小白菊内酯对大鼠肝脏缺血再灌注损伤的保护作用及其机制的实验研究
|
摘要
第一部分小白菊内酯对枯否细胞分泌功能的影响
目的：研究小白菊内酯对枯否细胞释放炎性因子的影响并阐明其作用机制。
方法：采用胶原酶原位灌注法分离及提纯枯否细胞。将细胞分为3组：A组为对照组(Control group),培养正常大鼠KCs: B组为LPS刺激组(LPS group),在开始培养KCs时,培养液中加入终浓度为10mg/1LPS；C组为LPS+PTN组(PTN group),培养液中先加入5μmol/l PTN培养1h,然后再加入lOmg/1LPS。各组分别于培养3h后获取标本作相应指标检测,重复8次实验后取其均值(n=8)。将各组细胞置于倒置的显微镜下观察其形态变化,台盼蓝拒染实验判断细胞活力,抗ED-2免疫组化染色检测纯度,ELISA法检测细胞上清液中IL-1和TNF-a的水平,EMSA法检测NF-κB DNA结合活性。
结果：新分离的KCs在倒置的显微镜下呈球形,悬浮于培养基中;约6h后,大部分细胞贴壁呈扁圆形,少数细胞伸出伪足；24h后大部分细胞伸出伪足,呈典型星形和多角形,细胞体积明显变大；各组枯否细胞分离纯度均为>90%,活性>96%。与A组比较,B组IL-1和TNF-a水平明显增高(P<0.05)；与B组比较,C两组IL-1和TNF-a水平明显较低(P<0.05)；与A组比较,B组NF-κB DNA结合活性显著增高(P<0.05)；与B组比较,C组NF-κB DNA结合活性显著降低(P<0.05)。
结论：
1、在LPS的刺激下,肝脏枯否细胞活化而释放大量炎性因子；
2、小白菊内酯可能通过下调NF-kB活性,抑制肝脏枯否细胞的活化,减少炎性因子的大量释放。
第二部分小白菊内酯对大鼠肝脏缺血再灌注损伤的作用
目的：研究小白菊内酯在大鼠肝脏缺血再灌注损伤中的作用及其相关机制。
方法：将健康雄性SD大鼠随机分为四组(n=18)：假手术组(A)、对照组(B)、小白菊内酯小剂量干预组(C)和小白菊内酯大剂量干预组(D)。缺血前10min分别给予小剂量干预组和大剂量干预组大鼠腹腔注射250和500μg/kg的小白菊内酯,建立肝左、中叶70%部分肝缺血再灌注模型,假手术组给予同样体积的0.1%DMSO。肝脏缺血90min后对缺血肝叶进行再灌注,分别于再灌注后2、6、24h收集血液及缺血肝叶组织标本,每个时点n=6。检测血清ALT、AST水平,肝组织HE染色后置光镜下观察病理形态学变化,并根据Suzuki's评分标准进行病理损伤半定量评分,ELISA检测肝组织中MPO活力和MDA含量检测。
结果：与对照组相比,小剂量和大剂量小白菊内酯干预组血清ALT、AST水平均明显下降(P<0.05),大剂量干预组较小剂量组更明显(P<0.05)；与对照组相比,小白菊内酯干预后肝脏组织病理学表现明显改善,Suzuki's评分明显降低(P<0.05),大剂量干预组较小剂量组更明显(P<0.05)；小白菊内酯干预后肝组织MPO活力和MDA含量较对照组明显下降(P<0.05),大剂量干预组较小剂量干预组更明显(P<0.05)。
结论：
1、小白菊内酯干预能有效改善大鼠肝脏缺血再灌注损伤引起的肝功能和肝脏病理损害；
2、小白菊内酯能抑制氧自由基的损伤作用,减轻脂质过氧化引发的组织损伤；
3、小白菊内酯干预能够减少大鼠肝脏缺血再灌注损伤后中性粒细胞的聚集浸润和活化,从而减轻炎症反应。
第三部分小白菊内酯在大鼠肝脏缺血再灌注损伤中对IKK/NF-kB信号通路的影响
目的：通过观察小白菊内酯对肝脏缺血再灌注损伤中IKK/NF-kB信号通路的影响,探讨其缺血再灌注保护作用的分子机制。
方法：将健康雄性SD大鼠随机分为三组(n=6)：假手术组(A)、对照组(B)、小白菊内酯干预组(C)。缺血前10min给予小白菊内酯干预组大鼠腹腔注射500μg/kg的小白菊内酯,建立肝左、中叶70%部分肝缺血再灌注模型,假手术组给予同样体积的0.1%DMSO。肝脏缺血90min后对缺血肝叶进行再灌注,于再灌注后6h收集血液及缺血肝叶组织标本。ELISA检测血清中TNF-α、ICAM-1及MIP-2水平；RT-PCR检测肝组织TNF-α、ICAM-1及MIP-2 mRNA的表达；EMSA法检测肝组织NF-kB DNA结合活性；Werstern blotting测定肝组织细胞核内NF-kB p65和肝组织中p-IKKser180/βser181和IkBα蛋白的表达。
结果：与对照组(B)比较,小白菊内酯干预后血清TNF-α、ICAM-1及MIP-2水平和肝组织TNF-α、ICAM-1及MIP-2 mRNA的表达均明显下降(P<0.05)；与对照组(B)比较,小白菊内酯干预组(B)肝组织NF-kB DNA结合活性和肝组织细胞核内NF-kB p65蛋白及肝脏组织p-IKKser180/βser181蛋白水平较对照组(B)显著降低(P<0.05),肝脏组织IKBa含量明显升高(P<0.05)。
结论：
小白菊内酯可能通过抑制IKK/NF-kB信号通路减少肝脏缺血再灌注损伤中炎性相关基因和蛋白表达。
第四部分JAK2/STAT3信号通路在大鼠肝脏缺血再灌注损伤的作用及小白菊内酯对JAK2/STAT3信号通路的影响
目的：探讨JAK/STAT信号通路在肝脏缺血再灌注损伤中的活化规律及作用机制,并观察小白菊内酯对JAK2/STAT3信号通路的影响,深入探讨其对缺血再灌注保护作用的分子机制。
方法：将健康雄性SD大鼠随机分为四组(n=6)：假手术组(A)、对照组(B)、AG490干预组(C)、小白菊内酯干预组(D)。缺血前10min分别给予AG490干预组大鼠腹腔注射500μg/kg的AG4901mg/kg和小白菊内酯干预组大鼠腹腔注射500μg/kg的小白菊内酯,建立肝左、中叶70%部分肝缺血再灌注模型,假手术组给予同样体积的0.1%DMSO。肝脏缺血90min后对缺血肝叶进行再灌注,于再灌注后6h收集血液及缺血肝叶组织标本。免疫组织化学染色和Werstern blotting检测p-JAk2和p-STAT3蛋白表达；RT-PCR检测肝组织TNF-amRNA的表达；ELISA检测血清中TNF-a水平。
结果：与假手术组(A)比较,对照组(B)肝组织p-JAk2和p-STAT3蛋白水平和TNF-amRNA的表达水平及血清中TNF-a水平明显升高(P<0.05)；与对照组(B)比较,AG490干预组(C)肝组织p-JAk2和p-STAT3蛋白水平和TNF-amRNA的表达水平及血清中TNF-a水平明显降低(P<0.05)；与对照组(B)比较,小白菊内酯干预组(D)肝组织p-JAk2和p-STAT3蛋白水平和TNF-amRNA的表达水平及血清中TNF-a水平明显降低(P<0.05)。
结论：
1、JAK2/STAT3信号通路在肝脏缺血再灌注损伤中激活；
2、阻断JAK2/STAT3信号通路的异常激活可能抑制肝脏缺血再灌注损伤中炎性相关基因和蛋白表达；
3、小白菊内酯可能通过抑制JAK2/STAT3信号通路减少肝脏缺血再灌注损伤中炎性相关基因和蛋白表达。
Part 1:Effects of parthenolide on the secretion function of Kupffer cells
Objective:To explore the effects of parthenolide on the inflammatory cytokines expression in kupffer cells and to elucidate the probable mechanism of the effects.
Methods:Kupffer Cells were isolated and purified by situ collagenase perfusion. The isolated and purified cells were then divided into 3 groups:Group A, control group in which kupffer cells were cultured normally; Group B, LPS group in which 10mg/l LPS was added into the nutrient solution; Group C, PTN group in which 5μmol/l parthenolide was added into the nutrient solution 1h before 10mg/l LPS was added. After 3h stimulating to each group, the morphology of kupffer cells were measured by an inverted microscope, the activity of kupffer cell was measured by trypan blue staining, the purity was measured by anti ED-2 immunohistochemical staining, the concentration of IL-1 and TNF-a in the supernatant were measured by ELISA, the NF-kB DNA binding activity were measured by EMSA. Treatments in each group were repeated for 8 times to obtain the mean value of each index as the final result.
Results:The shape of newly isolated kupffer cells were sphere like, suspending in the nutrient solution; Most of them became flat and adhered to the wall, pseudopodium formation occurred in few cells; After about 24h, pseudopodium formation occurred in most of the cells and all cells were extended totally with bigger size in star-shape or polygonal shape; The purity ratio of each group was 90%, and the activity ratio was more than 96%. Concentration of TNF-a and IL-1 of the nutrient solution in group B is much higher than that of group A (p＜0.05), Concentration of TNF-αand IL-1 of the nutrient solution in group C is much lower than that of group A,Group B was higher in DNA binding activity of NF-kB than that of group A (P＜0.05), Group C was lower in DNA binding activity of NF-kB than that of group B (P＜0.05).
Conclusions:
(1) LPS can activate the kupffer cells and as a result induce its ability of releasing cytokines.
(2) Parthenolide can inhibit the activation of NF-kB in kupffer cells and as a result reduce its ability of releasing cytokines.
Part 2:Effect of parthenolide on hepatic ischemia-reperfusion injury
Objective:To investigate the effect and related mechanisms of parthenolide on liver function and hepatic tissues in the liver ischemia-reperfusion injury.
Methods:healthy male SD rats were randomized into 4 groups (n=18):sham-operated group(A), model control group(B), low dosage of parthenolide treatment group(C) and large dosage of parthenolide treatment group(D).10 minutes before Ischemia, treatment group rats were intraperitoneally injected 250 or 500μg/kg parthenolide.Then the hepatic ischemia-reperfusion model of 70 percent of liver, including the left and middle hepatie lobe, were established.The I/R model control group and were administered with the same volume of DMSO.After 90 min ischemia,6 cases rats of each group were killed at 2h,6h and 24h after residual liver reperfusion respectively, blood and liver tissue samples were collected from the experimental groups. Serum levels of ALT and AST were measured, part of the liver tissues were made into paraffin-embedded specimens to detect rat liver histological change and grade hepatic IRI(Suzuki's score), the content of MDA and the activity of MPO in liver tissues were detected by ELISA.
Results:Compared with the model control group,serum ALT and AST in both treatment group of the low and large dosage parthenolide were significantly decreased(P<0.05),even lower in the large dosage group than in the low dosage group(P<0.05). Hepatic pathology performance was improved and Suzuki's scores was decreased significantly in both dosage group (P<0.05), the large dosage group is more significantly. The content of MDA and the activity of MPO in liver tissues were significantly decreased in both treatment groups when compared with the I/R model control group(P<0.05), also lower in the large dosage group than in the low dosage group(P<0.05).
Conclusion:
(1) Treatment with parthenolide can effectively improve the rat liver function and liver pathology damage induced by liver ischemia-reperfusion injury;
(2) Intervention with parthenolide can inhibit the effection of oxygen free radicals, and reduce the tissues damage induced by lipid peroxidation;
(3) Intervention with parthenolide can reduce the aggregation, infiltration and activation of neutrophil in the rat liver induced by ischemia-reperfusion injury,thereby reducing inflammatory response.
Part 3:Effects of parthenolide on IKK/NF-κB signaling pathway in the rat hepatic ischemia-reperfusion injury
Objective:To study the molecular mechanism of the effect of parthenolide inhibiting the inflammation signaling pathway of IKK/ NF-κB in the rat hepatic ischemia-reperfusion injury.
