2004, 125:754~765
6 蔡后荣, 戴令娟, 郑培德, 等. 博莱霉素致肺纤维化中TGF-β1表达. 上海免疫学杂志, 2001, 21(2):95~97
7 Yu Y, Sweeney M, Zhang S, et al. PDGF stimulate pul- monary vascular smooth muscle cell proliferation by up- regulating TR PC6 expression. Am J Physiol Cell Physiol, 2003, 284(2):C3 l6~30
8 Wang Q, Wang Y, Hyde DM, et al. Reduction of bleomycin induced lung fibrosis by transforming growth factor beta soluble receptor in hamsters. Thorax, 1999, 54(90):805~812
9 唐仕芳, 朱洪春, 李华强, 等. 外源性抗转化生长因子- β1抗体对新生大鼠高浓度氧致肺纤维化的影响. 中国循证儿科杂志, 2007, 2(2):132~137
10 何燕, 邓国忠, 高天. 肺纤维化细胞因子机制研究进展.中华创伤杂志, 2006, 22(6):477~480
11 Piguet PF,Collart MA ,Grau GE,et al. Requirement of tumor necrosis factor for development of silica-induced pulmonary fibrosis. Nature, 1990, 344:245~247
12 Piguet PF, Vesin C. Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Eur Respir J, 1994, 7:515~518
13 Gosset P, Lassalle P, Vanhee D, et al. Production of tumor necrosis factor-alpha and interleukin-6 by human alveolar macrophages exposed in vitro to coal mine dust. Am J Respir Cell Mol Biol, 1991, 5:431~436
14 Sullivan DE, Ferris M, Pociask D. Tumor necrosis factor- alpha induces transforming growth factor- beta1 express- ion in lung fibroblasts through the extracellular signal re- gulated kinase pathway. Am J Respir Cell Mol Biol, 2005, 32(4):342~349
15 Denis M, Cormier Y, Fournier M, et al. Tumor necrosis factor plays an essential role in determining hypersensiti- vity pneumonitis in a mouse model. Am J Respir Cell Mol Biol, 1991, 5(5):477~483
16 Ye Q, Chen B, Tong Z, et al. Thalidomide reduces IL-18, IL-8 and TNF-alpha release from alveolar macrophages in interstitial lung disease. Eur Respir J, 2006, 28:824~831
17 Reichert JM. Monoclonal antibodies in the clinic. Nat Biotechnol, 2001, 19:819~822
18 陈佰义. 肺泡巨噬细胞源细胞因子与肺纤维化. 国外医学呼吸系统分册, 1994, 14:185~187
19 Kobl M, Margetts PJ, Anthony DC, et al. Transient ex- pression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest, 2001, 107:1529~1536
20 Hutyrova B, Pantelidis P, Drabek J, et a1. Interleukin-1 gene cluster polymorphisms in sarcoidosis and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2002, 165(2):148~151
21 Piguet PF, Vesin C, Grau GE, et al. Interleukin-1 receptor antagonist( IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica. Cytokine, 1993, 5(1):57~61
