使用线粒体通透性转换孔（mPTP）抑制剂NIM-811减轻下肢缺血再灌注后骨骼肌和肾脏损伤。
Attenuation of skeletal muscle and renal injury to the lower limb following ischemia-reperfusion using mPTP inhibitor NIM-811.
作者信息
Garbaisz David, Turoczi Zsolt, Aranyi Peter, Fulop Andras, Rosero Oliver, Hermesz Edit, Ferencz Agnes, Lotz Gabor, Harsanyi Laszlo, Szijarto Attila
机构信息
Semmelweis University, 1st Department of Surgery, Budapest, Hungary.
University of Szeged, Department of Biochemistry and Molecular Biology, Szeged, Hungary.
出版信息
PLoS One. 2014 Jun 26;9(6):e101067. doi: 10.1371/journal.pone.0101067. eCollection 2014.
INTRODUCTION
Operation on the infrarenal aorta and large arteries of the lower extremities may cause rhabdomyolysis of the skeletal muscle, which in turn may induce remote kidney injury. NIM-811 (N-metyl-4-isoleucine-cyclosporine) is a mitochondria specific drug, which can prevent ischemic-reperfusion (IR) injury, by inhibiting mitochondrial permeability transition pores (mPTP).
OBJECTIVES
Our aim was to reduce damages in the skeletal muscle and the kidney after IR of the lower limb with NIM-811.
MATERIALS AND METHODS
Wistar rats underwent 180 minutes of bilateral lower limb ischemia and 240 minutes of reperfusion. Four animal groups were formed called Sham (receiving vehicle and sham surgery), NIM-Sham (receiving NIM-811 and sham surgery), IR (receiving vehicle and surgery), and NIM-IR (receiving NIM-811 and surgery). Serum, urine and histological samples were taken at the end of reperfusion. NADH-tetrazolium staining, muscle Wet/Dry (W/D) ratio calculations, laser Doppler-flowmetry (LDF) and mean arterial pressure (MAP) monitoring were performed. Renal peroxynitrite concentration, serum TNF-α and IL-6 levels were measured.
RESULTS
Less significant histopathological changes were observable in the NIM-IR group as compared with the IR group. Serum K+ and necroenzyme levels were significantly lower in the NIM-IR group than in the IR group (LDH: p<0.001; CK: p<0.001; K+: p = 0.017). Muscle mitochondrial viability proved to be significantly higher (p = 0.001) and renal function parameters were significantly better (creatinine: p = 0.016; FENa: p<0.001) in the NIM-IR group in comparison to the IR group. Serum TNF-α and IL-6 levels were significantly lower (TNF-α: p = 0.003, IL-6: p = 0.040) as well as W/D ratio and peroxynitrite concentration were significantly lower (p = 0.014; p<0.001) in the NIM-IR group than in the IR group.
CONCLUSION
NIM-811 could have the potential of reducing rhabdomyolysis and impairment of the kidney after lower limb IR injury.
引言
肾下主动脉及下肢大动脉手术可能导致骨骼肌横纹肌溶解，进而引发远隔肾损伤。NIM - 811（N - 甲基 - 4 - 异亮氨酸 - 环孢素）是一种线粒体特异性药物，可通过抑制线粒体通透性转换孔（mPTP）来预防缺血再灌注（IR）损伤。
目的
我们的目的是用NIM - 811减轻下肢IR后骨骼肌和肾脏的损伤。
材料与方法
Wistar大鼠经历180分钟双侧下肢缺血和240分钟再灌注。形成四组动物，分别称为假手术组（接受赋形剂和假手术）、NIM - 假手术组（接受NIM - 811和假手术）、IR组（接受赋形剂和手术）和NIM - IR组（接受NIM - 811和手术）。再灌注结束时采集血清、尿液和组织学样本。进行NADH - 四氮唑染色、计算肌肉湿/干（W/D）比值、激光多普勒血流仪（LDF）检测及平均动脉压（MAP）监测。检测肾过氧亚硝酸盐浓度、血清肿瘤坏死因子 - α（TNF - α）和白细胞介素 - 6（IL - 6）水平。
结果
与IR组相比，NIM - IR组的组织病理学变化不明显。NIM - IR组血清钾离子和坏死酶水平显著低于IR组（乳酸脱氢酶：p<0.001；肌酸激酶：p<0.001；钾离子：p = 0.017）。与IR组相比，NIM - IR组肌肉线粒体活力显著更高（p = 0.001），肾功能参数显著更好（肌酐：p = 0.016；滤过钠排泄分数：p<0.001）。NIM - IR组血清TNF - α和IL - 6水平显著更低（TNF - α：p = 0.003，IL - 6：p = 0.040），W/D比值和过氧亚硝酸盐浓度也显著更低（p = 0.014；p<0.001）。
结论
NIM - 811可能具有减轻下肢IR损伤后横纹肌溶解和肾脏损害的潜力。
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