Methods:healthy male SD rats were randomized into 3 groups (n=6):sham-operated group(A), model control group(B), parthenolide treatment group(C).10 minutes before Ischemia, treatment group rats were intraperitoneally injected 500μg/kg parthenolide.Then the hepatic ischemia-reperfusion model of 70 percent of liver, including the left and middle hepatie lobe, were established.The I/R model control group and were administered with the same volume of DMSO.After 90 min ischemia and 6h reperfusion,6 cases rats of each group were killed respectively, blood and liver tissue samples were collected from the experimental groups. Serum levels of TNF-a, MIP-2 and ICAM-1were measured by ELISA,TNF-a, MIP-2 and ICAM-1mRNA of liver were measured by RT-PCR, the NF-kB DNA binding activity were measured by EMSA, the level of protein of NF-kB p65 in caryon and p-IKKser180/βser181 and IkBαin the liver tissues were measured by Western blot.
Results:Compared with the model control group, the levels of TNF-a, MIP-2 and ICAM-1 in serum and mRNA of liver in parthenolide treatment group were significantly decreased(P<0.05);Compared with the model control group, the NF-kB DNA binding activity, the level of protein of NF-kB p65 in caryon, the level of protein of p-IKKser180/βser181 in parthenolide treatment group were significantly decreased(P<0.05), the level of protein of IkBbαwere significantly increased(P<0.05).
Conclusion:
Parthenolide reduces the expression of inflammatory gene and protein in hepatic ischemia-reperfusion injury probablely by suppressing IKK/NF-kB signal pathway activation.
Part 4:Effects of JAK2/STAT3 signal pathway on the rat hepatic ischemia-reperfusion injury and effects of parthenolide on JAK2/STAT3 signaling pathway
Objective:To identify the role of the activated JAK2/STAT3 in rat hepatic ischemia-reperfusion injury and investigate the mechanisms of JAK2/STAT3 signal pathway causing hepatic damage,to study the molecular mechanism of the effect of parthenolide on the JAK2/STAT3 signaling pathway in the rat hepatic ischemia-reperfusion injury.
Methods:healthy male SD rats were randomized into 4 groups (n=6):sham-operated group(A), model control group(B), AG490 treatment group(C) and parthenolide treatment group(D).10 minutes before Ischemia, AG490 treatment group and parthenolide treatment group treatment group rats were intraperitoneally injected lmg/kg AG490 and 500μg/kg parthenolide respectively.Then the hepatic ischemia-reperfusion model of 70 percent of liver, including the left and middle hepatie lobe, were established.The I/R model control group and were administered with the same volume of DMSO. After 90 min ischemia,6 cases rats of each group were killed at 6h after residual liver reperfusion respectively, blood and liver tissue samples were collected from the experimental groups. The level of protein of p-JAk2 and p-STAT3 were measured by immunohistochemical method and Western blot, TNF-amRNA of liver were measured by RT-PCR, Serum levels of TNF-αwere measured by ELISA.
Results:Compared with the sham-operated group, the levels of protein of pJAk2 and pSTAT3, TNF-amRNA of liver, serum levels of TNF-a in model control group(B)were significantly increased(P<0.05); compared with the model control group(B), the levels of protein of p-JAk2 and p-STAT3, TNF-amRNA of liver, serum levels of TNF-a in AG490 treatment group(C) were significantly increased(p<0.05); compared with the model control group(B), the levels of protein of p-JAk2 and p-STAT3, TNF-amRNA of liver, serum levels of TNF-a in parthenolide treatment group(D) were significantly increased(p<0.05).
Conclusion:
(1) JAK2/STAT3 signal pathway were activated in hepatic ischemia-reperfusion injury;
(2) suppressing JAK2/STAT3 signal pathway activation probablely reduce the expression of inflammatory gene and protein in hepatic ischemia-reperfusion injury;
(3) Parthenolide reduces the expression of inflammatory gene and protein in hepatic ischemia-reperfusion injury probablely by suppressing JAK2/STAT3 signal pathway activation.
目的：研究小白菊内酯对枯否细胞释放炎性因子的影响并阐明其作用机制。
方法：采用胶原酶原位灌注法分离及提纯枯否细胞。将细胞分为3组：A组为对照组(Control group),培养正常大鼠KCs: B组为LPS刺激组(LPS group),在开始培养KCs时,培养液中加入终浓度为10mg/1LPS；C组为LPS+PTN组(PTN group),培养液中先加入5μmol/l PTN培养1h,然后再加入lOmg/1LPS。各组分别于培养3h后获取标本作相应指标检测,重复8次实验后取其均值(n=8)。将各组细胞置于倒置的显微镜下观察其形态变化,台盼蓝拒染实验判断细胞活力,抗ED-2免疫组化染色检测纯度,ELISA法检测细胞上清液中IL-1和TNF-a的水平,EMSA法检测NF-κB DNA结合活性。
结果：新分离的KCs在倒置的显微镜下呈球形,悬浮于培养基中;约6h后,大部分细胞贴壁呈扁圆形,少数细胞伸出伪足；24h后大部分细胞伸出伪足,呈典型星形和多角形,细胞体积明显变大；各组枯否细胞分离纯度均为>90%,活性>96%。与A组比较,B组IL-1和TNF-a水平明显增高(P<0.05)；与B组比较,C两组IL-1和TNF-a水平明显较低(P<0.05)；与A组比较,B组NF-κB DNA结合活性显著增高(P<0.05)；与B组比较,C组NF-κB DNA结合活性显著降低(P<0.05)。
结论：
1、在LPS的刺激下,肝脏枯否细胞活化而释放大量炎性因子；
2、小白菊内酯可能通过下调NF-kB活性,抑制肝脏枯否细胞的活化,减少炎性因子的大量释放。
第二部分小白菊内酯对大鼠肝脏缺血再灌注损伤的作用
目的：研究小白菊内酯在大鼠肝脏缺血再灌注损伤中的作用及其相关机制。
方法：将健康雄性SD大鼠随机分为四组(n=18)：假手术组(A)、对照组(B)、小白菊内酯小剂量干预组(C)和小白菊内酯大剂量干预组(D)。缺血前10min分别给予小剂量干预组和大剂量干预组大鼠腹腔注射250和500μg/kg的小白菊内酯,建立肝左、中叶70%部分肝缺血再灌注模型,假手术组给予同样体积的0.1%DMSO。肝脏缺血90min后对缺血肝叶进行再灌注,分别于再灌注后2、6、24h收集血液及缺血肝叶组织标本,每个时点n=6。检测血清ALT、AST水平,肝组织HE染色后置光镜下观察病理形态学变化,并根据Suzuki's评分标准进行病理损伤半定量评分,ELISA检测肝组织中MPO活力和MDA含量检测。
结果：与对照组相比,小剂量和大剂量小白菊内酯干预组血清ALT、AST水平均明显下降(P<0.05),大剂量干预组较小剂量组更明显(P<0.05)；与对照组相比,小白菊内酯干预后肝脏组织病理学表现明显改善,Suzuki's评分明显降低(P<0.05),大剂量干预组较小剂量组更明显(P<0.05)；小白菊内酯干预后肝组织MPO活力和MDA含量较对照组明显下降(P<0.05),大剂量干预组较小剂量干预组更明显(P<0.05)。
结论：
1、小白菊内酯干预能有效改善大鼠肝脏缺血再灌注损伤引起的肝功能和肝脏病理损害；
2、小白菊内酯能抑制氧自由基的损伤作用,减轻脂质过氧化引发的组织损伤；
3、小白菊内酯干预能够减少大鼠肝脏缺血再灌注损伤后中性粒细胞的聚集浸润和活化,从而减轻炎症反应。
第三部分小白菊内酯在大鼠肝脏缺血再灌注损伤中对IKK/NF-kB信号通路的影响
目的：通过观察小白菊内酯对肝脏缺血再灌注损伤中IKK/NF-kB信号通路的影响,探讨其缺血再灌注保护作用的分子机制。
方法：将健康雄性SD大鼠随机分为三组(n=6)：假手术组(A)、对照组(B)、小白菊内酯干预组(C)。缺血前10min给予小白菊内酯干预组大鼠腹腔注射500μg/kg的小白菊内酯,建立肝左、中叶70%部分肝缺血再灌注模型,假手术组给予同样体积的0.1%DMSO。肝脏缺血90min后对缺血肝叶进行再灌注,于再灌注后6h收集血液及缺血肝叶组织标本。ELISA检测血清中TNF-α、ICAM-1及MIP-2水平；RT-PCR检测肝组织TNF-α、ICAM-1及MIP-2 mRNA的表达；EMSA法检测肝组织NF-kB DNA结合活性；Werstern blotting测定肝组织细胞核内NF-kB p65和肝组织中p-IKKser180/βser181和IkBα蛋白的表达。
结果：与对照组(B)比较,小白菊内酯干预后血清TNF-α、ICAM-1及MIP-2水平和肝组织TNF-α、ICAM-1及MIP-2 mRNA的表达均明显下降(P<0.05)；与对照组(B)比较,小白菊内酯干预组(B)肝组织NF-kB DNA结合活性和肝组织细胞核内NF-kB p65蛋白及肝脏组织p-IKKser180/βser181蛋白水平较对照组(B)显著降低(P<0.05),肝脏组织IKBa含量明显升高(P<0.05)。
结论：
小白菊内酯可能通过抑制IKK/NF-kB信号通路减少肝脏缺血再灌注损伤中炎性相关基因和蛋白表达。
第四部分JAK2/STAT3信号通路在大鼠肝脏缺血再灌注损伤的作用及小白菊内酯对JAK2/STAT3信号通路的影响
目的：探讨JAK/STAT信号通路在肝脏缺血再灌注损伤中的活化规律及作用机制,并观察小白菊内酯对JAK2/STAT3信号通路的影响,深入探讨其对缺血再灌注保护作用的分子机制。
方法：将健康雄性SD大鼠随机分为四组(n=6)：假手术组(A)、对照组(B)、AG490干预组(C)、小白菊内酯干预组(D)。缺血前10min分别给予AG490干预组大鼠腹腔注射500μg/kg的AG4901mg/kg和小白菊内酯干预组大鼠腹腔注射500μg/kg的小白菊内酯,建立肝左、中叶70%部分肝缺血再灌注模型,假手术组给予同样体积的0.1%DMSO。肝脏缺血90min后对缺血肝叶进行再灌注,于再灌注后6h收集血液及缺血肝叶组织标本。免疫组织化学染色和Werstern blotting检测p-JAk2和p-STAT3蛋白表达；RT-PCR检测肝组织TNF-amRNA的表达；ELISA检测血清中TNF-a水平。
结果：与假手术组(A)比较,对照组(B)肝组织p-JAk2和p-STAT3蛋白水平和TNF-amRNA的表达水平及血清中TNF-a水平明显升高(P<0.05)；与对照组(B)比较,AG490干预组(C)肝组织p-JAk2和p-STAT3蛋白水平和TNF-amRNA的表达水平及血清中TNF-a水平明显降低(P<0.05)；与对照组(B)比较,小白菊内酯干预组(D)肝组织p-JAk2和p-STAT3蛋白水平和TNF-amRNA的表达水平及血清中TNF-a水平明显降低(P<0.05)。
结论：
1、JAK2/STAT3信号通路在肝脏缺血再灌注损伤中激活；
2、阻断JAK2/STAT3信号通路的异常激活可能抑制肝脏缺血再灌注损伤中炎性相关基因和蛋白表达；
3、小白菊内酯可能通过抑制JAK2/STAT3信号通路减少肝脏缺血再灌注损伤中炎性相关基因和蛋白表达。
Part 1:Effects of parthenolide on the secretion function of Kupffer cells
Objective:To explore the effects of parthenolide on the inflammatory cytokines expression in kupffer cells and to elucidate the probable mechanism of the effects.
Methods:Kupffer Cells were isolated and purified by situ collagenase perfusion. The isolated and purified cells were then divided into 3 groups:Group A, control group in which kupffer cells were cultured normally; Group B, LPS group in which 10mg/l LPS was added into the nutrient solution; Group C, PTN group in which 5μmol/l parthenolide was added into the nutrient solution 1h before 10mg/l LPS was added. After 3h stimulating to each group, the morphology of kupffer cells were measured by an inverted microscope, the activity of kupffer cell was measured by trypan blue staining, the purity was measured by anti ED-2 immunohistochemical staining, the concentration of IL-1 and TNF-a in the supernatant were measured by ELISA, the NF-kB DNA binding activity were measured by EMSA. Treatments in each group were repeated for 8 times to obtain the mean value of each index as the final result.