22 Moussad EE, Brigstock DR. Connective tissue growth factor: What’s in a name ? Mol Genet Metab, 2000, 71: 276~292.
23 Lasky JA, Ortiz LA, Tonthat B, et al. Connective tissue growth factor mRNA expression in upregulated in bleomycine-induced lung fibrosis. Am J Physiol, 1998, 275:L365~L371
24 Twigg SM, Joly AH, Chen MM, et al. Connective tissue growth factor/IGF-binding protein-related protein-2 is a mediator in the induction of fibro- nectin by advanced glycosylation endproducts in human dermal fibroblast. Endocrinology, 2002, 143 (4):1260
25 Bonniaud P, Martin G, Margetts PJ, et a1. Connective tissue growth factor is crucial to inducing a profibrotic environment in “fibrosis- resistant” Balb/c mouse lungs. Am J Respir Cell Mol Biol, 2004, 31(5):510~516
26 Shiwen X, Pennington D, Holmes A, et al. Autocrine overexpression of CTGF maintains fibrosis: RDA analysis of fibrosis genes in systemic sclerosis. Exp Cell Res, 2000, 259(1):213
27 Maeyama, Takashige, Kazuyoshi Kuwano, et al. Attenuation of bleomycin-induced pneumopathy in mice by monoclonal antibody to interleukin-12. Am J Physiol Lung Cell Mol Physiol, 2001, 280: L1128~L1137
28 Li X, Erikson U. Novel PDGF family members:PDGF-C and PDGF-D. Cytokine Growth Factor Rev, 2003,14: 91~98
29 Melleni B, Lesur o, Bouhadiba T, et al. Effect of exposure to silica on human AM in supporting growth activity in type Ⅱ epithelial cells. Thorax, 1996, 51:781~786
30 Lasky JA, Tonthat B,L iu JY, et al. Upregulation of PDGF-alpha receptor precedes asbestos-induced lung fibrosis in rat. Am J Respir Crit Care Med, 1998, 157:1652~1657
31 Amir Abdollahi,Minglun Li,Gong Ping,et a1. Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. JEM,2005,201(6):925~935
32 Coker RK, Laurent GJ. Anticytokine approaches in pulmonary fibrosis: bringing factors into focus. Thorax, 1997, 52:294~296 .
2 Piguet PF, Collart MA, Grau GE, et al. Requirement of tumor necrosis factor for development of silica-induced pulmonary fibrosis. Nature, 1990, 344: 245~247
3 Piguet PF, Vesin C. Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Eur Respir J, 1994, 7:515~518
4 Gosset P, Lassalle P, Vanhee D, et al . Production of tumor necrosis factor-alpha and interleukin-6 by human alveolar macrophages exposed in vitro to coal mine dust. Am J Respir Cell Mol Biol, 1991, 5:431~436
5 Vanhee D, Gosset P, Boitelle A, et al. Cytokines and cytokine network in silicosis and coal workers’ pneumoconiosis. Eur Respir J, 1995, 8:834~842.
6 Sullivan DE, Ferris M, Pociask D. Tumor necrosis factor- alpha induces transforming growth factor-beta1 expression in lung fibroblasts through the extracellular signal regulat- ed kinase pathway. Am J Respir Cell Mol Biol, 2005, 32 (4):342~349
7 冯国贤, 南培宏, 于建军, 等. 早期矽肺患者支气管肺泡灌洗液中生物标志物的研究. 中华劳动卫生职业病杂志,2000, 18:226~228
8 Reichert JM. Monoclonal antibodies in the clinic. NatBiotechnol, 2001, 19:819~822
9 王泊云,李玉松,黄高升,等. 病理学技术. 北京: 人民卫生出版社. 第一版, 2000, 128~130
10 Milita C, Gunilla NF, Prediman KS, et al. Pravastatin treatment increases collagen content and dreasea lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques. Circulation, 2001, 103:926~933
11 刘俊达. L-精氨酸一氧化氮代谢通路的生理功能与致病作用. 国外医学情报, 1995, 16(22):628
12 苗丽娟, 邹吉敏, 吴俊艳, 等. 矽肺患者血清NO、sIL- 2R、IL - 10测定及其意义. 中国煤炭工业医学杂志, 2002, 4:400~402
13 Mayoral P, Criado M, Hidalgo F, et al. Effects of chronic nitric oxide activation or inhibition on early hepatic fibrosis in rats with bile duct ligation. Clin Sci, 1999, 96:297~305.
