快速耳蜗损伤小鼠模型的建立及应用
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摘要
第一部分两种小鼠耳蜗损伤方法的比较
目的：
比较两种小鼠耳蜗损伤方法的效果。
方法：
采用两种不同的方法损伤CBA/J小鼠耳蜗。第一种方案：卡那霉素700mg/kg,皮下注射,每日2次,连续14日。第二种方案：卡那霉素1000mg/kg,皮下注射,30-45min后呋塞米400mg/kg,腹腔注射。在给药前、给药结束后1天(d1)及给药结束后7天(d7)应用听性脑干反应(auditory brainstem response, ABR)评估小鼠听觉功能改变；在d7应用琥珀酸脱氢酶(succinate dehydrogenase, SDH)染色评价毛细胞(hair cells, HCs)线粒体功能损伤情况。
结果：
CBA/J小鼠在单独应用卡那霉素后,ABR阈值在d1明显升高,随后在d7继续升高。形态学结果显示耳蜗底回绝大部分外毛细胞(outer hair cells, OHCs) SDH活性消失,而内毛细胞(inner hair cells, IHCs) SDH活性保存完好；顶回部分OHCs SDH活性减弱,而IHCs SDH活性绝大部分保存完好。CBA/J小鼠在联合应用卡那霉素及呋塞米后,ABR阈值同样在d1明显升高,在d7继续升高,且最终阈移大于单独应用卡那霉素之阈移。形态学结果显示耳蜗底回及顶回OHCs SDH活性完全消失,而IHCsSDH活性保存完好。
结论：
两种方法均能造成小鼠耳蜗损伤,但联合应用卡那霉素及呋塞米较单独应用卡那霉素对耳蜗损伤程度更大,且操作更简便。
第二部分联合应用卡那霉素和呋塞米快速诱导小鼠耳蜗损伤
目的：
探讨卡那霉素和呋塞米联合应用对小鼠耳蜗的毒性作用,建立一种可靠的小鼠感音神经性聋模型。
方法：
选用3-4周龄的CBA/J小鼠为实验对象,按1000mg/kg的剂量皮下注射卡那霉素,30-45min后按400mg/kg的剂量腹腔注射呋塞米。在注射前、注射后12小时(d0.5)、1天(d1)、2天(d2)、7天(d7)、14天(d14)、28天(d28)及112天(d112)分别应用听性脑干反应(auditory brainstem response, ABR)检测小鼠听觉功能的改变；应用异硫氰酸荧光素标记的鬼笔环肽及碘化丙锭染色、半薄切片甲苯胺蓝染色、脱氧核苷酸末端转移酶介导的dUTP缺口末端标记(terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL)技术、扫描电镜等观察小鼠毛细胞(hair cells, HCs)和螺旋神经节细胞(spiral ganglion neurons, SGNs)死亡的模式和程度。
结果：
小鼠ABR阈值在d0.5开始上升,随后至d2期间继续进行性上升,继而趋于稳定在90 dB SPL左右。应用激光共聚焦显微镜在d0.5观察到耳蜗底回外毛细胞(outer hair cells, OHCs)开始出现死亡,d1时底回OHCs基本全部消失,同时顶回OHCs开始出现死亡,至d2时整个耳蜗OHCs绝大部分死亡；而内毛细胞(inner hair cells, IHCs)的损伤至d7时才开始出现,随时间推移仍有部分IHCs完好无损。TUNEL结果显示死亡的HCs均具有典型的凋亡细胞特征。扫描电镜显示卡那霉素和呋塞米联合应用后HCs首先出现纤毛消失,表皮板塌陷,随后支持细胞增生并在该处形成瘢痕。SGNs在d2保持完整,但在d7开始出现体积减小,d14天出现数量减少,至d28大部分死亡,至d112仅余少数细胞残留。
结论：
单剂量序贯应用卡那霉素及呋塞米能快速诱导小鼠耳蜗HCs大量死亡,并能造成SGNs延迟性死亡,适用于建立小鼠感音神经性聋模型。
第三部分小鼠耳蜗外侧壁在感音神经性聋发生后的反应
目的：
探讨感音神经性聋发生后小鼠耳蜗外侧壁形态和功能的改变。
方法：
选用3-4周龄的CBA/J小鼠为实验对象,联合应用卡那霉素及呋塞米致聋。在给药后12小时(d0.5)、1天(d1)、2天(d2)、7天(d7)、14天(d14)、28天(d28)及112天(d112)监测耳蜗内电位(endocochlear potential, EP)的改变；应用苏木素伊红(hematoxylin and eosin, H&E)染色、扫描电镜、透射电镜、免疫化学、逆转录聚合酶链反应(reverse transcriptase polymerase chain reaction, RT-PCR)等方法检测耳蜗外侧壁形态以及四种K+转运蛋白α1,a 2Na,K-ATPase、NKCC1和KCNQ1的变化。
结果：
小鼠EP自d0.5开始下降,至d1进行性下降,至d2完全恢复正常并在随后长时期保持稳定。HE染色显示毛细胞损失和耳蜗外侧壁萎缩是主要病理改变。扫描电镜观察发现血管纹表面边缘细胞在给药后出现胞体肿胀,随后边缘细胞表面大部分微绒毛消失,胞体呈“石块”样改变。透射电镜结果显示血管纹厚度在致聋后进行性下降,主要为边缘细胞萎缩造成。免疫化学结果表明耳蜗外侧壁α1,a 2Na,K-ATPase和NKCC1的蛋白表达水平明显下降,而KCNQ1的蛋白表达水平无明显改变。RT-PCR结果同样提示α1,a 2Na,K-ATPase和NKCC1 mRNA的表达水平下降而KCNQ1 mRNA的表达水平未受影响。
结论：
萎缩后的耳蜗外侧壁在毛细胞严重缺失的情况下仍然可以保证EP的正常维持,其原因可能是a 1, a 2Na,K-ATPase和NKCC1的共同下调使K+在耳蜗外侧壁的转运在一个新的水平上达到平衡。
PART 1 Two regimes for cochlear lesions in mice