Results:The shape of newly isolated kupffer cells were sphere like, suspending in the nutrient solution; Most of them became flat and adhered to the wall, pseudopodium formation occurred in few cells; After about 24h, pseudopodium formation occurred in most of the cells and all cells were extended totally with bigger size in star-shape or polygonal shape; The purity ratio of each group was 90%, and the activity ratio was more than 96%. Concentration of TNF-a and IL-1 of the nutrient solution in group B is much higher than that of group A (p＜0.05), Concentration of TNF-αand IL-1 of the nutrient solution in group C is much lower than that of group A,Group B was higher in DNA binding activity of NF-kB than that of group A (P＜0.05), Group C was lower in DNA binding activity of NF-kB than that of group B (P＜0.05).
Conclusions:
(1) LPS can activate the kupffer cells and as a result induce its ability of releasing cytokines.
(2) Parthenolide can inhibit the activation of NF-kB in kupffer cells and as a result reduce its ability of releasing cytokines.
Part 2:Effect of parthenolide on hepatic ischemia-reperfusion injury
Objective:To investigate the effect and related mechanisms of parthenolide on liver function and hepatic tissues in the liver ischemia-reperfusion injury.
Methods:healthy male SD rats were randomized into 4 groups (n=18):sham-operated group(A), model control group(B), low dosage of parthenolide treatment group(C) and large dosage of parthenolide treatment group(D).10 minutes before Ischemia, treatment group rats were intraperitoneally injected 250 or 500μg/kg parthenolide.Then the hepatic ischemia-reperfusion model of 70 percent of liver, including the left and middle hepatie lobe, were established.The I/R model control group and were administered with the same volume of DMSO.After 90 min ischemia,6 cases rats of each group were killed at 2h,6h and 24h after residual liver reperfusion respectively, blood and liver tissue samples were collected from the experimental groups. Serum levels of ALT and AST were measured, part of the liver tissues were made into paraffin-embedded specimens to detect rat liver histological change and grade hepatic IRI(Suzuki's score), the content of MDA and the activity of MPO in liver tissues were detected by ELISA.
Results:Compared with the model control group,serum ALT and AST in both treatment group of the low and large dosage parthenolide were significantly decreased(P<0.05),even lower in the large dosage group than in the low dosage group(P<0.05). Hepatic pathology performance was improved and Suzuki's scores was decreased significantly in both dosage group (P<0.05), the large dosage group is more significantly. The content of MDA and the activity of MPO in liver tissues were significantly decreased in both treatment groups when compared with the I/R model control group(P<0.05), also lower in the large dosage group than in the low dosage group(P<0.05).
Conclusion:
(1) Treatment with parthenolide can effectively improve the rat liver function and liver pathology damage induced by liver ischemia-reperfusion injury;
(2) Intervention with parthenolide can inhibit the effection of oxygen free radicals, and reduce the tissues damage induced by lipid peroxidation;
(3) Intervention with parthenolide can reduce the aggregation, infiltration and activation of neutrophil in the rat liver induced by ischemia-reperfusion injury,thereby reducing inflammatory response.
Part 3:Effects of parthenolide on IKK/NF-κB signaling pathway in the rat hepatic ischemia-reperfusion injury
Objective:To study the molecular mechanism of the effect of parthenolide inhibiting the inflammation signaling pathway of IKK/ NF-κB in the rat hepatic ischemia-reperfusion injury.
Methods:healthy male SD rats were randomized into 3 groups (n=6):sham-operated group(A), model control group(B), parthenolide treatment group(C).10 minutes before Ischemia, treatment group rats were intraperitoneally injected 500μg/kg parthenolide.Then the hepatic ischemia-reperfusion model of 70 percent of liver, including the left and middle hepatie lobe, were established.The I/R model control group and were administered with the same volume of DMSO.After 90 min ischemia and 6h reperfusion,6 cases rats of each group were killed respectively, blood and liver tissue samples were collected from the experimental groups. Serum levels of TNF-a, MIP-2 and ICAM-1were measured by ELISA,TNF-a, MIP-2 and ICAM-1mRNA of liver were measured by RT-PCR, the NF-kB DNA binding activity were measured by EMSA, the level of protein of NF-kB p65 in caryon and p-IKKser180/βser181 and IkBαin the liver tissues were measured by Western blot.
Results:Compared with the model control group, the levels of TNF-a, MIP-2 and ICAM-1 in serum and mRNA of liver in parthenolide treatment group were significantly decreased(P<0.05);Compared with the model control group, the NF-kB DNA binding activity, the level of protein of NF-kB p65 in caryon, the level of protein of p-IKKser180/βser181 in parthenolide treatment group were significantly decreased(P<0.05), the level of protein of IkBbαwere significantly increased(P<0.05).
Conclusion:
Parthenolide reduces the expression of inflammatory gene and protein in hepatic ischemia-reperfusion injury probablely by suppressing IKK/NF-kB signal pathway activation.
Part 4:Effects of JAK2/STAT3 signal pathway on the rat hepatic ischemia-reperfusion injury and effects of parthenolide on JAK2/STAT3 signaling pathway
Objective:To identify the role of the activated JAK2/STAT3 in rat hepatic ischemia-reperfusion injury and investigate the mechanisms of JAK2/STAT3 signal pathway causing hepatic damage,to study the molecular mechanism of the effect of parthenolide on the JAK2/STAT3 signaling pathway in the rat hepatic ischemia-reperfusion injury.
Methods:healthy male SD rats were randomized into 4 groups (n=6):sham-operated group(A), model control group(B), AG490 treatment group(C) and parthenolide treatment group(D).10 minutes before Ischemia, AG490 treatment group and parthenolide treatment group treatment group rats were intraperitoneally injected lmg/kg AG490 and 500μg/kg parthenolide respectively.Then the hepatic ischemia-reperfusion model of 70 percent of liver, including the left and middle hepatie lobe, were established.The I/R model control group and were administered with the same volume of DMSO. After 90 min ischemia,6 cases rats of each group were killed at 6h after residual liver reperfusion respectively, blood and liver tissue samples were collected from the experimental groups. The level of protein of p-JAk2 and p-STAT3 were measured by immunohistochemical method and Western blot, TNF-amRNA of liver were measured by RT-PCR, Serum levels of TNF-αwere measured by ELISA.
Results:Compared with the sham-operated group, the levels of protein of pJAk2 and pSTAT3, TNF-amRNA of liver, serum levels of TNF-a in model control group(B)were significantly increased(P<0.05); compared with the model control group(B), the levels of protein of p-JAk2 and p-STAT3, TNF-amRNA of liver, serum levels of TNF-a in AG490 treatment group(C) were significantly increased(p<0.05); compared with the model control group(B), the levels of protein of p-JAk2 and p-STAT3, TNF-amRNA of liver, serum levels of TNF-a in parthenolide treatment group(D) were significantly increased(p<0.05).
Conclusion:
(1) JAK2/STAT3 signal pathway were activated in hepatic ischemia-reperfusion injury;
(2) suppressing JAK2/STAT3 signal pathway activation probablely reduce the expression of inflammatory gene and protein in hepatic ischemia-reperfusion injury;
(3) Parthenolide reduces the expression of inflammatory gene and protein in hepatic ischemia-reperfusion injury probablely by suppressing JAK2/STAT3 signal pathway activation.
引文
[1]Jaesehke H,Smith CV,Spolaries Mitchell,et al.Reactive oxygen species during isehemia-reflow injury in isolated perfused rat liver. J Clin Inves,1998,81:1240-1246.
[2]Heinrich M, Robles M, West JE, Rodriguez D.Ethnopharmacology of Mexican asteraceae (Compositae).Annu. Rev. Pharmacol. Toxicol.1998,38: 539-565.
[3]Hehner SP, Hoffman TG, Droge W, and Schmitz ML.The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kB by targeting the IkB kinase complex. J. Immunol.1999,63:5617-5623.
[4]Sobota R.,Szwed M.,Kasza A.,Bugno M.,Kordula T. Parthenolide inhibits activation of signal transducers and activators of transcription (STATs)induced by cytokines of the IL-6family Biochem.Biophys.Res.Commun.2000,267:329-333.
[5]Kono H, Fujii H, Asakawa M, et al. Functional heterogeneity of the kupfer cell population is involved in the mechanism of gadolinium chloride in rats administered endotoxin.J Surg Res,2002,106:179-187.
[6]TothCA, Thomas P. Hepatic endocytosis and Kupffer cells.Hepatology,1992;16:255.
[7]Muriel P,Escobar Y. Kupffer cells are responsible for liver cirrhosis induced by carbon tetrachloride. J Appl Toxicol,2003,23(1):103-108.
[8]Jaeschke H,Farhood A, Bautista AP,Spolarics Z, Spitzer J J. Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am. J. Physiol,1993,264:801-809.
[9]Hehner SP, Hoffman TG, Droge W, and Schmitz ML.The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kB by targeting the IkB kinase complex. J. Immunol.1999,63,5617-5623.
[10]Weiskirchen R, Gressner A M. Isolation and culture of hepatic stellate cells. Methods Mol Med,2005,117:99-113.
[11]Olynyk J K, Clarke SL. Isolation and primary culture of rat Kupffer cells. Journal of Gastroenterology and Hepatology,1998,13:841-844.
[12]Wake K.Cell-cell organization and functions of 'sinusoids' in liver microcirculation system.J Electron Microsc(Tokyo)1999;48:89-98.
[13]Kolle P,Lohr H,Treichel U,Dienes HP, Lohse A,Schiaack J,Gerken GParenchymal and nonparenchymal liver cells and their interaction in the localimmune response.ZGastroentero,1995,133:613-620.
[14]Liang J,Yamaguchi Y,Matsumura F,et al. Calcium-channel blocker attenuates Kupffer cell production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion in the rat liver. Dig Dis Sci,2000,4 (1):201-209.
[15]Shen XD,Ke B,Zhai Y,Gao F,Busuttil RW,Cheng G,Kupiec-Weglinski JW.Toll-like receptor and heme oxygenase-1 signaling in hepatic ischemia/reperfusion injury.Am J Transplant 2005;5:1793-1800.
[16]Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. Am J Physiol,1991,260(3 Pt 1): G355-G362.
[17]Lentsch AB, Yoshidome H, Cheadle WG, et al. Chemokine involvement in hepatic ischemia/reperfusion injury in mice:roles for macrophage inflammatory protein-2 and KC. Hepatology,1998,27(4):1172-1177.
[18]Jaeschke H, Smith CW. Mechanisms of neutrophil-induced parenchymal cell injury. J Leukoc Biol,1997,61(6):647-653.
[19]BykovI,Ylipaasto P,Eerola L,et al.Scand J Gastroenterol.2003;38:1256-1261.
[20]Lentsch AB, Yoshidome H, Kato A, et al. Requirement for interleukin-12 in the pathogenesis of warm hepatic ischemia/reperfusion injury in mice. Hepatology, 1999,30(6):1448-1453.
[21]Siendones E, Fouad D, Diaz-Guerra MJ, et al. PGE1-induced NO reduces apoptosis by D-galactosamine through atenuation of NF-kappaB and NOS-2 expression in rat hepatocytes.Hepatology,2004,40:1295-1303.
[22]Zwacka R M, Zhang YL, Zhon WH, et al. Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor-KB independently of IkB degradation. Hepatology,1998,28(5):1022-1030.
[23]Xu J, Xie J, Bao M, et al. NF-kappaB/I-kappaB pathway during ischemia reperfusion injury of rat liver. Chin Med J (Eng),2003,116(8):1146-1149.
[24]Serafin A, Rosello-Catafau J, Prats N, et al. Ischemic preconditioning increases the tolerance of Fatty liver to hepatic ischemia-reperfusion injury in the rat. Am J Pathol,2002,161(2):587-601.
[25]Funaki H, Shimizu K, Harada S, et al. Essential role for nuclear factor kappaB in ischemic preconditioning for ischemia-reperfusion injury of the mouse liver. Transplantation,2002,74(4):551-556.
[26]Takahashi Y, Ganster RW, Ishikawa T, et al. Protective role of NF-kappaB in liver cold ischemia/reperfusion injury:effects of IkappaB gene therapy. Transplant Proc,2001,33(1-2):602.
[27]Gu XP,Jiang Y,Xu FT,Qiu YD,Ding YT.Effect of cold ischemia time on nuclear factor kB activation and inflammatory response in graft after orthotopic liver transplantation in rats.World J Gastroenterol,2004,10(7):1000-1004.
[28]Chen F,Lu Y.Demers LM,Rojanasakul Y.Shi X,Vallyathan V.Castranova V.Role of hydroxyl radical in silica-induced NF-kB activation in macrophages.Ann Clin Lab Sci,1998,28:1-13.