14 Hayashi T, Stetler-Stevenson W G, Fleming MV, et a1. Immunohischemical study of metalloproteinases and their tissue inhibitors in the lungs of patients with diffuse alveolar damage and idiopathic pulmonary fibrosis. Am J Pathol, 1996, 149(4): 1241~1256
15 Raghow R, Streker LJ, Hudson LD, et a1. Extracellular matrix in normal and fibrotic human lungs. Am Rev Respir Dis, 1985, 131:281~289
16 牟晓燕, 辛洪涛, 靳长俊, 等. 肺纤维化鼠I型前胶原和Ⅲ型前胶原mRNA表达及芪丹颗粒剂的干预效应. 中国组织工程研究与临床康复, 2007, 29:5733~5736
17 郑向鹏, 滑炎卿, 张国桢, 等. Ⅲ型前胶原纤维在实验性特发性肺纤维化早期的动态研究. 上海医学, 2002, 25(4): 205~209
18 Kelley J, Chrin L, Coflesky JT, et a1. Localization of procollagen In the rat lung:biochemical quantitation of type I and Ⅲ procollagen in small airways, vessels, and parenchyma. Lung, 1989, 167:313~322
19 Shahzei S, Mulier B, Crombrugghe B, et a1. Enhanced Ⅲ procollagen gene expression during bleomycin-induced lung fibrosis. Thorax, 1993, 48:622~628
20 柴文戌, 李永春, 刘玉玲, 等. 博莱霉素致肺纤维化大鼠形态学变化的实验研究. 中国实验动物学报, 2003, 11(2): 77~80
21 Driscoll KE, Maurer J K. Cytokine and growth factor release by alveolar macrophages: potential biomarkers of pulmonary toxicity. Toxicol Pathol, 1991, 19:398~405
22 Savici D, He B, Geist LJ, et a1. Silica increases tumor necrosis factor(TNF)production, in part, by upregulating the TNF promoter. Exp Lung Res, 1994, 20:613~625
23 Andrea KH, Cynthia RT, Arti S, et a1. Activation of NF-κB-dependent gene expression by silica in lungs of luciferase reporter mice. Am J Physiol Lung Cell Mol Physiol, 2002, 282:L968~L975
24 XY Zhang, Sanae S, Tohru M, et a1. Antisense oligonucl- eotides to NF-κB improve survival in Bleomycin-inducedPneumopathy of the Mousr Am. J Respir Crit Care Med, 2000, 162:1561~1568
25 Evelyne G, Luis AO, XY Zou, et a1. Silica-induced apoptosis in murine macrophage involvement of tumor necrosis factor and nuclear factor-κB activation. Am J Respir Cell Mol Bio1, 2002, 27: 91~98
26 Kapanci Y, Desmouliere A, Pache JC, et a1. Cytoskeletal protein modulation in pulmonary alveolar myofibroblasts during idiopathic pulmonary fibrosis. Possible role of transforming growth factor beta and tumor necrosis factor alpha. Am J Respir Crit Care Med, 1995, 152, (22):163~ 169
27 Carlo V, MafiaAS, ValerioT, et a1. Diferent expression of TNF-α receptors and prostaglandin E2 production in normal and fibrotic lung fibroblasts potential implications for the evolution of the inflammatory process. Am J Respir Cell Mol Biol, 2000, 22(5):628~634
28 Tomas S, Wilkinson, Susan PP, et aI. Pro- and anti- inflammatory factors cooperate to control hyaluronan synthesis in lung fibroblasts. Am J Respir Cell Mol Biol, 2004, 31:92~99
29 Dionne S, Agata ID, Ruemmele, et al. Tyrosine kinase and MAPK inhibition of TNF-α and EGF-stimulated IEL-6 cell growth. Biochem Res Commum, 1998, 242 (2):146~150
30 Sun Tiezheng, Lu Housan, Yao Libo, et al. Role of proteintyrosine kinase in activation of MAPKs induced by TNF- α in fibroblast-like synoviocytes of rheumatoid arthritis. Chin J Microbiol Immunol, 2001, 21(1):70~74
31 Sime PJ, Marr RA, Gauldie D, et al. Transforming of tumor necrosis factor-α to rat lung induces severe pulmo- nary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-β1 and myofibroblasts. Am J Pathol, 1998, 153(3):825~832