Objective:To compare the effects of two regimes for cochlear lesions in mice.
Methods:Experimental mice were received either 700 mg of kanamycin/kg body weight by subcutaneous injection twice daily for 14 days or a sigle subcutaneous injection of kanamycin at 1000 mg/kg body weight, followed 30-45 min later by a sigle intraperitoneal injection of furosemide at 400 mg/kg body weight. The auditory brainstem response were performed prior to the beginning of the study,1 day and 7 days after drug adminstration. Succinate dehydrogenase (SDH) activty was examined at 7 days after drug adminstration to assesse the mitochondrial energetic function in hair cells.
Results:After 14 days of kanamycin treatment, animals developed significant threshold shifts and the threshold shifts increased further during the third week. In animals treated with kanamycin and furosemide, threshold shifts were also elevated at 1 day posttreatment and continuted to increase during the second week. The threshold shifts in the latter group were larger than those in the former group. SDH staining results showed there was a significant reduction of SDH activity in outer hair cells (OHCs) in the basal turn in the animals treated with kanamycin alone. In contrast, SDH activity was reduced in OHCs in both basal turn and apical turn in the animals treated with kanamycin and furosemide. In both cases, SDH activity showed no change in inner hair cells.
Conclusions:Cochlear lesions can be induced by both regimes but co-administration of kanamycin and furosemide can cause a more severe damage to the cochlea and this precedure is easy to perform.
PART 2 Rapid cochlear lesions induced by co-administration of kanamycin and furosemide in mice
Objective:To investigate the ototoxicity of co-administration of kanamycin and furosemide in mice and present a reliable approach for induing a rapid and profound sensorineural hearing loss.
Methods:CBA/J mice,3-4 weeks old received a sigle subcutaneous injection of kanamycin at 1000 mg/kg body weight, followed 30-45 min later by a sigle intraperitoneal injection of furosemide at 400 mg/kg body weight. The auditory brainstem response (ABR) threshold shifts, extent and defining characteristics of the cochlear lesions were assessed and verified by propidium iodide and phalloidin staining, toluidine blue staining, TUNEL, scanning electron microscopy (SEM) prior to the beginning of the study,12 hours,1,2,7,14,28 and 112 days after injections.
