舒芬太尼调节Ras/Raf/MEK/ERK信号通路对骨关节炎大鼠炎症反应和软骨细胞凋亡的影响OA北大核心CSTPCD
Influences of sufentanil on inflammatory response and chondrocyte apoptosis in osteoarthritis rats by modulating Ras/Raf/MEK/ERK signaling pathway
目的:探讨舒芬太尼(Suf)调节Ras/Raf/丝裂原激活蛋白激酶激酶(MEK)/细胞外信号调节激酶(ERK)信号通路对骨关节炎(OA)大鼠炎症反应和软骨细胞凋亡的影响.方法:SD大鼠分为正常对照组(NC组)、空白对照组(Blank组)、低剂量Suf组(Suf-L组,1 μg/kg)、高剂量Suf组(Suf-H组,5 μg/kg)、双醋瑞因(DC组,54 mg/kg)、Suf-H+ML-099(Ras/Raf/MEK/ERK通路激活剂)组(5 μg/kg Suf+11.7 mg/kg ML-099),每组12只.除NC组外,其他组大鼠均采用横断大鼠右膝关节内侧半月板胫骨韧带构建OA模型,成功建模后开始给药,而 NC组、Blank组大鼠需腹腔注射,而NC组、Blank组大鼠腹腔注射且灌胃等量生理盐水,每天给药1次,持续给药3周.末次给药24 h后,监测大鼠压痛阈值、热痛阈值变化;ELISA检测血清中TNF-α、IL-1β、IL-6水平;番红O-固绿染色检测软骨组织病理变化;TUNEL染色检测软骨细胞凋亡;Western blot检测软骨组织中Ras/Raf/MEK/ERK信号通路蛋白及基质金属蛋白酶13(MMP-13)蛋白表达.结果:与NC组比较,Blank组大鼠压痛阈值、热痛阈值降低(P<0.05),软骨组织病理损伤严重,TNF-α、IL-1β、IL-6水平、Mankin评分、软骨细胞凋亡率、Ras、Raf、MEK、p-ERK1/2、MMP-13蛋白表达升高(P<0.05);与Blank组比较,Suf-L组、Suf-H组、DC组对应指标变化趋势与上述相反(P<0.05);ML-099减弱了高剂量Suf对OA大鼠的影响.结论:Suf可能通过下调Ras/Raf/MEK/ERK通路抑制OA大鼠炎症和软骨细胞凋亡.
Objective:To investigate the influences of sufentanil(Suf)on the inflammatory response and chondrocyte apopto-sis in rats with osteoarthritis(OA)by modulating Ras/Raf/mitogen-activated protein kinase kinase(MEK)/extracellular signal-regulated kinase(ERK)signaling pathway.Methods:SD rats were grouped into normal control group(NC group),blank control group(Blank group),low-dose Suf group(Suf-L group,1 μg/kg),high-dose Suf group(Suf-H group,5 μg/kg),Diacerein group(DC group,54 mg/kg),and Suf-H+ML-099(Ras/Raf/MEK/ERK pathway activator)group(5 μg/kg Suf+11.7 mg/kg ML-099),with 12 rats in each group.Except for the NC group,the other groups were all constructed OA rat models by transection of the medial meniscus tibial ligament of the right knee joint.After the modeling was successful,the corresponding drug treatment was carried out,and the rats in the NC group and the Blank group were intraperitoneally injected and gavaged with the same amount of normal saline,administer once a day for 3 weeks.Twenty-four hours after the last administration,the changes of tenderness threshold and thermal pain threshold of rats were monitored;serum levels of TNF-α,IL-1β and IL-6 were detected by ELISA;Safranin O-Fast green staining was used to detect the pathological changes of cartilage tissue;TUNEL staining was used to detect chondrocyte apoptosis;Western blot was used to detect the expressions of Ras/Raf/MEK/ERK signaling pathway protein and matrix metalloproteinase 13(MMP-13)protein in carti-lage tissue.Results:Compared with NC group,the tenderness threshold and heat pain threshold of rats in Blank group were decreased(P<0.05),and the pathological injury of cartilage tissue was serious,TNF-α,IL-1β,IL-6 levels,Mankin score,chondrocyte apopto-sis rate,Ras,Raf,MEK,p-ERK1/2,MMP-13 protein expressions were increased(P<0.05);compared with the Blank group,the change trends of the corresponding indicators in Suf-L group,Suf-H group and DC group were opposite to the above(P<0.05);ML-099 attenuated the effect of high dose Suf on OA rats.Conclusion:Suf may attenuate the inflammatory response and chondrocyte apoptosis in OA rats by inhibiting the Ras/Raf/MEK/ERK signaling pathway.
张洪远;张腾;杜建国;陶宏
济宁医学院附属滕州市中心人民医院,滕州 277599
临床医学
舒芬太尼骨关节炎炎症Ras/Raf/丝裂原激活蛋白激酶激酶/细胞外信号调节激酶信号通路
SufentanilOsteoarthritisInflammationRas/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathway
《中国免疫学杂志》 2024 (010)
2071-2075,2082 / 6
徐州医科大学附属医院发展基金项目(XYFM2020046).
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