[29]Hwang D, Fischer NH, Jang BC, Tak H, Kim JK, Lee W. Inhibition of the expression of inducible cyclooxygenase and proinflammatory cytokines by sesquiterpene lactones in macrophages correlates with the inhibition of MAP kinases. Biochem Biophys Res Commun.1996;226:810-818.
[30]Mazor RL, Menendez IY, Ryan MA, Fiedler MA, Wong HR. Sesquiterpene lactones are potent inhibitors of interleukin 8 gene expression in cultured human respiratory epithelium. Cytokine.2000;12:239-245.
[31]Robert FS,David AB.Mechanisms of Liver Injury.I.TNF-a- induced liver injury:role of IKK,JNK,and ROS pathways.Am J Physiol Gastrointest Liver Physiol,2006,290:583-589.
[32]Heinrich M, Robles M, West JE, Rodriguez D.Ethnopharmacology of Mexican asteraceae (Compositae).Annu. Rev. Pharmacol. Toxicol.1998,38: 539-565.
[33]Zingarelli B,Hake PW,Denenberg A,Wong HR.Sesquiterpene lactone parthenolide,an inhibitor of IkappaB kinase complex and nuclear factor-kappaB,exerts beneficial effects in myocardial reperfusion injury. Shock,2001,17:127-134.
[34]Zhai Y,Shen X,O'Connell R,et al.Cutting Edge:TLR-4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway.J Immunol 2004;173:7115.
[35]Suzuki S,Toledo-Pereyra LH,Rodriguez FJ,et al.NeutroPhil infiltration as an important factor in liver ischemia and reperfusion injury.Modulating effects of FK506 and cyclosporine.Transplantation,1993,55(6):1265-1272.
[36]Wong HR,Menendez IY, Sesquiterpene lactones inhibit inducible nitric oxide synthase gene expression in cultured rat aortic smooth muscle cells. Biochem Biophys Res Commun,1999,262:375-380,1999.
[37]Hwang D, Fischer NH, Jang BC, Tak H, Kim JK and Lee W,Inhibition of the expression of inducible cyclooxygenase and proinflammatory cytokines by sesquiterpene lactones in macrophages correlates with the inhibition of MAP kinases.Biochem Biophys Res Commun,1996,226:810-818.
[38]Brown AM, Edwards CM, Davey MR, Power JB and Lowe KC, Pharmacological activity of feverfew:Assessment by inhibition of human polymorphonuclear leukocyte chemiluminescence in vitro.J Pharm Pharmacol,1997,49:558-561.
[39]Rodriguez E, Towers GHN,J.C. Mitchell JC, Biological activities of sesquiterpene lactones, Phytochemistry,1976,15:1573-1580.
[40]Zhang WH,Wang JS,Zhou Y,Li JY.Gadolinium chloride and salvia miltiorrhiza compound ameliorate reperfusion injury in hepatocellular mitochondria.World J Gastroenterol.2003;9(9):2040-2044.
[41]Burne MJ,Haq M,Matsuse H,et al.Genetic susceptibility to renal ischemia reperfusion injury revealed in a murine model.Transplantation,2000,69(5): 1023-1025.
[42]Nguyen WD, Kim DH,Alam HB,et al. Polyethylene glycol superoxide dismutase inhibits lipid peoroxidation inhepatic ischemic reperfusion injury.Crit Rare,1999,3(5):127-30.
[43]Vonrllar B,Riehter S,Menger MD.Leckucyte etasis in hepatic sinusoids.Am J physiol,1996,270(5):G798-803.
[44]Loft S,Larsen PN,Rusmussen A,et al.oxidative DNA damage afer tansplantation of the liver and small intestine in pigs. Tansplantation,1995,59(1):16-8.
[45]Yao H, Tang X, Shao X Feng L, Wu N, Yao K. Parthenolide protects human lens epithelial cells from oxidative stressinduced apoptosis via inhibition of activation of caspase-3 and caspase-9. Cell Res.2007,17F:565-571.
[46]Wen J, You KR,Lee SY, Song CH, Kim DG, Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide,J Biol Chem, 2002,277:38954-38964.
[47]Jaeschke H,Farhood A,Smith CW.Neutrophils contribute to ischemia/reperfusion injury in rat liver in vivo.FASEB J,1990,4:3355-9.
[48]Lentsch AB,Atsushi K,Yoshidome H,et al.Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia and reperfusion injury.Hepatololgy,2000,32(2):169-173.
[49]Fedrinnad S,FRCSI,Ngay A,et al.Hepatic ischemia-reperfusion injury.Am J Surg,2001,181(2):160-166.
[50]Martinez,Toledo P,Meduffie JE,et al.Neutrophil depletion and chemokine response after liver ischemia and reperfusion.J Invest Sugr,2001,14(1):99-107.
[51]Tosi MF,Stark JM,Wane C.Inducting of ICAM-1 expression on human airway epithelial cells by inflammatory cytokines:effect on neutrophil-epithelial adhension.AM J Respir,1992,7(2):214-221.
[52]Bradlay PP,Pkiebat DA,Cristensen RD,et al.Measurement of cutaneous inflammation:estimation of neutrofile content with an enzyme marker.J Invest Dermatol,1982,78(3):206-209.
[53]Jiang Y,Gu XP,Qiu YD,et al.Ischemia preconditioning decrease C-X-C chemokine expression and neutrophila accumulation early after liver transplantation in rats.World J Gastroenterol.2003,9(9):2025-2029.
[54]Lentsch AB,Yoshidome W,Cheadle F,et al.Chemokine involvement in hepatic ischemia reperfusion injury in mice roles for microphage inflammatory protein-2 and kupffer cell,Hepatology,1998,27(3):507-51.
[55]ThomasAB,JohnP.Early Gene Respose Hepatic Ischemia Reperfusion.J Surg Res,1996,63:98-104.
[56]Jr Baldwin AS. The NF-kB and IkB proteins:new discoveries and insights. Annu Rev Immunol,1996,14:649.
[57]Zandi E,Chen Y. Karin M.Direct phosphorylation of IkB by IKK a and IKK β:Discrimination between free and N-bound substrate.Science,1998,281:1360-1363.
[58]Andrade C, Kaneda H, Der S, et al. Effects of ischemia/reperfusion on gene expression of toll-like receptors and cytokines during human lung transplantation. Am J Respir Crit Care Med,2004,169:203.
[59]Hehner SP, Hofmann TG, Droge W, Schmitz ML. The anti-inflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the Ikappa B kinase complex. J Immunol 1999,163:5617-23.
[60]Teoh N, Leclercq I, Pena AD, et al. Low-dose TNF-alpha protects against hepatic ischemia-reperfusion injury in mice:implications for preconditioning. Hepatology,2003,37(1):118-128.
[61]Yassin MM,Harikin DW,Barros DpSa AA,et al.Lower limb isehemia reperfusion injury triggers a systemic inflammatory response and multiple organ dysfunetion.World J Surg,2002,26(1):115-121.
[62]Ohkohchi N, Shibuya H, Tsukamoto S, et al. Kupffer's cells modulate neutrophile activity by superoxide anion and tumor necrosis factor-delta in reperfusion injury of liver transplantation mechanisms of radical generation and reperfusion injury after cold ischemia.Transplant Proc,1999,31(1-2):1055-1058.
[63]Zwacka RM, Zhang Y, Halldorson J, et al. CD4+T-lymphocytes mediate ischemia/reperfusion induced inflammatory responses in mouse liver. J Clin Invest, 1997,100:279-289.
[64]Teoh N, Field J, Sutton J, et al. Dual role of tumor necrosis factor-α in hepatic ischemia-reperfusion injury:studies in tumor necrosis factor-agene knockout mice. Hepatology,2004,39(2):412-422.
[65]Colletti LM,Green ME,Burdick MD,et al.The ratio of ELR+ toELR-CXC chemokines affects the lung and liver injury followinghepatic ischemia/reperfusion in the rat.Hepatology,2000,31:435-445.
[66]Colletti LM, Kunkel SL, Walz A. et al. The role of cytokine networks in the local liver injury following hepatic ischemia/reperfusion in the rat. Hepatology, 1996,23:506-514.
[67]Lentsch AB, Yoshidome H, Cheadle WG, et al. Chemokine involvement in hepatic ischemia/reperfusion injury in mice:roles for macrophage inflammatory protein-2 and Kupffer cells. Hepatology,1998,27(2):507-512.
[68]Ohira H, Ueno T. Cultured rat hepatic sinusoidal endothelial cells express intercellular adehension molecule-1 by tumor necrosis factor-a stimulation.J Hepatology,1994,20(3):729-734.
[69]Colletti LM,Cortis A,Lukacs N,et al.Tumor necrosis factor upregulates intercellular adhesion molecule 1,which is important in the neutrophil-dependent lung and liver injury associated with hepatic ischemia and reperfusion in the rat.Shock,1998,10:182-191.
[70]Jaeschke H, Farhood A, Bautista A,et al.The F(ab)2 fragment of anti-ICAM-1 monoclonal antibody attenuate liver after orthotopic liver transplantation. Transplantation,1996,61 (1):99-104.
[71]Ghosh S.et al. NF-kappa B and Rel proteins:evolutionarily conserved mediators of immune responses.Annu.Rev.Immunol.1998:16:225-260.
[72]Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins:evolutionarily conserved mediators of immune responses.Annu Rev Immunol,1998,16:225-260.
[73]Wheele MD,Yamashina S,Froh M, et al.Adenoviral gene delivery can inactivate Kuffer cell:role of oxidants in NF- kappa B activation and eytokine production.J Leukoe Biol,2001,69(4):622-630.
[74]McDonald MC,Mota-Filipe H,PaulA,et al.Calpain inhibitor 1 reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagie shock..FASEB J,2001,15(1):171-186.
[75]Tsoulfas G,Takahashi Y,Ganster RW,et al.Activation of the lipopolysaccharide signaling pathway in hepatic transplantation preservation injury.Transplantation,2002,74(1):7-13.
[76]Xu J, Xie J, Bao M, et al. NF-kappaB/I-kappaB pathway during ischemia reperfusion injury of rat liver. Chin Med J (Eng),2003,116(8):1146-1149.
[77]Yoshidome H,Kato A,Edwards MJ.IL-10 suppresses hepatic ischemia/reperfusion injury in mice:Implication of a central role for muclear kB,Hepatology,1999,30:203-208.
[78]Matsui N,Kasajima K,Hada M,et al.Inhibiton of NF-kappaB activation during ischemia reduces hepatic ischemia/reperfusion injury in rats.J Toxicol Sci,2005,30(2):103-110.
[79]Uchinami H,Yamamoto Y,Kume M,et al.Effect of heat shock preconditioning on NF-kappaB/I-kappaB pathway during I/R injury of the rat liver[J].Am J Physiol Gastrointest Liver Physiol,2002,282(6):962-971.
[80]Yoshidome H,Kato A,Edwards MJ,et al.Interleukin-10 suppresses hepatic isehemia/reperfusion injury in mice:implications of a central role for nuclear factor kappa B.Hepatology,1999,30(1):203-208.
[81]Ghosh S,May MJ,Kopp EB.NF-kappa B and Rel proteins:evolutionarily conserved mediators of immune response.Annu Rev Immunol,1998,16:225-229.
[82]Zwacka R M, Zhang YL, Zhon WH, et al. Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor-κB independently of IκB degradation. Hepatology,1998,28 (5):1022-1030.
[83]Zandi E, Rothwarf MD,Delhase M,Hayakawa M. Karin M.The IkappaB kinase complex(IKK) contains two kinasesubunits,IKKalpha and IKKbeta,necessary for IkappaB phosphorylation and N-kappa B activation.Cell,1997,91,243-252.
[84]Yamaoka S.et al.Complementation cloning of NEMO,a component of the IkappaB kinase complex essential for NF-kappaB activation.Cell,1998,93:1231-1240.
[85]Zandi E, Rothwarf DM, Delhase M, et al. The Ⅰ kappa B kinase complex (IKK) containstwo kinase subunits. IKKα and IKKβ, necessary for Ⅰ kappaB phosphorylation and NF kappa B activation. Cell.1997,91(2):243-252.
[86]May MJ,D'Acquisto F, et al.Selective inhibition of NF-kB activation by a complex.Seience.2000,289:1550-1554.
[87]DiDonato AJ,Hayakawa M,Rothwarf DM,Zandi E, Karin M.A cytokine-responsive IkB kinase that activates the transcription factor NF-KB.Natuer,1997,388:548-554.