Results:This drug combination resulted in an significant increased ABR threshold shifts firstly at 12h posttreatment, which increased further in the first 2 days posttreatment and then stabilized around 90 dB SPL thereafter. Histopathological examination showed an absence of outer hair cells (OHCs) at basal turn rapidly from 12 hours posttreatment. By 2 days the most commonly observed lesion was that all OHCs throughout the length of the cochlea were killed, while inner hair cells (IHCs) loss were delayed and mild. TUNEL-positive nuclei demonstrated that most hair cells died via an apoptotic pathway. In SEM abundance of damaged OHCs were detected by 1 day posttreatment, in which reticular lamina were collapsed. Then all OHCs were repalced by expansion of heads of the supporting cells. Spiral ganglion neurons also exhibited remarkable degeneration.
Conclusion:This reliable systemic protocol eliminated hair cells extensively in vivo and is a means with which to examine different aspects of cochlear pathology in transgenic or mutant strains.
PART 3 Morphological and functional response of cochlear lateral wall following a sensorineural hearing loss in mice
Objective:To investigate the alteration of the endocochlear potential (EP) and experssion pattern of some key potassium transporters in the cochlear lateral wall following a long-term sensorineural hearing loss (SNHL).
Methods:CBA/J mice were administered a single dose of kanamycin followed by furosemide. The alteration of EP, morphological change of the lateral wall, expression of the a 1 and a 2 isoforms of Na,K-ATPase, Na-K-2Cl-Cotransporter-1 (NKCC1) and potassium channel KCNQ1 were assessed.
Results:The EP displayed a significant decline at 12 hours posttreatment followed by complete recovery by 2 days posttreatment. Then the EP maintained at near normal levels in animals deafened for periods up to 112 days. By 2 days posttreatment marginal cells were swollen and some of them were observed to be fused. By 14 days nearly all microvillis were lost and marginal cells presented a sign of stone-like change. There was also a significant and progressive decrease in stria vascularis thickness, which was predominantly due to atrophy of marginal cells. Meanwhile both protein and mRNA expression of a 1 and a 2 isoforms of Na,K-ATPase and NKCC1 in the lateral wall were dramatically reduced following a long-term deafening but KCNQ1 expression remained unchanged.
Conclusion:The EP remained at normal levels following a long-term aminoglycoside-induced hearing loss. Simultaneously reduced NKCC1 and Na,K-ATPase expression in the cochlear lateral wall may contribute to such conservation of EP.
目的：
比较两种小鼠耳蜗损伤方法的效果。
方法：
采用两种不同的方法损伤CBA/J小鼠耳蜗。第一种方案：卡那霉素700mg/kg,皮下注射,每日2次,连续14日。第二种方案：卡那霉素1000mg/kg,皮下注射,30-45min后呋塞米400mg/kg,腹腔注射。在给药前、给药结束后1天(d1)及给药结束后7天(d7)应用听性脑干反应(auditory brainstem response, ABR)评估小鼠听觉功能改变；在d7应用琥珀酸脱氢酶(succinate dehydrogenase, SDH)染色评价毛细胞(hair cells, HCs)线粒体功能损伤情况。
