链霉素致听性脑干反应阈值明显上移时豚鼠肾脏的病理学改变

Pathological changes of kidney in guinea pigs when the threshold of auditory brainstem responses are obviously increased induced by streptomycin sulfate

目的:观察链霉素致听觉脑干反应阈值明显上移时豚鼠肾脏病理学改变,探讨听觉脑干反应检查作为链霉素耳肾毒副作用无损伤监测手段可行性。方法:①实验于2002-12/2003-05在中国医科大学听觉研究室和沈阳医学院机能研究中心完成。选用2月龄的健康白色红目豚鼠25只,雌雄不拘。②将双耳阈值<5dB健康白色红目豚鼠分为链霉素组[腹腔注射链霉素(大连美罗大药厂生产,批号:20010905,0.5g/支)150mg/(kg·d),并每日测量体质量以调整药量]和正常对照组[腹腔注射生理盐水2.5mL/(kg·d)]。均均连续干预10d。③用6kHz单周正弦波短声连续测定听觉脑干反应阈值,待两耳阈值明显上移时留取肾组织,用光镜和电镜检测技术观察肾脏组织学改变。结果:大鼠25只均进入结果分析。①用6kHz单周正弦波短声连续测定听觉脑干反应阈值10d,链霉素组中,有10只豚鼠用药前后听觉脑干反应阈值上移明显(双耳听觉脑干反应阈值≥5dB),而另5只听觉脑干反应阈值无显著改变(双耳听觉脑干反应阈值<5dB)。听觉脑干反应阈值上移豚鼠用药10d后听觉脑干反应阈值明显高于正常对照组和用药前(t=37.12,38.44,P<0.01)。②用链霉素10d后,听觉脑干反应阈值上移不明显豚鼠肾脏病理学检测未见异常改变,而听觉脑干反应阈值明显上移豚鼠虽然光镜所见肾小球无明显改变,但电镜结果表明肾小球有改变,表现为肾小球轴突融合、内皮细胞有泡状结构和毛细血管内红细胞雍塞等现象,而链霉素未导致听觉脑干反应阈值上移者肾小球可保持其结构正常。听觉脑干反应阈值上移的豚鼠光镜和电镜均可见肾小管有不同程度的损伤,在近曲小管和远曲小管均可见凋亡细胞,而正常对照组和听觉脑干反应阈值未上移鼠肾小管结构基本正常。结论:①链霉素致耳毒性存在个体差异。②链霉素致听觉脑干反应阈值上移时对整个肾脏均有毒副作用,且对肾小管的损害比肾小球严重。链霉素致听功能有改变时肾脏已出现不同程度的损伤。听觉脑干反应检查可作为链霉素耳肾毒副作用的无损伤监测手段。

AIM： To observe the pathological alteration of kidney when the threshold of auditory brainstem responses （ABR） are obvious increased induced by streptomycin sulfate in guinea pigs, and investigate the feasibility of ABS as an invasive means in monitoring the ototoxicity and nephrotoxicity of streptomycin sulfate. METHODS： （1） The experiment was carried out in the auditory research room of China Medical University and the functional research center of Shenyang Medical College from December 2002 to May 2004. Twenty-five male or temale healthy albinoa guinea pigs of 2 months were used. （2） The albinoa guinea pigs with both of ears＇ threshold of ABR ≤ 5 dB were divided into streptomycin sultate group and normal control group. The guinea pigs in the streptomycin sulfate group were treated with intraperitoneal injection of streptomycin sulfate （produced by Dianlian Meiluo Pharmacological Factory, No： 20010905; 0.5 g per piece） 150 mg/kg per day, and the dosage was adjusted every day according to the body mass, and those in the normal control group were given intraperitoneal injection of sodium chloride solution, 2.5 mL/kg per day, all the guinea pigs were treated for 10 days continuously. （3） The threshold of ABR was measured successively with 6 kHz one-circle sine wave short distance, and the renal tissue was reserved when the threshold of ABR was obviously increased to observe the renal histological changes under light and electron mieroseopes. RESULTS： All the guinea pigs were involved in the analysis of results. （1） After the threshold of ABR was detected with 6 kHz one-circle sine wave short distance for 10 days, in the streptomycin sulfate group, the threshold of ABR was obviously increased after treatment in 10 guinea pigs （the thresholds of bilateral ABR ≥ 5dB）, and those of the other 5 guinea pigs had no significant change （the thresholds of bilateral ABR〈 5 dB）. The threshold of ABR in the guinea pigs with obvious increase of the threshold of ABR at 10 days after treatment was obviously higher than that in the control group and that before treatment （t=37.12, 38.44, P 〈 0.01）. （2） At 10 days alter medication of streptomycin sulfate, the guinea pigs without obvious increase of the threshold of ABR had no abnonnal ehanges in the renal pathological detection, hut for those with increase of the threshold of ABR, the obvious change of renal corpuscles was not observed under light microscope, but the changes were observed under electron microscope, manifested by axis-cylinder confluence of renal corpuscles, bubble-like structure of endothelial cells and the occlusion of erythrocyte in blood capillary, but the renal corpuscle couht maintain its normal structure in those without increase of the threshold of ABR induced by streptomycin sulfate. Injury of different severity of renal corpuscles could be observed under light and electron microscopes in the guinea pigs with obvious increase of the threshold of ABR, apoptosis was also observed at proximal convoluted tubule and distal convoluted tubule, but the structure was generally normal in the control group and guinea pigs without obvious increase of the threshold of ABR. CONCLUSION： （1） Ototoxicity induced by streptomycin sulfate has individual difference, （2） The streptomycin sulfate induced increase of the threshold of ABR has nephrotoxicity, and has greater damage on renal tubule than on renal corpuscle. The kidney has had injuries of different severity when there, is change of auditory filnetion induced by streptomycin sulfate. ABR test could be taken as an invasive means in monitoring the ototoxicity and nephrotoxicity of streptomycin sulfate.