持续高G对豚鼠前庭耳石器的影响及预习服防护措施的实验研究
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摘要
高G环境是航空航天活动中常见的对人体有较大影响的因素之一。随着航
空航天技术及人体防护措施的发展，飞行人员需要承受的G值越来越大，宇航
员在发射阶段也常需要承受高G值的作用。然而，以往航空航天医学工作者主
要着眼于高G值对心脑血管系统的影响及防护等方面，对直接感受高G值作用
的前庭耳石器的影响却没有引起足够的重视。耳石器是否能承受如此高的G值
而正常工作？这是一个值得深入探讨的问题。因为如果高G值造成耳石器的损
害，可引发眩晕、空间定向障碍等，造成严重后果。另外，如果宇航员在发射
阶段造成了耳石器的损害，是否会与航天适应综合征（Space adaptation
syndrome，SAS）发病有关等也不得而知。因此，探讨、明确高G是否会造成耳
石器损伤具有十分重要的理论和现实意义。另外，如果耳石器受到损伤，在防
护上也存在一系列问题。这是因为，由于耳石器解剖，生理上的特殊性，使其
不可能象对心脑血管系统那样从装备等方面进行防护，可能的方法只能是通过
锻炼等手段，提高其对高G值作用的耐受值。预适应是生物界普遍存在的一种
现象，对于保护各系统器官具有一定积极意义。前庭系统是否也存在预适应现
象，其是否可提高豚鼠对高G值作用的耐受值，从而对高G作用所致前庭功能
损害起到一定的防护作用？这也是一个值得深入探讨的问题。
染凹车医人学博士学位论义
本文采用行为学、形态学、细胞生物学、分子生物学等手段，观察了
＋ltoy oin暴露对豚鼠前庭耳石器的影响以及Z 8天的预习服对其防护作用。
主要结果如下：
1．＋lmy初in的暴露（、l地组）可5！起22／28门狐）豚鼠行为学的异
常，包括自发眼震、眼位偏斜、头位震颤、头位偏斜、身体转圈、侧滚转等；
而在给子＋lffiy SInin的暴露前经过预习服（预习服组）的行为异常率只有14／28
（h）。提示高G可造成豚鼠前庭功能紊乱，预习服具有一定的防护作用。
2．采用光镜、电镜形态学观察方法发现：光镜下八op组和预习服组均有
一定程度细胞空泡化。电镜下显示：＋ltoy组于＋ltoy暴露后0．sh呈现两种性质
的耳石改变：①耳石消失及耳石再生前体一一球状物的出现：②耳石的变性融
合，即耳石失去原有形态，融合为一个整体。24h后表现为耳石膜明显增厚；
高倍镜下证实其主要为哑铃状不成熟耳石。预习服组于＋l％y暴露后队sh表现
为耳石有裂纹出现和层状化，24h后呈现出耳石质地疏松和微细孔状结构出
现。另外两组豚鼠均有纤毛粘连和倒伏。左右耳未见差别。
3．应用原位末端标记的方法（11jNlilM法）在两组均检测到可疑凋亡细胞，
两组之间未见明显区别。对照组未见凋亡细胞。
4．应用核酸原位杂交技术，发现预习服组在＋hey暴露后 HSP70 InRNA表达
明显增强，其次为＋l地直接暴露组，对照组最弱。
5．应用免疫组织化学方法，发现细胞骨架蛋白cytokeratin在各组间没有
变化，actin在各组均呈阴性反应。
6．应用免疫组织化学方法。发现两组ChAT染色均明显高于对照组，不过
两组之间未见明显差别。
7．观察到不仅支持细胞可以分泌产生耳石前体——球状物，而且1型细胞
也可以产生，证实丰富了前庭生理学中有关耳石再生来源的理论。
扼此，提出高G引起豚鼠行为表现异常的主要机理是：①高过载环境下，耳
石重量相对增加，引起耳石层与下方胶质层切线力增大，其问结合受到损害，从而
《
第四军医大学博士学位论文
耳石移位和／或耳石、囊斑上皮细胞代谢障碍，引起一系列病变，导致行为学表现
异常；②高过载环境下，心肺工作效率下降，血氧饱和度下降，组织能量代谢
障碍是引起一系列囊斑病变，导致行为表现异常的又一原因：③内耳血供的一
些特点（如缺乏侧枝循环）和囊斑上皮细胞对缺氧等的高敏感性加剧了囊斑病变，
对行为学表现异常起到了恶化促进作用；④高过载环境下，外周传入信息增
加，中枢乙酚胆碱升高，也是行为学表现异常的因素之一。预习服防护机理在
于：恤6G值环境下，耳石层与胶质层之间结合发生改变，如结合更紧密等，
从而在高过载作用时不易受损，病变减轻：②组织对缺氧耐受性增加，不易发
生能量代谢障碍；＠一系列保护因子如HSNQ［lltNA表达增强，发挥其对组织细
胞的保护作用。通过以上途径，囊斑病变减轻，行为学表现异常明显改善
People are often exposed to high G environment in aerospace activities. Sometimes
the G values they are subjected to may be even more than 10G. Can otolith organs not be damaged and work properly in this environment? The answer to this question is critical to solve the problems such as vertigo, spatial disorientation, space adaptation syndrome(SAS) etc.