结果：
CBA/J小鼠在单独应用卡那霉素后,ABR阈值在d1明显升高,随后在d7继续升高。形态学结果显示耳蜗底回绝大部分外毛细胞(outer hair cells, OHCs) SDH活性消失,而内毛细胞(inner hair cells, IHCs) SDH活性保存完好；顶回部分OHCs SDH活性减弱,而IHCs SDH活性绝大部分保存完好。CBA/J小鼠在联合应用卡那霉素及呋塞米后,ABR阈值同样在d1明显升高,在d7继续升高,且最终阈移大于单独应用卡那霉素之阈移。形态学结果显示耳蜗底回及顶回OHCs SDH活性完全消失,而IHCsSDH活性保存完好。
结论：
两种方法均能造成小鼠耳蜗损伤,但联合应用卡那霉素及呋塞米较单独应用卡那霉素对耳蜗损伤程度更大,且操作更简便。
第二部分联合应用卡那霉素和呋塞米快速诱导小鼠耳蜗损伤
目的：
探讨卡那霉素和呋塞米联合应用对小鼠耳蜗的毒性作用,建立一种可靠的小鼠感音神经性聋模型。
方法：
选用3-4周龄的CBA/J小鼠为实验对象,按1000mg/kg的剂量皮下注射卡那霉素,30-45min后按400mg/kg的剂量腹腔注射呋塞米。在注射前、注射后12小时(d0.5)、1天(d1)、2天(d2)、7天(d7)、14天(d14)、28天(d28)及112天(d112)分别应用听性脑干反应(auditory brainstem response, ABR)检测小鼠听觉功能的改变；应用异硫氰酸荧光素标记的鬼笔环肽及碘化丙锭染色、半薄切片甲苯胺蓝染色、脱氧核苷酸末端转移酶介导的dUTP缺口末端标记(terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL)技术、扫描电镜等观察小鼠毛细胞(hair cells, HCs)和螺旋神经节细胞(spiral ganglion neurons, SGNs)死亡的模式和程度。
结果：
小鼠ABR阈值在d0.5开始上升,随后至d2期间继续进行性上升,继而趋于稳定在90 dB SPL左右。应用激光共聚焦显微镜在d0.5观察到耳蜗底回外毛细胞(outer hair cells, OHCs)开始出现死亡,d1时底回OHCs基本全部消失,同时顶回OHCs开始出现死亡,至d2时整个耳蜗OHCs绝大部分死亡；而内毛细胞(inner hair cells, IHCs)的损伤至d7时才开始出现,随时间推移仍有部分IHCs完好无损。TUNEL结果显示死亡的HCs均具有典型的凋亡细胞特征。扫描电镜显示卡那霉素和呋塞米联合应用后HCs首先出现纤毛消失,表皮板塌陷,随后支持细胞增生并在该处形成瘢痕。SGNs在d2保持完整,但在d7开始出现体积减小,d14天出现数量减少,至d28大部分死亡,至d112仅余少数细胞残留。
结论：
单剂量序贯应用卡那霉素及呋塞米能快速诱导小鼠耳蜗HCs大量死亡,并能造成SGNs延迟性死亡,适用于建立小鼠感音神经性聋模型。
第三部分小鼠耳蜗外侧壁在感音神经性聋发生后的反应
目的：
探讨感音神经性聋发生后小鼠耳蜗外侧壁形态和功能的改变。
方法：
选用3-4周龄的CBA/J小鼠为实验对象,联合应用卡那霉素及呋塞米致聋。在给药后12小时(d0.5)、1天(d1)、2天(d2)、7天(d7)、14天(d14)、28天(d28)及112天(d112)监测耳蜗内电位(endocochlear potential, EP)的改变；应用苏木素伊红(hematoxylin and eosin, H&E)染色、扫描电镜、透射电镜、免疫化学、逆转录聚合酶链反应(reverse transcriptase polymerase chain reaction, RT-PCR)等方法检测耳蜗外侧壁形态以及四种K+转运蛋白α1,a 2Na,K-ATPase、NKCC1和KCNQ1的变化。
结果：
小鼠EP自d0.5开始下降,至d1进行性下降,至d2完全恢复正常并在随后长时期保持稳定。HE染色显示毛细胞损失和耳蜗外侧壁萎缩是主要病理改变。扫描电镜观察发现血管纹表面边缘细胞在给药后出现胞体肿胀,随后边缘细胞表面大部分微绒毛消失,胞体呈“石块”样改变。透射电镜结果显示血管纹厚度在致聋后进行性下降,主要为边缘细胞萎缩造成。免疫化学结果表明耳蜗外侧壁α1,a 2Na,K-ATPase和NKCC1的蛋白表达水平明显下降,而KCNQ1的蛋白表达水平无明显改变。RT-PCR结果同样提示α1,a 2Na,K-ATPase和NKCC1 mRNA的表达水平下降而KCNQ1 mRNA的表达水平未受影响。
结论：
萎缩后的耳蜗外侧壁在毛细胞严重缺失的情况下仍然可以保证EP的正常维持,其原因可能是a 1, a 2Na,K-ATPase和NKCC1的共同下调使K+在耳蜗外侧壁的转运在一个新的水平上达到平衡。
PART 1 Two regimes for cochlear lesions in mice
Objective:To compare the effects of two regimes for cochlear lesions in mice.
Methods:Experimental mice were received either 700 mg of kanamycin/kg body weight by subcutaneous injection twice daily for 14 days or a sigle subcutaneous injection of kanamycin at 1000 mg/kg body weight, followed 30-45 min later by a sigle intraperitoneal injection of furosemide at 400 mg/kg body weight. The auditory brainstem response were performed prior to the beginning of the study,1 day and 7 days after drug adminstration. Succinate dehydrogenase (SDH) activty was examined at 7 days after drug adminstration to assesse the mitochondrial energetic function in hair cells.
