CAJ | 학술논문

目的探讨环氧化酶(COX)抑制剂氟比洛芬减轻肝脏缺血再灌注(IR)损伤的作用及机制.方法将C57BL/6小鼠分为假手术组、IR组和氟比洛芬组(根据药物剂量不同分为A、B、C、D组4个亚组).除假手术组外,其余组建立70％小鼠肝IR损伤模型,肝脏缺血时间为90 min.A、B、C、D组于缺血前20 min经小鼠尾静脉分别注射5、7.5、10和15 mg/kg的氟比洛芬.再灌注后通过血清学和组织学指标观察肝损伤情况,比较各组COX及其相关炎症因子的基因表达情况,检测各组肝细胞线粒体膜转换孔(mPTP)的敏感性.结果与IR组比较,再灌注后氟比洛芬组血清天冬氨酸转氨酶和丙氨酸转氨酶均明显降低(P＜0.05),其中C组下降最为明显.再灌注6h,与IR组比较,氟比洛芬组肝组织损伤较轻,凋亡细胞数明显减少(P＜0.05)；同时,肝组织COX-2及相关炎症因子白细胞介素1β(IL-1β)、IL-6和肿瘤坏死因子α(TNF-α)的基因表达也明显减少(P＜0.05)；再灌注后6h,氟比洛芬组mPTP对外源性Ca2+刺激的耐受性增加.结论氟比洛芬预处理能减轻小鼠肝脏IR损伤,该作用可能与减少炎症因子IL-1β、IL-6和TNF-α的表达,以及抑制mPTP.
목적 탐토배양화매(COX)억제제불비락분감경간장결혈재관주(IR)손상적작용급궤제.방법 장C57BL/6소서분위가수술조、IR조화불비락분조(근거약물제량불동분위A、B、C、D조4개아조).제가수술조외,기여조건립70％소서간IR손상모형,간장결혈시간위90 min.A、B、C、D조우결혈전20 min경소서미정맥분별주사5、7.5、10화15 mg/kg적불비락분.재관주후통과혈청학화조직학지표관찰간손상정황,비교각조COX급기상관염증인자적기인표체정황,검측각조간세포선립체막전환공(mPTP)적민감성.결과 여IR조비교,재관주후불비락분조혈청천동안산전안매화병안산전안매균명현강저(P＜0.05),기중C조하강최위명현.재관주6h,여IR조비교,불비락분조간조직손상교경,조망세포수명현감소(P＜0.05)；동시,간조직COX-2급상관염증인자백세포개소1β(IL-1β)、IL-6화종류배사인자α(TNF-α)적기인표체야명현감소(P＜0.05)；재관주후6h,불비락분조mPTP대외원성Ca2+자격적내수성증가.결론 불비락분예처리능감경소서간장IR손상,해작용가능여감소염증인자IL-1β、IL-6화TNF-α적표체,이급억제mPTP.
Objective To investigate the protective effect of a COX inhibitor,flurbiprofen (Flurb) on hepatic ischemia/reperfusion (IR) injury in rats and the action mechanism.Method C57BL/6 mice were randomized into sham,IR and Flurb (4 different doses) groups.The model of segmental (70％) warm hepatic ischemia was established in IR and Flurb groups.Flurbiprofen of different doses (5,7.5,10 and 15 mg/kg) was injected via the tail vein 20 min before ischemia.At different time points after reperfusion,liver cell necrosis and apoptosis were evaluated by HE and TUNEL staining.The COX and inflammatory cytokine gene expression was detected by using realtime PCR.Liver mitochondria were separated and mitochondrial permeability transition (MPT) pore sensitivity was examined by using swelling assay and fluorescence spectrophotometry assay.Result In flurbiprofen groups of different doses,the serum AST and ALT levels were significantly decreased at 6 h after reperfusion as compared with IR group.Moreover,10 mg/kg Flurb pretreatment significantly inhibited the mitochondrial permeability transition (MPT) pore opening,and thus alleviated liver cell damage and prevented mitochondria-related cell death and apoptosis by inhibiting COX-2 and inflammatory factor genes expression such as IL-1β,IL-6 and TNF-α.Conclusion Flurbiprofen protects mice from hepatic I/R injury possibly by inhibiting mitochondrial permeability transition and IL-1β,IL-6 and TNF-α expression,which may provide experimental evidence for clinical use of flurbiprofen to protect liver function in surgical settings other than its conventional use for pain relief.