[88]Delhase M,Hayakawa M,Chen Y,Karin M.Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation,Science, 1999,284:309-313.
[89]Li,H.Y.,et al.,Deactivation of the kinase IKK by CUEDC2 through recruitment of the phosphatase PPl.Nat Immunol,2008.9(5):p.533-41.
[90]Karin M. The beginning of the end:IikB kinase(IKK)and NF-kB activation. Biol Chem,1999,274:27339-27342.
[91]Steffen P. Hehner, Thomas G. Hofmann, Wulf Droge and M. Lienhard Schmitz. The Antiinflammatory Sesquiterpene Lactone Parthenolide Inhibits NF-kB by Targeting the IkB Kinase Complex. The Journal of Immunology,1999,163: 5617-5623.
[92]Aicha Saadane, Sophia Masters, Joseph DiDonato, Jingfeng Li, Melvin Berger. Parthenolide Inhibits I[kappa]B Kinase, NF-[kappa]B Activation, and Inflammatory Response in Cystic Fibrosis Cells and MiceAmerican Journal of Respiratory Cell and Molecular Biology.2007,36,(6):728-9.
[93]Igaz P,Toth S,Falus A.Biological and clinical significance of the JAK-STAT pathway,lessons from knockout mice.Inflamm Res2002,50(9):435-441.
[94]Krasilnikov M,Ivanov VN,Dong J,et al.ERK and PI3K negatively regulate STAT transcriptioal activities in human melanoma cells; implications towards sensitization to apotosisi.Oncogene,2003,22(26):4091-4101.
[95]Krasilnikov M,Ivanov VN,Dong J,et al.ERK and PI3K negatively regulate STAT transcriptioal activities in human melanoma cells; implications towards sensitization to apotosisi.Oncogene,2003,22(26):4091-4101.
[96]沈诚,范士志,陈建明。抑制J炎性相关基因和蛋白表达AK/STAT通路对缺血再灌注损伤心肌TNF-a和IL-6表达的影响。重庆医学,2006,35(1)：38-42。
[97]Radoslaw Sobota, Marcin Szwed,Aneta Kasza, Marcin Bugno, Tomasz Kordula, Parthenolide inhibits activation of signal transducers and activators of transcription (STATs) induced by cytokines of the IL-6 family1. Biochemical and Biophysical Research Communications,2000,267:329-333.
[98]O'Shea, J.J. et al. Cytokine signaling in 2002:new surprises in the Jak/Stat pathway. Cell.2002,109:121-131.
[99]Levy DE,Darnell JE.Stats:transcriptional control and biological impact.Nat Rev Mol Cell Biol,2002,3(9):651-662.
[100]Osiak A,Utermohlen O,Niendorf S,Horak I,Knobeloch KP.ISG15,an interferon-stimulated ubiquitin-like protein,is not essential for STAT1 signaling and responses against vesicular stomatitis and lymphocytic choriomeningitis virus.Mol CellBiol.2005,25(15):6338-6345.
[101]Krebs DL,Hilton DJ.SOCS proteins:Negative regulation of cytokine signal.StemCells,2001,19(5):378-387.
[102]黄文林,朱孝峰主编。信号转导,北京：人民卫生出版社,2005。182-191。
[103]Ananthakrishnan R,Hallam K,Li Q,et al.JAK-STAT pathway in cardiac ischemic stress.Vascul Pharmacol.2005,43(5):353-356.
[104]Mascareno E,EI-Shafei M,Maullk N,et al.JAK-STAT signaling is associatd with cardiac dysfunction during ischemia and reperfusion. Circulation,2001,104(3):325-329.
[105]Irawan Satriotomo,Kellie K. Bowen,Raghu Vemuganti.JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia. Journal of Neurochemistry,2006,98:1353-1368.
[106]Yang N, Luo M, Li R, Huang Y, Zhang R, Wu Q, Wang F, Li Y, Yu X. Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rat. Nephrol Dial Transplant.2008,23(1):91-100.
[107]Schindler CW.Series introduction JAK-STAT signaling in human disease.J Clin Invest,2002,109(9):1133-1137.
[108]Akira S, Nishio Y, Inoue M, Wang X.J, et al.Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp 130-mediatedsignaling pathway. Cell,1994,77:63-71.
[109]姚胜,姚咏明,李红云,等。抑制JA K/STAT通路对烫伤后金黄色葡萄球菌脓毒症大鼠肝损害的影响。Chinese Critical Care Medicine,June 2002,1(14):16336-339.
[110]姚胜,姚咏明,李红云,等。烫伤脓毒症大鼠肝、肺组织STAT3(?)舌化 规律及意义。解放军医学志,2002,27(9)：763-765。
[111]郭婧芸,朱人敏,张晓华。抑制JAK/STAT信号通路对实验性急性胰腺炎大鼠肝损伤的保护作用。胃肠病学,2008,13(12)：719-722。
[112]毛一雷,于卓,桑新亭,卢欣,杨志英,钟守先。阻断炎症介质的信号转导对极限肝切除术后大鼠肝内细胞因子表达的影响。中华外科杂志,2005,43(1)：6-9。
[113]Lee YK,Isham CR,Kaufman SH,Bible KC.Flavopiridol disrupts STAT3/DNA interactions,attenuates STAT3-directed transcription,and combines with the Jak kinase inhibitor AG490 to achieve cytotoxic synergy.Mol Cancer Ther.2006,5(1):138-148.
[114]Radoslaw Sobota, Marcin Szwed,Aneta Kasza, Marcin Bugno, andTomasz Kordula, Parthenolide inhibits activation of signal transducers and activators of transcription (STATs) induced by cytokines of the IL-6 family1. Biochemical and Biophysical Research Communications,2000,267:329-333.
[115]Won YK, Ong CN, Shi X, Shen HM. Chemopreventive activity of parthenolide against UVB-induced skin cancer and its mechanisms. Carcinogenesis. 2004;25:1449-1458.
[116]Kurdi M,Booz GW.Evidence that IL-6-type cytokine signaling in cardiomyocytes is inhibited by oxidative stress:parthenolide targets JAK1 activation by generating ROS. Journal of Cellular Physiology,2007,212(2):424-431.
[1]O'Shea, J.J. et al. Cytokine signaling in 2002:new surprises in the Jak/Stat pathway. Cell.2002,109:121-131.
[2]Rodig SJ,Meraz MA,White JM,Lampe PA,Riley JK,Arthur CD,et al.Disruption of the Jakl gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses.Cell.1998;93:373-83.
[3]Schindler C,Strehlow I.Cytokines and STAT signaling.Ady.Pharmacol, 2000,47:113-174.
[4]Neubauer H,Cumano A,Mueller M,Wu H,Huffstadt U,Pfeffer K.Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis.Cell 1998;93:397-09.
[5]Tefferi A. JAK and MPL mutations in myeloid malignancies. Leuk Lymphoma.2008;49:388-97.
[6]Minegishi Y,Saito M,Morio T,Watanabe K,Agematsu K,Tsuchiya S,.Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.Immunity.2006;25:745-55.
[7]Karaghiosoff M,Neubauer H,Lassnig C,Kovarik P,Schindler H,Pircher H.Partial impairment of cytokine responses in Tyk2-deficient mice.Immunity,2000;13:549-60.
[8]Levy DE,Darnell JE.Stats:transcriptional control and biological impact.Nat Rev Mol Cell Biol,2002,3(9):651-662.
[9]Becker S, Groner B, Muller CW. Three-dimensional structure of the Stat3 beta homodimer bound to DNA. Nature 1998;394:145-51.
[10]Chen X, Vinkemeier U, Zhao Y, Jeruzalmi D, Darnell Jr JE, Kuriyan J. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 1998;93:827-39.
[11]Mao X, Ren Z, Parker GN, Sondermann H, Pastorello MA,WangW, et al. Structural bases of unphosphorylated STAT1 association and receptor binding. Mol Cell 2005;17:761-71.
[12]Schindler C, Levy DE, Decker T. JAK-STAT signaling:from interferons to cytokines. J Biol Chem 2007;282:20059-63.
[13]McBride KM, Reich NC. The ins and outs of STAT1 nuclear transport. Sci STKE 2003;2003:RE13.
[14]Bhattacharya S, Schindler C. Regulation of Stat3 nuclear export. J Clin Invest 2003;111:553-9.
[15]Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell Jr JE.Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell 1994;76:821-8.
[16]Mertens C, Zhong M, Krishnaraj R, Zou W, Chen X, Darnell Jr JE. Dephosphorylation of phosphotyrosine on STAT1 dimers requires extensive spatial reorientation of the monomers facilitated by the N-terminal domain. Sci STKE 2003;2003:RE13.
[17]Neculai D,Neculai AM, Verrier S, Straub K, Klumpp K, Pfitzner E. Structure of the unphosphorylated STAT5a dimer. J Biol Chem 2005;280:40782-7.
[18]Park C, Lecomte MJ, Schindler C. Murine Stat2 is uncharacteristically divergent.Nucleic Acids Res 1999;27:4191-9.
[19]Decker T, Muller M, Kovarik P. Regulation of Stats by posttranslational modification.In:Seghal PB, Hirano T, Levy DE, editors. Signal transducers andactivators of transcription (Stats):activation and biology. Kluwer Academic;2003.
[20]Wang D, Moriggl R, Stravopodis D, Carpino N, Marine JC, Teglund S. A small amphipathic alpha-helical region is required for transcriptional activities and proteasome-dependent turnover of the tyrosine-phosphorylated Stat5. EMBO J 2000;19:392-9.
[21]Schindler C, Fu XY, Improta T, Aebersold R, Darnell Jr JE. Proteins of transcription factor ISGF-3:one gene encodes the 91- and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc Natl Acad Sci USA 1992;89:7836-9.
[22]Shuai K, Schindler C, Prezioso V, Darnell JE. Activation of transcription by IFN-y:tyrosine phosphorylation of a 91-kDa DNA binding protein. Science,1992;258:1808-12.
[23]Zhang G, Ghosh S. Molecular mechanisms of NF-KappaB activation-induced by bacterial lipopolysaccharide through Toll-like receptors. J Endotoxin Res, 2000,6(6):453-457.
[24]Chapgier A, Boisson-Dupuis S, Jouanguy E, Vogt G, Feinberg J, Prochnicka-Chalufour A, et al. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease. PLoS Genet 2006;2:131.
[25]Jouanguy E, Lamhamedi-Cherradi S, Lammas D, Dorman SE, Fondaneche MC,Dupuis S, et al. A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nat Genet 1999;21:370-8.
[26]Schindler C, Levy DE, Decker T. JAK-STAT signaling:from interferons to cytokines. J Biol Chem 2007;282:20059-63.
[27]Bluyssen HAR,Levy DE.Stat2 is a transcriptional activator that requires sequence specific contacts provided by Statl and p48 for stable interaction with DNAJ.Biol.Chem,1997,272:4600-4605.
[28]Bromberg JF,Wrzeszezynska MH,Devgan G,et al.Stat3 as an Oncogene.Cell,1999,98:295-03.
[29]Takeda K,T Zhang G, Ghosh S. Molecular mechanisms of NF-KappaB activation- ninduced by bacterial lipopolysaccharide through Toll-like receptors. J Endotoxin Res,2000,6(6):453-457.
[30]Takeda K,Noguchi K,Shi W,et al.Targeted disruption of the mouse Stat3 gene leads to early lethality.Proe.Natl.Aead.Sci.USA,1997,94:3801-3804.
[31]Kaplan MH,Sun H,Hoey T,et al.Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice.Nature,1996,382:174-177.
[32]Gately MK,Renzetti LM,Magram J,et al.The interleukin-12/ interleukin-12-receptor system:role in normal and pathologic immune responses..Annu.Rev Immunol,1998,16:495-521.
[33]Sehindler C,Strehlow I.Cytokines and STAT signaling.Ady.Pharmaeol, 2000,47:113-174.
[34]Teglund S,McKay C Schuetz E,et al.Stat5a and Stat5b proteins have essential roles and nonessential,or redundant,roles in cytokine responses.Cell,1998,93:841-850.
[35]Hou J,Sehindler U,Henzel WJ,et al.An interleukin-4 induced transcription factor:IL-4 Stat.Scienee,1994,265:1701-1705.
[36]Lin J-X,Migone,TS,Tsang M,et al.The role of shared receptor motifs and common STAT proteins in the generation of cytokine pleiotropy and redundancy by IL-2,IL-4,IL-7,IL-13,andIL-15.Immunity,1995,2:331-339.