In this work, guinea pigs' vestibular disorders, the ultrastructure of the macula, the apoptosis cells, the expression of HSP70 mRNA, cytokeratin and actin in macula of the utricle, and the ChAT activities in VNC(vestibular necleon complex)were observed after they were exposed to +10Gy for 5mia A countermeasure of 8 days pre-habituation in 2G force-field was also tested. The results are as follows:
1. Abnormalities of behavior, vestibule-spinal reflex (VSR) and vestibule-ocular
reflex (VOR) were found in 22/28 of the guinea pigs after exposed to +10Gy for 5min(+10Gy group), which included head tremble, head deviation, spontaneous nystagmus, eye deviation, body roll and looping. All the symptoms disappeared within 30 rain. Among them, head tremble was of the highest incidence. In the group which was exposed to 2G environment for 8 days before being exposed to 10Gy(habituation group), only 14/28 showed vestibular disorders, which was statistically significant lower compared with that of +10Gy group.
2. In +10Gy group, 0.5h later after lOGy exposure, two kinds of otoconia ultrastructure changes were observed: ヾisappearance of the otoconia and appearance of its precursor 棗global substance; ヾegeneration and fusion of the otoconia, including the disappearance of its classical prism-like structure and fusing into a larger one. 24h later, the incrassation of the utricle macula was prominent, and large dumb-bell shaped immature otoconia were observed in a high-power view. In habituation group, emergence of flaws and porous of otoconia were observed 0. 5h and 24h later respectively after lOGy exposure. Conglutination and sloping of the hair cell cilia were observed in both +10Gy group and habituation group. By using transmission electron microscope(TEM), plasmolysis and cell nucleus condensation were observed prominent in +10Gy group, while in habituation group, only a few cells showed cell nucleus condensation. By using HE staining method, both groups showed the cell swelling and vacuolation. The differences in ultrastructure changes between right and left utricles were non-significant.
3. By using a TUNEL(terminal-deoxynucleotidyl transferase mediated d~LTP nick end labeling) method, The apoptosis hair cells were detected in both T10Gy and habituation groups, but absent in control group.
4. The expression of HSP70 (by in situ hybridization methods) in habituation group is the strongest, +10Gy group was the second, and the control group was the weakest.
5. No significant differences of expression of cytokeratin in macula were found
among +10Gy, habituation and control groups by inmunohistochemistry technique. Negative reaction of actin was observed among above three groups.
6.The ChAT(choHne acetytransferase) activities in VNC in brain stem were investigated by immunohistochemistry technique. The relative gamma of staining showed that the content of ChAT in VNC of the +lOGy group and habituated group were significant higher than that in control group, but no significant differences were found between the +10Gy and habituation groups.