32 宋明臣, 何冰, 邱忠民, 等. 肺纤维化大鼠肺泡Ⅱ型细胞中细胞因子的表达. 中华结核和呼吸杂志, 1998, 4:08~12
33 Denis M, Cormier Y, Fournier M, et al. Tumor necrosis factor plays an essential role in determining hypersensiti- vity pneumonitis in a mouse model. Am J Respir Cell Mol Biol, 1991, 5(5):477~483
34 Ye Q, Chen B, Tong Z, et al. Thalidomide reduces IL-18, IL-8 and TNF-alpha release from alveolar macrophages in interstitial lung disease. Eur Respir J, 2006, 28: 824~831
35 Kobl M, Margetts PJ, Anthony DC, et a1. Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest, 2001, 107:1529~1536
36 Bartram U, Christian P, The role of transforming growth factor β in lung development and disease. Chest, 2004, 125:754~765
37 蔡后荣, 戴令娟, 郑培德, 等. 博莱霉素致肺纤维化中TGF-β1 表达. 上海免疫学杂志, 2001, 21(2):95~97
38 Yu Y, Sweeney M, Zhan g S, et al. PDGF stimulate pulmonary vascular smooth muscle cell proliferation by upregulating TR PC6 expression. Am J Physiol Cell Physiol, 2003, 284(2):C3 l6~30
39 Schwarts MD, Moore EM, Moore FA, et al. Nuclear factor-JB is activated in alveolar macrophages from patients withacute respiratory distress syndrome. Crit Care Med, 1996, 24:1285~1292
40 Thanos D, Maniatis T. NF-Kappa B a lesson in family value Cell, 1995, 80:529~532
41 曾庆富, 牛海艳. 肺纤维化机制的研究进展. 中华病理学杂志, 2001, 30(5):371~373
42 Hellerbrand C, Jobin C, Limuro Y, et al. Inhibition of NF kappa B in activated rat hepatic stellate cell by proteasome inhibitors and I kappa B super-respressor. Hepatology, 1998, 27:1285~1295
43 齐曼古丽·吾守尔, 程继荣. 喘消雾化液对博莱霉素诱导大鼠肺纤维化模型IL-8、TNF-α水平的影响. 新疆医科大学学报, 2005, 6:499~502
44 陈莉, 姜志明, 刘秋芳, 等. 染石英尘大鼠肺灌洗液中TNF水平. 中华劳动卫生职业病杂志,1995,13(6):358~361
45 Sullivan DE, Ferris M, Pociask D. Tumor necrosis factor-alpha induces transforming growth factor-beta1 expression in lung fibroblasts through the extracellularsignal regulated kinase pathway. Am J Respir Cell Mol Biol, 2005, 32(4):342~349
46 lnayama M, Nishioka Y, Azuma M. A novel Ikappa B kinase-beta inhibitor ameliorates bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med, 2006, 173(9):1016~1022
47 Arnold R, Konig B, Galatti H, et a1. Cytokine (IL-8, IL-6, TNF-alpha) and soluble TNF receptor-I release from human peripheral blood mononuclear cells after respiratory syncytial virus infection. Immunology, 1995, 85(3):364~ 372
48 何凤生,主编. 中华职业医学. 北京:人民卫生出版社, 1999,814~815
49 Coker RK, Laurent GJ. Anticytokine approaches in pulmonary fibrosis: bringing factors into focus. Thorax, 1997, 52: 294~296
1 Baughman RP, Alabi Fo. Nonsteroidal therapy for idiopa- thic pulmonary fibrosis. Curr Opin Pulm Med, 2001, 7: 309~313
2 Kohler G,Milstein C. Continuous cultures of fused cells secretingantibody of predefined specificity. Nature,1975, 256:495~497
3 Chamow SM, Ashkenazi A. Immunoadhesins: principles and applications. Trends Biotechnol, 1996, 14:52~60
4 Arend WP, Malyak M, Guthridge CJ, et al. Inter- leukin-1 receptor antagonist: Role in biology. Annu Rev Immunol, 1998, 16:27~55
5 Bartram U,Christian P.The Role Of Transforming Growth Factor β in Lung Development and Disease. Chest, 2004, 125:754~765
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