[37]Kaplan MH, Schindler U,Smiley ST, et al.Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells.Immunity,1996,4:313-319.
[38]黄文林,朱孝峰。信号转导。第一版,北京：人民卫生出版社。2005,7：183。
[39]Osiak A,Utermohlen O,Niendorf S,Horak I,Knobeloch KP.ISG15,an interferon-stimulated ubiquitin-like protein,is not essential for STAT1 signaling and responses against vesicular stomatitis and lymphocytic choriomeningitis virus.Mol Cell Biol.2005,25(15):6338-6345.
[40]Zhang G, Ghosh S. Molecular mechanisms of NF-KappaB activation-ninduced by bacterial lipopolysaccharide through Toll-like receptors. J Endotoxin Res, 2000,6(6):453-457.
[41]Shuai K.Regulation of cytokine signaling pathways by PIAS proteins.Cell Res.2006,16(2):196-202.
[42]Wu C,Guan Q,Wang Y,Zhao ZJ,Zhou GW.SHP-1 suppresses cancer cell growth by promoting degradation of JAK kinases.J Cell Biochem.2003,90 (5):1026-1037.
[43]Fawcett VC,Lorenz U.Localization of Src homology 2 domain-containing phosphatase 1(SHP-1)to lipid rafts in T lymphocytes:functional implications and a role for the SHP-1 carboxyl terminus.J Immunol,2005,174(5):2849-2859.
[44]Natarajan,C.etal.Signaling through JAK2-STAT5 pathway is essential for IL-3-induced activation of microglia.Glia.2004.45(2):188-196.
[45]Darnell JE Jr.STATs and gene regulation. Science,1997,277 (5332):1630-1635.
[46]Mascareno E,EI-Shafei M,Maulik N,et al.JAK-STAT signaling is associated with cardiac dysfunection during ischemia and reperfusion. Circulation,2001,104(4):325-329.
[47]沈诚,范士志,陈建明,李志平,何勇.抑制JAK/STAT通路对缺血再灌注损伤心肌TNF-a和IL-6表达的影响.重庆医学,2006,35(1)：38-39.
[48]Justicia C,Gabriel C,Planas AM.Activation of the JAK/STAT pathyway following transient focal cerebral ischemia:signaling through JAK1 and STAT3 in astrocytes. Glia,2000,30(3):253-270.
[49]West DA,Valentim LM,Lythgoe MF,et al.MR imaged-guided investigation of regional signal transducers and activators of ranscription activation in a rat model of focal cerebral ischemia.Neuroscience,2004,127(2):333-339.
[50]Suzuki S,Yamashita T,Tanaka K,et al.Activation of cytokine signaling through leukemia inhibitory factor receptor(LIFR/gP130)attenuates ischemic brain injury in rats.J Cereb Blood Flow Metab,2005,25(6):685-693.
[51]谢惠芳,徐如祥,魏继鹏,刘振华,姜晓丹。JAK2/STAT3信号转导通路在缺血性脑损伤中作用机制的研究.中风与神经疾病杂志。2008,25(2)：135-137。
[52]Yang N, Luo M, Li R, Huang Y, Zhang R, Wu Q, Wang F, Li Y, Yu X. Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rat. Nephrol Dial Transplant.2008,23(1):91-100.
[53]蓝柳根,彭民浩,卢景宁,陈滨。FK409对大鼠肝脏移植缺血再灌注损伤后JAK2/STAT3信号通路的影响。中国现代医学杂志,2009,19,(3)：390-394。
[54]丁忠阳,张峰,蔡兵,王学浩,王彤。抑制JAK/STAT信号通路对大鼠肝移植缺血再灌注损伤的影响。实用医学杂志,2008,24,(21)：3649-3651。
[2]Heinrich M, Robles M, West JE, Rodriguez D.Ethnopharmacology of Mexican asteraceae (Compositae).Annu. Rev. Pharmacol. Toxicol.1998,38: 539-565.
[3]Hehner SP, Hoffman TG, Droge W, and Schmitz ML.The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kB by targeting the IkB kinase complex. J. Immunol.1999,63:5617-5623.
[4]Sobota R.,Szwed M.,Kasza A.,Bugno M.,Kordula T. Parthenolide inhibits activation of signal transducers and activators of transcription (STATs)induced by cytokines of the IL-6family Biochem.Biophys.Res.Commun.2000,267:329-333.
[5]Kono H, Fujii H, Asakawa M, et al. Functional heterogeneity of the kupfer cell population is involved in the mechanism of gadolinium chloride in rats administered endotoxin.J Surg Res,2002,106:179-187.
[6]TothCA, Thomas P. Hepatic endocytosis and Kupffer cells.Hepatology,1992;16:255.
[7]Muriel P,Escobar Y. Kupffer cells are responsible for liver cirrhosis induced by carbon tetrachloride. J Appl Toxicol,2003,23(1):103-108.
[8]Jaeschke H,Farhood A, Bautista AP,Spolarics Z, Spitzer J J. Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am. J. Physiol,1993,264:801-809.
[9]Hehner SP, Hoffman TG, Droge W, and Schmitz ML.The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kB by targeting the IkB kinase complex. J. Immunol.1999,63,5617-5623.
[10]Weiskirchen R, Gressner A M. Isolation and culture of hepatic stellate cells. Methods Mol Med,2005,117:99-113.
[11]Olynyk J K, Clarke SL. Isolation and primary culture of rat Kupffer cells. Journal of Gastroenterology and Hepatology,1998,13:841-844.
[12]Wake K.Cell-cell organization and functions of 'sinusoids' in liver microcirculation system.J Electron Microsc(Tokyo)1999;48:89-98.
[13]Kolle P,Lohr H,Treichel U,Dienes HP, Lohse A,Schiaack J,Gerken GParenchymal and nonparenchymal liver cells and their interaction in the localimmune response.ZGastroentero,1995,133:613-620.
[14]Liang J,Yamaguchi Y,Matsumura F,et al. Calcium-channel blocker attenuates Kupffer cell production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion in the rat liver. Dig Dis Sci,2000,4 (1):201-209.
[15]Shen XD,Ke B,Zhai Y,Gao F,Busuttil RW,Cheng G,Kupiec-Weglinski JW.Toll-like receptor and heme oxygenase-1 signaling in hepatic ischemia/reperfusion injury.Am J Transplant 2005;5:1793-1800.
[16]Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. Am J Physiol,1991,260(3 Pt 1): G355-G362.
[17]Lentsch AB, Yoshidome H, Cheadle WG, et al. Chemokine involvement in hepatic ischemia/reperfusion injury in mice:roles for macrophage inflammatory protein-2 and KC. Hepatology,1998,27(4):1172-1177.
[18]Jaeschke H, Smith CW. Mechanisms of neutrophil-induced parenchymal cell injury. J Leukoc Biol,1997,61(6):647-653.
[19]BykovI,Ylipaasto P,Eerola L,et al.Scand J Gastroenterol.2003;38:1256-1261.
[20]Lentsch AB, Yoshidome H, Kato A, et al. Requirement for interleukin-12 in the pathogenesis of warm hepatic ischemia/reperfusion injury in mice. Hepatology, 1999,30(6):1448-1453.
[21]Siendones E, Fouad D, Diaz-Guerra MJ, et al. PGE1-induced NO reduces apoptosis by D-galactosamine through atenuation of NF-kappaB and NOS-2 expression in rat hepatocytes.Hepatology,2004,40:1295-1303.
[22]Zwacka R M, Zhang YL, Zhon WH, et al. Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor-KB independently of IkB degradation. Hepatology,1998,28(5):1022-1030.
[23]Xu J, Xie J, Bao M, et al. NF-kappaB/I-kappaB pathway during ischemia reperfusion injury of rat liver. Chin Med J (Eng),2003,116(8):1146-1149.
[24]Serafin A, Rosello-Catafau J, Prats N, et al. Ischemic preconditioning increases the tolerance of Fatty liver to hepatic ischemia-reperfusion injury in the rat. Am J Pathol,2002,161(2):587-601.
[25]Funaki H, Shimizu K, Harada S, et al. Essential role for nuclear factor kappaB in ischemic preconditioning for ischemia-reperfusion injury of the mouse liver. Transplantation,2002,74(4):551-556.
[26]Takahashi Y, Ganster RW, Ishikawa T, et al. Protective role of NF-kappaB in liver cold ischemia/reperfusion injury:effects of IkappaB gene therapy. Transplant Proc,2001,33(1-2):602.
[27]Gu XP,Jiang Y,Xu FT,Qiu YD,Ding YT.Effect of cold ischemia time on nuclear factor kB activation and inflammatory response in graft after orthotopic liver transplantation in rats.World J Gastroenterol,2004,10(7):1000-1004.
[28]Chen F,Lu Y.Demers LM,Rojanasakul Y.Shi X,Vallyathan V.Castranova V.Role of hydroxyl radical in silica-induced NF-kB activation in macrophages.Ann Clin Lab Sci,1998,28:1-13.
[29]Hwang D, Fischer NH, Jang BC, Tak H, Kim JK, Lee W. Inhibition of the expression of inducible cyclooxygenase and proinflammatory cytokines by sesquiterpene lactones in macrophages correlates with the inhibition of MAP kinases. Biochem Biophys Res Commun.1996;226:810-818.
[30]Mazor RL, Menendez IY, Ryan MA, Fiedler MA, Wong HR. Sesquiterpene lactones are potent inhibitors of interleukin 8 gene expression in cultured human respiratory epithelium. Cytokine.2000;12:239-245.
[31]Robert FS,David AB.Mechanisms of Liver Injury.I.TNF-a- induced liver injury:role of IKK,JNK,and ROS pathways.Am J Physiol Gastrointest Liver Physiol,2006,290:583-589.
[32]Heinrich M, Robles M, West JE, Rodriguez D.Ethnopharmacology of Mexican asteraceae (Compositae).Annu. Rev. Pharmacol. Toxicol.1998,38: 539-565.
[33]Zingarelli B,Hake PW,Denenberg A,Wong HR.Sesquiterpene lactone parthenolide,an inhibitor of IkappaB kinase complex and nuclear factor-kappaB,exerts beneficial effects in myocardial reperfusion injury. Shock,2001,17:127-134.
[34]Zhai Y,Shen X,O'Connell R,et al.Cutting Edge:TLR-4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway.J Immunol 2004;173:7115.
[35]Suzuki S,Toledo-Pereyra LH,Rodriguez FJ,et al.NeutroPhil infiltration as an important factor in liver ischemia and reperfusion injury.Modulating effects of FK506 and cyclosporine.Transplantation,1993,55(6):1265-1272.
[36]Wong HR,Menendez IY, Sesquiterpene lactones inhibit inducible nitric oxide synthase gene expression in cultured rat aortic smooth muscle cells. Biochem Biophys Res Commun,1999,262:375-380,1999.
[37]Hwang D, Fischer NH, Jang BC, Tak H, Kim JK and Lee W,Inhibition of the expression of inducible cyclooxygenase and proinflammatory cytokines by sesquiterpene lactones in macrophages correlates with the inhibition of MAP kinases.Biochem Biophys Res Commun,1996,226:810-818.
[38]Brown AM, Edwards CM, Davey MR, Power JB and Lowe KC, Pharmacological activity of feverfew:Assessment by inhibition of human polymorphonuclear leukocyte chemiluminescence in vitro.J Pharm Pharmacol,1997,49:558-561.
[39]Rodriguez E, Towers GHN,J.C. Mitchell JC, Biological activities of sesquiterpene lactones, Phytochemistry,1976,15:1573-1580.
[40]Zhang WH,Wang JS,Zhou Y,Li JY.Gadolinium chloride and salvia miltiorrhiza compound ameliorate reperfusion injury in hepatocellular mitochondria.World J Gastroenterol.2003;9(9):2040-2044.
[41]Burne MJ,Haq M,Matsuse H,et al.Genetic susceptibility to renal ischemia reperfusion injury revealed in a murine model.Transplantation,2000,69(5): 1023-1025.
[42]Nguyen WD, Kim DH,Alam HB,et al. Polyethylene glycol superoxide dismutase inhibits lipid peoroxidation inhepatic ischemic reperfusion injury.Crit Rare,1999,3(5):127-30.
[43]Vonrllar B,Riehter S,Menger MD.Leckucyte etasis in hepatic sinusoids.Am J physiol,1996,270(5):G798-803.
[44]Loft S,Larsen PN,Rusmussen A,et al.oxidative DNA damage afer tansplantation of the liver and small intestine in pigs. Tansplantation,1995,59(1):16-8.