Results:After 14 days of kanamycin treatment, animals developed significant threshold shifts and the threshold shifts increased further during the third week. In animals treated with kanamycin and furosemide, threshold shifts were also elevated at 1 day posttreatment and continuted to increase during the second week. The threshold shifts in the latter group were larger than those in the former group. SDH staining results showed there was a significant reduction of SDH activity in outer hair cells (OHCs) in the basal turn in the animals treated with kanamycin alone. In contrast, SDH activity was reduced in OHCs in both basal turn and apical turn in the animals treated with kanamycin and furosemide. In both cases, SDH activity showed no change in inner hair cells.
Conclusions:Cochlear lesions can be induced by both regimes but co-administration of kanamycin and furosemide can cause a more severe damage to the cochlea and this precedure is easy to perform.
PART 2 Rapid cochlear lesions induced by co-administration of kanamycin and furosemide in mice
Objective:To investigate the ototoxicity of co-administration of kanamycin and furosemide in mice and present a reliable approach for induing a rapid and profound sensorineural hearing loss.
Methods:CBA/J mice,3-4 weeks old received a sigle subcutaneous injection of kanamycin at 1000 mg/kg body weight, followed 30-45 min later by a sigle intraperitoneal injection of furosemide at 400 mg/kg body weight. The auditory brainstem response (ABR) threshold shifts, extent and defining characteristics of the cochlear lesions were assessed and verified by propidium iodide and phalloidin staining, toluidine blue staining, TUNEL, scanning electron microscopy (SEM) prior to the beginning of the study,12 hours,1,2,7,14,28 and 112 days after injections.
Results:This drug combination resulted in an significant increased ABR threshold shifts firstly at 12h posttreatment, which increased further in the first 2 days posttreatment and then stabilized around 90 dB SPL thereafter. Histopathological examination showed an absence of outer hair cells (OHCs) at basal turn rapidly from 12 hours posttreatment. By 2 days the most commonly observed lesion was that all OHCs throughout the length of the cochlea were killed, while inner hair cells (IHCs) loss were delayed and mild. TUNEL-positive nuclei demonstrated that most hair cells died via an apoptotic pathway. In SEM abundance of damaged OHCs were detected by 1 day posttreatment, in which reticular lamina were collapsed. Then all OHCs were repalced by expansion of heads of the supporting cells. Spiral ganglion neurons also exhibited remarkable degeneration.
Conclusion:This reliable systemic protocol eliminated hair cells extensively in vivo and is a means with which to examine different aspects of cochlear pathology in transgenic or mutant strains.
PART 3 Morphological and functional response of cochlear lateral wall following a sensorineural hearing loss in mice
Objective:To investigate the alteration of the endocochlear potential (EP) and experssion pattern of some key potassium transporters in the cochlear lateral wall following a long-term sensorineural hearing loss (SNHL).
Methods:CBA/J mice were administered a single dose of kanamycin followed by furosemide. The alteration of EP, morphological change of the lateral wall, expression of the a 1 and a 2 isoforms of Na,K-ATPase, Na-K-2Cl-Cotransporter-1 (NKCC1) and potassium channel KCNQ1 were assessed.
Results:The EP displayed a significant decline at 12 hours posttreatment followed by complete recovery by 2 days posttreatment. Then the EP maintained at near normal levels in animals deafened for periods up to 112 days. By 2 days posttreatment marginal cells were swollen and some of them were observed to be fused. By 14 days nearly all microvillis were lost and marginal cells presented a sign of stone-like change. There was also a significant and progressive decrease in stria vascularis thickness, which was predominantly due to atrophy of marginal cells. Meanwhile both protein and mRNA expression of a 1 and a 2 isoforms of Na,K-ATPase and NKCC1 in the lateral wall were dramatically reduced following a long-term deafening but KCNQ1 expression remained unchanged.
Conclusion:The EP remained at normal levels following a long-term aminoglycoside-induced hearing loss. Simultaneously reduced NKCC1 and Na,K-ATPase expression in the cochlear lateral wall may contribute to such conservation of EP.
引文
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