7. The precursor of otoconia global substance can be generated from both supporting cells and type I hair cells.
According to the results, the following points may contribute to the mechanism of high G induced vestibular disorders: ?the otoconia displacement and/or its metabolic disorder, which was caused by high G induced damage of conjunction between the otoconia layer and gelatin layer;@under high G environment, the inefficiency of cardiopulmonary system, reduction in blood oxygen saturation, and metabolic disorder of energy in related tissues were another reason causing behavior abnormalities;?the hi
空航天技术及人体防护措施的发展，飞行人员需要承受的G值越来越大，宇航
员在发射阶段也常需要承受高G值的作用。然而，以往航空航天医学工作者主
要着眼于高G值对心脑血管系统的影响及防护等方面，对直接感受高G值作用
的前庭耳石器的影响却没有引起足够的重视。耳石器是否能承受如此高的G值
而正常工作？这是一个值得深入探讨的问题。因为如果高G值造成耳石器的损
害，可引发眩晕、空间定向障碍等，造成严重后果。另外，如果宇航员在发射
阶段造成了耳石器的损害，是否会与航天适应综合征（Space adaptation
syndrome，SAS）发病有关等也不得而知。因此，探讨、明确高G是否会造成耳
石器损伤具有十分重要的理论和现实意义。另外，如果耳石器受到损伤，在防
护上也存在一系列问题。这是因为，由于耳石器解剖，生理上的特殊性，使其
不可能象对心脑血管系统那样从装备等方面进行防护，可能的方法只能是通过
锻炼等手段，提高其对高G值作用的耐受值。预适应是生物界普遍存在的一种
现象，对于保护各系统器官具有一定积极意义。前庭系统是否也存在预适应现
象，其是否可提高豚鼠对高G值作用的耐受值，从而对高G作用所致前庭功能
损害起到一定的防护作用？这也是一个值得深入探讨的问题。
染凹车医人学博士学位论义
本文采用行为学、形态学、细胞生物学、分子生物学等手段，观察了
＋ltoy oin暴露对豚鼠前庭耳石器的影响以及Z 8天的预习服对其防护作用。
主要结果如下：
1．＋lmy初in的暴露（、l地组）可5！起22／28门狐）豚鼠行为学的异
常，包括自发眼震、眼位偏斜、头位震颤、头位偏斜、身体转圈、侧滚转等；
而在给子＋lffiy SInin的暴露前经过预习服（预习服组）的行为异常率只有14／28
（h）。提示高G可造成豚鼠前庭功能紊乱，预习服具有一定的防护作用。
2．采用光镜、电镜形态学观察方法发现：光镜下八op组和预习服组均有
一定程度细胞空泡化。电镜下显示：＋ltoy组于＋ltoy暴露后0．sh呈现两种性质
的耳石改变：①耳石消失及耳石再生前体一一球状物的出现：②耳石的变性融
合，即耳石失去原有形态，融合为一个整体。24h后表现为耳石膜明显增厚；
高倍镜下证实其主要为哑铃状不成熟耳石。预习服组于＋l％y暴露后队sh表现
为耳石有裂纹出现和层状化，24h后呈现出耳石质地疏松和微细孔状结构出
现。另外两组豚鼠均有纤毛粘连和倒伏。左右耳未见差别。
3．应用原位末端标记的方法（11jNlilM法）在两组均检测到可疑凋亡细胞，
两组之间未见明显区别。对照组未见凋亡细胞。
4．应用核酸原位杂交技术，发现预习服组在＋hey暴露后 HSP70 InRNA表达
明显增强，其次为＋l地直接暴露组，对照组最弱。
5．应用免疫组织化学方法，发现细胞骨架蛋白cytokeratin在各组间没有
变化，actin在各组均呈阴性反应。
6．应用免疫组织化学方法。发现两组ChAT染色均明显高于对照组，不过
两组之间未见明显差别。
7．观察到不仅支持细胞可以分泌产生耳石前体——球状物，而且1型细胞
也可以产生，证实丰富了前庭生理学中有关耳石再生来源的理论。
扼此，提出高G引起豚鼠行为表现异常的主要机理是：①高过载环境下，耳
石重量相对增加，引起耳石层与下方胶质层切线力增大，其问结合受到损害，从而
《
第四军医大学博士学位论文
耳石移位和／或耳石、囊斑上皮细胞代谢障碍，引起一系列病变，导致行为学表现
异常；②高过载环境下，心肺工作效率下降，血氧饱和度下降，组织能量代谢
障碍是引起一系列囊斑病变，导致行为表现异常的又一原因：③内耳血供的一
些特点（如缺乏侧枝循环）和囊斑上皮细胞对缺氧等的高敏感性加剧了囊斑病变，
对行为学表现异常起到了恶化促进作用；④高过载环境下，外周传入信息增
加，中枢乙酚胆碱升高，也是行为学表现异常的因素之一。预习服防护机理在
于：恤6G值环境下，耳石层与胶质层之间结合发生改变，如结合更紧密等，
从而在高过载作用时不易受损，病变减轻：②组织对缺氧耐受性增加，不易发
生能量代谢障碍；＠一系列保护因子如HSNQ［lltNA表达增强，发挥其对组织细
胞的保护作用。通过以上途径，囊斑病变减轻，行为学表现异常明显改善
People are often exposed to high G environment in aerospace activities. Sometimes
the G values they are subjected to may be even more than 10G. Can otolith organs not be damaged and work properly in this environment? The answer to this question is critical to solve the problems such as vertigo, spatial disorientation, space adaptation syndrome(SAS) etc.