[45]Yao H, Tang X, Shao X Feng L, Wu N, Yao K. Parthenolide protects human lens epithelial cells from oxidative stressinduced apoptosis via inhibition of activation of caspase-3 and caspase-9. Cell Res.2007,17F:565-571.
[46]Wen J, You KR,Lee SY, Song CH, Kim DG, Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide,J Biol Chem, 2002,277:38954-38964.
[47]Jaeschke H,Farhood A,Smith CW.Neutrophils contribute to ischemia/reperfusion injury in rat liver in vivo.FASEB J,1990,4:3355-9.
[48]Lentsch AB,Atsushi K,Yoshidome H,et al.Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia and reperfusion injury.Hepatololgy,2000,32(2):169-173.
[49]Fedrinnad S,FRCSI,Ngay A,et al.Hepatic ischemia-reperfusion injury.Am J Surg,2001,181(2):160-166.
[50]Martinez,Toledo P,Meduffie JE,et al.Neutrophil depletion and chemokine response after liver ischemia and reperfusion.J Invest Sugr,2001,14(1):99-107.
[51]Tosi MF,Stark JM,Wane C.Inducting of ICAM-1 expression on human airway epithelial cells by inflammatory cytokines:effect on neutrophil-epithelial adhension.AM J Respir,1992,7(2):214-221.
[52]Bradlay PP,Pkiebat DA,Cristensen RD,et al.Measurement of cutaneous inflammation:estimation of neutrofile content with an enzyme marker.J Invest Dermatol,1982,78(3):206-209.
[53]Jiang Y,Gu XP,Qiu YD,et al.Ischemia preconditioning decrease C-X-C chemokine expression and neutrophila accumulation early after liver transplantation in rats.World J Gastroenterol.2003,9(9):2025-2029.
[54]Lentsch AB,Yoshidome W,Cheadle F,et al.Chemokine involvement in hepatic ischemia reperfusion injury in mice roles for microphage inflammatory protein-2 and kupffer cell,Hepatology,1998,27(3):507-51.
[55]ThomasAB,JohnP.Early Gene Respose Hepatic Ischemia Reperfusion.J Surg Res,1996,63:98-104.
[56]Jr Baldwin AS. The NF-kB and IkB proteins:new discoveries and insights. Annu Rev Immunol,1996,14:649.
[57]Zandi E,Chen Y. Karin M.Direct phosphorylation of IkB by IKK a and IKK β:Discrimination between free and N-bound substrate.Science,1998,281:1360-1363.
[58]Andrade C, Kaneda H, Der S, et al. Effects of ischemia/reperfusion on gene expression of toll-like receptors and cytokines during human lung transplantation. Am J Respir Crit Care Med,2004,169:203.
[59]Hehner SP, Hofmann TG, Droge W, Schmitz ML. The anti-inflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the Ikappa B kinase complex. J Immunol 1999,163:5617-23.
[60]Teoh N, Leclercq I, Pena AD, et al. Low-dose TNF-alpha protects against hepatic ischemia-reperfusion injury in mice:implications for preconditioning. Hepatology,2003,37(1):118-128.
[61]Yassin MM,Harikin DW,Barros DpSa AA,et al.Lower limb isehemia reperfusion injury triggers a systemic inflammatory response and multiple organ dysfunetion.World J Surg,2002,26(1):115-121.
[62]Ohkohchi N, Shibuya H, Tsukamoto S, et al. Kupffer's cells modulate neutrophile activity by superoxide anion and tumor necrosis factor-delta in reperfusion injury of liver transplantation mechanisms of radical generation and reperfusion injury after cold ischemia.Transplant Proc,1999,31(1-2):1055-1058.
[63]Zwacka RM, Zhang Y, Halldorson J, et al. CD4+T-lymphocytes mediate ischemia/reperfusion induced inflammatory responses in mouse liver. J Clin Invest, 1997,100:279-289.
[64]Teoh N, Field J, Sutton J, et al. Dual role of tumor necrosis factor-α in hepatic ischemia-reperfusion injury:studies in tumor necrosis factor-agene knockout mice. Hepatology,2004,39(2):412-422.
[65]Colletti LM,Green ME,Burdick MD,et al.The ratio of ELR+ toELR-CXC chemokines affects the lung and liver injury followinghepatic ischemia/reperfusion in the rat.Hepatology,2000,31:435-445.
[66]Colletti LM, Kunkel SL, Walz A. et al. The role of cytokine networks in the local liver injury following hepatic ischemia/reperfusion in the rat. Hepatology, 1996,23:506-514.
[67]Lentsch AB, Yoshidome H, Cheadle WG, et al. Chemokine involvement in hepatic ischemia/reperfusion injury in mice:roles for macrophage inflammatory protein-2 and Kupffer cells. Hepatology,1998,27(2):507-512.
[68]Ohira H, Ueno T. Cultured rat hepatic sinusoidal endothelial cells express intercellular adehension molecule-1 by tumor necrosis factor-a stimulation.J Hepatology,1994,20(3):729-734.
[69]Colletti LM,Cortis A,Lukacs N,et al.Tumor necrosis factor upregulates intercellular adhesion molecule 1,which is important in the neutrophil-dependent lung and liver injury associated with hepatic ischemia and reperfusion in the rat.Shock,1998,10:182-191.
[70]Jaeschke H, Farhood A, Bautista A,et al.The F(ab)2 fragment of anti-ICAM-1 monoclonal antibody attenuate liver after orthotopic liver transplantation. Transplantation,1996,61 (1):99-104.
[71]Ghosh S.et al. NF-kappa B and Rel proteins:evolutionarily conserved mediators of immune responses.Annu.Rev.Immunol.1998:16:225-260.
[72]Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins:evolutionarily conserved mediators of immune responses.Annu Rev Immunol,1998,16:225-260.
[73]Wheele MD,Yamashina S,Froh M, et al.Adenoviral gene delivery can inactivate Kuffer cell:role of oxidants in NF- kappa B activation and eytokine production.J Leukoe Biol,2001,69(4):622-630.
[74]McDonald MC,Mota-Filipe H,PaulA,et al.Calpain inhibitor 1 reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagie shock..FASEB J,2001,15(1):171-186.
[75]Tsoulfas G,Takahashi Y,Ganster RW,et al.Activation of the lipopolysaccharide signaling pathway in hepatic transplantation preservation injury.Transplantation,2002,74(1):7-13.
[76]Xu J, Xie J, Bao M, et al. NF-kappaB/I-kappaB pathway during ischemia reperfusion injury of rat liver. Chin Med J (Eng),2003,116(8):1146-1149.
[77]Yoshidome H,Kato A,Edwards MJ.IL-10 suppresses hepatic ischemia/reperfusion injury in mice:Implication of a central role for muclear kB,Hepatology,1999,30:203-208.
[78]Matsui N,Kasajima K,Hada M,et al.Inhibiton of NF-kappaB activation during ischemia reduces hepatic ischemia/reperfusion injury in rats.J Toxicol Sci,2005,30(2):103-110.
[79]Uchinami H,Yamamoto Y,Kume M,et al.Effect of heat shock preconditioning on NF-kappaB/I-kappaB pathway during I/R injury of the rat liver[J].Am J Physiol Gastrointest Liver Physiol,2002,282(6):962-971.
[80]Yoshidome H,Kato A,Edwards MJ,et al.Interleukin-10 suppresses hepatic isehemia/reperfusion injury in mice:implications of a central role for nuclear factor kappa B.Hepatology,1999,30(1):203-208.
[81]Ghosh S,May MJ,Kopp EB.NF-kappa B and Rel proteins:evolutionarily conserved mediators of immune response.Annu Rev Immunol,1998,16:225-229.
[82]Zwacka R M, Zhang YL, Zhon WH, et al. Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor-κB independently of IκB degradation. Hepatology,1998,28 (5):1022-1030.
[83]Zandi E, Rothwarf MD,Delhase M,Hayakawa M. Karin M.The IkappaB kinase complex(IKK) contains two kinasesubunits,IKKalpha and IKKbeta,necessary for IkappaB phosphorylation and N-kappa B activation.Cell,1997,91,243-252.
[84]Yamaoka S.et al.Complementation cloning of NEMO,a component of the IkappaB kinase complex essential for NF-kappaB activation.Cell,1998,93:1231-1240.
[85]Zandi E, Rothwarf DM, Delhase M, et al. The Ⅰ kappa B kinase complex (IKK) containstwo kinase subunits. IKKα and IKKβ, necessary for Ⅰ kappaB phosphorylation and NF kappa B activation. Cell.1997,91(2):243-252.
[86]May MJ,D'Acquisto F, et al.Selective inhibition of NF-kB activation by a complex.Seience.2000,289:1550-1554.
[87]DiDonato AJ,Hayakawa M,Rothwarf DM,Zandi E, Karin M.A cytokine-responsive IkB kinase that activates the transcription factor NF-KB.Natuer,1997,388:548-554.
[88]Delhase M,Hayakawa M,Chen Y,Karin M.Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation,Science, 1999,284:309-313.
[89]Li,H.Y.,et al.,Deactivation of the kinase IKK by CUEDC2 through recruitment of the phosphatase PPl.Nat Immunol,2008.9(5):p.533-41.
[90]Karin M. The beginning of the end:IikB kinase(IKK)and NF-kB activation. Biol Chem,1999,274:27339-27342.
[91]Steffen P. Hehner, Thomas G. Hofmann, Wulf Droge and M. Lienhard Schmitz. The Antiinflammatory Sesquiterpene Lactone Parthenolide Inhibits NF-kB by Targeting the IkB Kinase Complex. The Journal of Immunology,1999,163: 5617-5623.
[92]Aicha Saadane, Sophia Masters, Joseph DiDonato, Jingfeng Li, Melvin Berger. Parthenolide Inhibits I[kappa]B Kinase, NF-[kappa]B Activation, and Inflammatory Response in Cystic Fibrosis Cells and MiceAmerican Journal of Respiratory Cell and Molecular Biology.2007,36,(6):728-9.
[93]Igaz P,Toth S,Falus A.Biological and clinical significance of the JAK-STAT pathway,lessons from knockout mice.Inflamm Res2002,50(9):435-441.
[94]Krasilnikov M,Ivanov VN,Dong J,et al.ERK and PI3K negatively regulate STAT transcriptioal activities in human melanoma cells; implications towards sensitization to apotosisi.Oncogene,2003,22(26):4091-4101.
[95]Krasilnikov M,Ivanov VN,Dong J,et al.ERK and PI3K negatively regulate STAT transcriptioal activities in human melanoma cells; implications towards sensitization to apotosisi.Oncogene,2003,22(26):4091-4101.
[96]沈诚,范士志,陈建明。抑制J炎性相关基因和蛋白表达AK/STAT通路对缺血再灌注损伤心肌TNF-a和IL-6表达的影响。重庆医学,2006,35(1)：38-42。
[97]Radoslaw Sobota, Marcin Szwed,Aneta Kasza, Marcin Bugno, Tomasz Kordula, Parthenolide inhibits activation of signal transducers and activators of transcription (STATs) induced by cytokines of the IL-6 family1. Biochemical and Biophysical Research Communications,2000,267:329-333.
[98]O'Shea, J.J. et al. Cytokine signaling in 2002:new surprises in the Jak/Stat pathway. Cell.2002,109:121-131.
[99]Levy DE,Darnell JE.Stats:transcriptional control and biological impact.Nat Rev Mol Cell Biol,2002,3(9):651-662.
[100]Osiak A,Utermohlen O,Niendorf S,Horak I,Knobeloch KP.ISG15,an interferon-stimulated ubiquitin-like protein,is not essential for STAT1 signaling and responses against vesicular stomatitis and lymphocytic choriomeningitis virus.Mol CellBiol.2005,25(15):6338-6345.
[101]Krebs DL,Hilton DJ.SOCS proteins:Negative regulation of cytokine signal.StemCells,2001,19(5):378-387.
[102]黄文林,朱孝峰主编。信号转导,北京：人民卫生出版社,2005。182-191。
[103]Ananthakrishnan R,Hallam K,Li Q,et al.JAK-STAT pathway in cardiac ischemic stress.Vascul Pharmacol.2005,43(5):353-356.
[104]Mascareno E,EI-Shafei M,Maullk N,et al.JAK-STAT signaling is associatd with cardiac dysfunction during ischemia and reperfusion. Circulation,2001,104(3):325-329.
[105]Irawan Satriotomo,Kellie K. Bowen,Raghu Vemuganti.JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia. Journal of Neurochemistry,2006,98:1353-1368.
[106]Yang N, Luo M, Li R, Huang Y, Zhang R, Wu Q, Wang F, Li Y, Yu X. Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rat. Nephrol Dial Transplant.2008,23(1):91-100.
[107]Schindler CW.Series introduction JAK-STAT signaling in human disease.J Clin Invest,2002,109(9):1133-1137.
[108]Akira S, Nishio Y, Inoue M, Wang X.J, et al.Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp 130-mediatedsignaling pathway. Cell,1994,77:63-71.
[109]姚胜,姚咏明,李红云,等。抑制JA K/STAT通路对烫伤后金黄色葡萄球菌脓毒症大鼠肝损害的影响。Chinese Critical Care Medicine,June 2002,1(14):16336-339.
[110]姚胜,姚咏明,李红云,等。烫伤脓毒症大鼠肝、肺组织STAT3(?)舌化 规律及意义。解放军医学志,2002,27(9)：763-765。
[111]郭婧芸,朱人敏,张晓华。抑制JAK/STAT信号通路对实验性急性胰腺炎大鼠肝损伤的保护作用。胃肠病学,2008,13(12)：719-722。
[112]毛一雷,于卓,桑新亭,卢欣,杨志英,钟守先。阻断炎症介质的信号转导对极限肝切除术后大鼠肝内细胞因子表达的影响。中华外科杂志,2005,43(1)：6-9。
[113]Lee YK,Isham CR,Kaufman SH,Bible KC.Flavopiridol disrupts STAT3/DNA interactions,attenuates STAT3-directed transcription,and combines with the Jak kinase inhibitor AG490 to achieve cytotoxic synergy.Mol Cancer Ther.2006,5(1):138-148.
[114]Radoslaw Sobota, Marcin Szwed,Aneta Kasza, Marcin Bugno, andTomasz Kordula, Parthenolide inhibits activation of signal transducers and activators of transcription (STATs) induced by cytokines of the IL-6 family1. Biochemical and Biophysical Research Communications,2000,267:329-333.
[115]Won YK, Ong CN, Shi X, Shen HM. Chemopreventive activity of parthenolide against UVB-induced skin cancer and its mechanisms. Carcinogenesis. 2004;25:1449-1458.
[116]Kurdi M,Booz GW.Evidence that IL-6-type cytokine signaling in cardiomyocytes is inhibited by oxidative stress:parthenolide targets JAK1 activation by generating ROS. Journal of Cellular Physiology,2007,212(2):424-431.
[1]O'Shea, J.J. et al. Cytokine signaling in 2002:new surprises in the Jak/Stat pathway. Cell.2002,109:121-131.
[2]Rodig SJ,Meraz MA,White JM,Lampe PA,Riley JK,Arthur CD,et al.Disruption of the Jakl gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses.Cell.1998;93:373-83.
[3]Schindler C,Strehlow I.Cytokines and STAT signaling.Ady.Pharmacol, 2000,47:113-174.
[4]Neubauer H,Cumano A,Mueller M,Wu H,Huffstadt U,Pfeffer K.Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis.Cell 1998;93:397-09.
[5]Tefferi A. JAK and MPL mutations in myeloid malignancies. Leuk Lymphoma.2008;49:388-97.
[6]Minegishi Y,Saito M,Morio T,Watanabe K,Agematsu K,Tsuchiya S,.Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.Immunity.2006;25:745-55.
[7]Karaghiosoff M,Neubauer H,Lassnig C,Kovarik P,Schindler H,Pircher H.Partial impairment of cytokine responses in Tyk2-deficient mice.Immunity,2000;13:549-60.
[8]Levy DE,Darnell JE.Stats:transcriptional control and biological impact.Nat Rev Mol Cell Biol,2002,3(9):651-662.
[9]Becker S, Groner B, Muller CW. Three-dimensional structure of the Stat3 beta homodimer bound to DNA. Nature 1998;394:145-51.
[10]Chen X, Vinkemeier U, Zhao Y, Jeruzalmi D, Darnell Jr JE, Kuriyan J. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 1998;93:827-39.
[11]Mao X, Ren Z, Parker GN, Sondermann H, Pastorello MA,WangW, et al. Structural bases of unphosphorylated STAT1 association and receptor binding. Mol Cell 2005;17:761-71.
[12]Schindler C, Levy DE, Decker T. JAK-STAT signaling:from interferons to cytokines. J Biol Chem 2007;282:20059-63.
[13]McBride KM, Reich NC. The ins and outs of STAT1 nuclear transport. Sci STKE 2003;2003:RE13.
[14]Bhattacharya S, Schindler C. Regulation of Stat3 nuclear export. J Clin Invest 2003;111:553-9.
[15]Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell Jr JE.Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell 1994;76:821-8.
[16]Mertens C, Zhong M, Krishnaraj R, Zou W, Chen X, Darnell Jr JE. Dephosphorylation of phosphotyrosine on STAT1 dimers requires extensive spatial reorientation of the monomers facilitated by the N-terminal domain. Sci STKE 2003;2003:RE13.
[17]Neculai D,Neculai AM, Verrier S, Straub K, Klumpp K, Pfitzner E. Structure of the unphosphorylated STAT5a dimer. J Biol Chem 2005;280:40782-7.
[18]Park C, Lecomte MJ, Schindler C. Murine Stat2 is uncharacteristically divergent.Nucleic Acids Res 1999;27:4191-9.
[19]Decker T, Muller M, Kovarik P. Regulation of Stats by posttranslational modification.In:Seghal PB, Hirano T, Levy DE, editors. Signal transducers andactivators of transcription (Stats):activation and biology. Kluwer Academic;2003.
[20]Wang D, Moriggl R, Stravopodis D, Carpino N, Marine JC, Teglund S. A small amphipathic alpha-helical region is required for transcriptional activities and proteasome-dependent turnover of the tyrosine-phosphorylated Stat5. EMBO J 2000;19:392-9.
[21]Schindler C, Fu XY, Improta T, Aebersold R, Darnell Jr JE. Proteins of transcription factor ISGF-3:one gene encodes the 91- and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc Natl Acad Sci USA 1992;89:7836-9.
[22]Shuai K, Schindler C, Prezioso V, Darnell JE. Activation of transcription by IFN-y:tyrosine phosphorylation of a 91-kDa DNA binding protein. Science,1992;258:1808-12.
[23]Zhang G, Ghosh S. Molecular mechanisms of NF-KappaB activation-induced by bacterial lipopolysaccharide through Toll-like receptors. J Endotoxin Res, 2000,6(6):453-457.
[24]Chapgier A, Boisson-Dupuis S, Jouanguy E, Vogt G, Feinberg J, Prochnicka-Chalufour A, et al. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease. PLoS Genet 2006;2:131.
[25]Jouanguy E, Lamhamedi-Cherradi S, Lammas D, Dorman SE, Fondaneche MC,Dupuis S, et al. A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nat Genet 1999;21:370-8.
[26]Schindler C, Levy DE, Decker T. JAK-STAT signaling:from interferons to cytokines. J Biol Chem 2007;282:20059-63.
[27]Bluyssen HAR,Levy DE.Stat2 is a transcriptional activator that requires sequence specific contacts provided by Statl and p48 for stable interaction with DNAJ.Biol.Chem,1997,272:4600-4605.
[28]Bromberg JF,Wrzeszezynska MH,Devgan G,et al.Stat3 as an Oncogene.Cell,1999,98:295-03.
[29]Takeda K,T Zhang G, Ghosh S. Molecular mechanisms of NF-KappaB activation- ninduced by bacterial lipopolysaccharide through Toll-like receptors. J Endotoxin Res,2000,6(6):453-457.
[30]Takeda K,Noguchi K,Shi W,et al.Targeted disruption of the mouse Stat3 gene leads to early lethality.Proe.Natl.Aead.Sci.USA,1997,94:3801-3804.
[31]Kaplan MH,Sun H,Hoey T,et al.Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice.Nature,1996,382:174-177.
[32]Gately MK,Renzetti LM,Magram J,et al.The interleukin-12/ interleukin-12-receptor system:role in normal and pathologic immune responses..Annu.Rev Immunol,1998,16:495-521.
[33]Sehindler C,Strehlow I.Cytokines and STAT signaling.Ady.Pharmaeol, 2000,47:113-174.
[34]Teglund S,McKay C Schuetz E,et al.Stat5a and Stat5b proteins have essential roles and nonessential,or redundant,roles in cytokine responses.Cell,1998,93:841-850.
[35]Hou J,Sehindler U,Henzel WJ,et al.An interleukin-4 induced transcription factor:IL-4 Stat.Scienee,1994,265:1701-1705.
[36]Lin J-X,Migone,TS,Tsang M,et al.The role of shared receptor motifs and common STAT proteins in the generation of cytokine pleiotropy and redundancy by IL-2,IL-4,IL-7,IL-13,andIL-15.Immunity,1995,2:331-339.
[37]Kaplan MH, Schindler U,Smiley ST, et al.Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells.Immunity,1996,4:313-319.
[38]黄文林,朱孝峰。信号转导。第一版,北京：人民卫生出版社。2005,7：183。
[39]Osiak A,Utermohlen O,Niendorf S,Horak I,Knobeloch KP.ISG15,an interferon-stimulated ubiquitin-like protein,is not essential for STAT1 signaling and responses against vesicular stomatitis and lymphocytic choriomeningitis virus.Mol Cell Biol.2005,25(15):6338-6345.
[40]Zhang G, Ghosh S. Molecular mechanisms of NF-KappaB activation-ninduced by bacterial lipopolysaccharide through Toll-like receptors. J Endotoxin Res, 2000,6(6):453-457.
[41]Shuai K.Regulation of cytokine signaling pathways by PIAS proteins.Cell Res.2006,16(2):196-202.
[42]Wu C,Guan Q,Wang Y,Zhao ZJ,Zhou GW.SHP-1 suppresses cancer cell growth by promoting degradation of JAK kinases.J Cell Biochem.2003,90 (5):1026-1037.
[43]Fawcett VC,Lorenz U.Localization of Src homology 2 domain-containing phosphatase 1(SHP-1)to lipid rafts in T lymphocytes:functional implications and a role for the SHP-1 carboxyl terminus.J Immunol,2005,174(5):2849-2859.
[44]Natarajan,C.etal.Signaling through JAK2-STAT5 pathway is essential for IL-3-induced activation of microglia.Glia.2004.45(2):188-196.
[45]Darnell JE Jr.STATs and gene regulation. Science,1997,277 (5332):1630-1635.
[46]Mascareno E,EI-Shafei M,Maulik N,et al.JAK-STAT signaling is associated with cardiac dysfunection during ischemia and reperfusion. Circulation,2001,104(4):325-329.
[47]沈诚,范士志,陈建明,李志平,何勇.抑制JAK/STAT通路对缺血再灌注损伤心肌TNF-a和IL-6表达的影响.重庆医学,2006,35(1)：38-39.
[48]Justicia C,Gabriel C,Planas AM.Activation of the JAK/STAT pathyway following transient focal cerebral ischemia:signaling through JAK1 and STAT3 in astrocytes. Glia,2000,30(3):253-270.
[49]West DA,Valentim LM,Lythgoe MF,et al.MR imaged-guided investigation of regional signal transducers and activators of ranscription activation in a rat model of focal cerebral ischemia.Neuroscience,2004,127(2):333-339.
[50]Suzuki S,Yamashita T,Tanaka K,et al.Activation of cytokine signaling through leukemia inhibitory factor receptor(LIFR/gP130)attenuates ischemic brain injury in rats.J Cereb Blood Flow Metab,2005,25(6):685-693.
[51]谢惠芳,徐如祥,魏继鹏,刘振华,姜晓丹。JAK2/STAT3信号转导通路在缺血性脑损伤中作用机制的研究.中风与神经疾病杂志。2008,25(2)：135-137。
[52]Yang N, Luo M, Li R, Huang Y, Zhang R, Wu Q, Wang F, Li Y, Yu X. Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rat. Nephrol Dial Transplant.2008,23(1):91-100.
[53]蓝柳根,彭民浩,卢景宁,陈滨。FK409对大鼠肝脏移植缺血再灌注损伤后JAK2/STAT3信号通路的影响。中国现代医学杂志,2009,19,(3)：390-394。
[54]丁忠阳,张峰,蔡兵,王学浩,王彤。抑制JAK/STAT信号通路对大鼠肝移植缺血再灌注损伤的影响。实用医学杂志,2008,24,(21)：3649-3651。