In this work, guinea pigs' vestibular disorders, the ultrastructure of the macula, the apoptosis cells, the expression of HSP70 mRNA, cytokeratin and actin in macula of the utricle, and the ChAT activities in VNC(vestibular necleon complex)were observed after they were exposed to +10Gy for 5mia A countermeasure of 8 days pre-habituation in 2G force-field was also tested. The results are as follows:
1. Abnormalities of behavior, vestibule-spinal reflex (VSR) and vestibule-ocular
reflex (VOR) were found in 22/28 of the guinea pigs after exposed to +10Gy for 5min(+10Gy group), which included head tremble, head deviation, spontaneous nystagmus, eye deviation, body roll and looping. All the symptoms disappeared within 30 rain. Among them, head tremble was of the highest incidence. In the group which was exposed to 2G environment for 8 days before being exposed to 10Gy(habituation group), only 14/28 showed vestibular disorders, which was statistically significant lower compared with that of +10Gy group.
2. In +10Gy group, 0.5h later after lOGy exposure, two kinds of otoconia ultrastructure changes were observed: ヾisappearance of the otoconia and appearance of its precursor 棗global substance; ヾegeneration and fusion of the otoconia, including the disappearance of its classical prism-like structure and fusing into a larger one. 24h later, the incrassation of the utricle macula was prominent, and large dumb-bell shaped immature otoconia were observed in a high-power view. In habituation group, emergence of flaws and porous of otoconia were observed 0. 5h and 24h later respectively after lOGy exposure. Conglutination and sloping of the hair cell cilia were observed in both +10Gy group and habituation group. By using transmission electron microscope(TEM), plasmolysis and cell nucleus condensation were observed prominent in +10Gy group, while in habituation group, only a few cells showed cell nucleus condensation. By using HE staining method, both groups showed the cell swelling and vacuolation. The differences in ultrastructure changes between right and left utricles were non-significant.
3. By using a TUNEL(terminal-deoxynucleotidyl transferase mediated d~LTP nick end labeling) method, The apoptosis hair cells were detected in both T10Gy and habituation groups, but absent in control group.
4. The expression of HSP70 (by in situ hybridization methods) in habituation group is the strongest, +10Gy group was the second, and the control group was the weakest.
5. No significant differences of expression of cytokeratin in macula were found
among +10Gy, habituation and control groups by inmunohistochemistry technique. Negative reaction of actin was observed among above three groups.
6.The ChAT(choHne acetytransferase) activities in VNC in brain stem were investigated by immunohistochemistry technique. The relative gamma of staining showed that the content of ChAT in VNC of the +lOGy group and habituated group were significant higher than that in control group, but no significant differences were found between the +10Gy and habituation groups.
7. The precursor of otoconia global substance can be generated from both supporting cells and type I hair cells.
According to the results, the following points may contribute to the mechanism of high G induced vestibular disorders: ?the otoconia displacement and/or its metabolic disorder, which was caused by high G induced damage of conjunction between the otoconia layer and gelatin layer;@under high G environment, the inefficiency of cardiopulmonary system, reduction in blood oxygen saturation, and metabolic disorder of energy in related tissues were another reason causing behavior abnormalities;?the hi
引文
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50． Marlinsky VV. The effect of somatosensory stimilation on second-order and efferent vestibular neurons in the decerebrate decerebellate guinea pig. Neuroscience, 1995,69:661-669．
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