老年鼠肺水通道基因表达及肺泡水转运率研究
摘要
水通道蛋白(aquaporin, AQPs)是一族广泛存在于细胞膜上的持续开放的、不需要消耗能量、选择性高效转运水分子的特异孔道。水通道的发现为多种细胞的跨细胞膜快速水转运提供了生物化学基础。迄今为止,已发现的动物水通道蛋白有13种,他们广泛分布于全身各组织器官,包括大脑、肝脏、肺脏、心脏、肾脏、肌肉、骨骼和血细胞等,并在机体一些重要的生理和病理生理活动中发挥着重要作用。
呼吸系统的主要功能是提供呼吸通路、发声,同时具有免疫防御功能。其另外的一个作用是参与吸入气体的加温加湿,参与液体的吸收和分泌。水通道中的AQP1、AQP3、AQP4和AQP5在呼吸系统表达:AQP1主要在毛细血管内皮细胞和胸膜上表达;AQP3主要在气道基细胞的基底边膜表达;AQP4只在气道上皮细胞表达;AQP5在I型肺泡顶膜上高表达。此外,纤毛柱状细胞、支气管腺体细胞中也有表达。
肺在出生前为液体分泌器官,而在出生后则迅速转为液体吸收器官,从而为肺泡呼吸做好准备。研究表明,大鼠胎肺在孕19天时首先出现AQP1的表达,且这种表达水平持续升高,从孕21天到出生后1天内可以增加5倍,而且这种高水平表达可以持续到成年以后。而AQP3、AQP4、AQP5的表达则发生在出生后2周内。水通道蛋白这种在出生前后的表达变化主要是与其出生前后的功能变化相适应的。
已有研究显示,肺泡腔内过量的液体清除随年龄的老化而下降,其确切机制尚不十分明确。本研究的目的是探讨小鼠肺内水通道蛋白的表达在老年状态下的变化及其与老年鼠肺泡水转运功能的关系。由于AQP1和AQP5在外周肺组织表达,直接参与肺泡腔和血管室之间的水转运过程,因此他们成为本研究的主要研究对象。Western blot和RT-PCR的结果提示了AQP1和AQP5在老年鼠肺组织内的表达有明显下调。通过一种改造的重力测定方法,对肺泡腔和肺毛细血管腔之间的渗透性和压力性水转运率进行了测量,结果显示,两种方法测定的老年鼠肺泡水转运率均较青年鼠显著下降,而组织形态学分析提示老年鼠和青年鼠之间的肺组织结构无显著差异,这说明老年鼠肺泡水转运率的下降与其肺组织结构变化无关,而与AQP1和AQP5在老年鼠肺组织内的下调表达有关。以往的研究表明,糖皮质激素可以上调AQP1表达,因此,我们比较了老年鼠和青年鼠血清糖皮质激素水平,与预期结果一致,老年鼠的糖皮质激素水平明显低于青年鼠的糖皮质激素水平,肌肉注射糖皮质激素可以上调AQP1的表达,并能够提高老年鼠肺泡水转运率,然而糖皮质激素对AQP5的表达并无作用。
本研究首次证明了老年鼠肺内水转运率下降、以及这种下降的功能改变与老年鼠AQP1和AQP5的下调表达有关。此外,糖皮质激素能够上调老年鼠肺内AQP1的表达、并改善肺水转运功能,为糖皮质激素应用于急性肺水肿的治疗提供了一条新的作用机制。
Aquaporins (AQPs) are a family of small and integral membrane proteins that facilitate water transport across cell membranes in response to osmotic gradients. Discovery of AQPs has provided a molecular explanation for rapid water transport across the membranes of many types of cells. AQPs are expressed extensively in the body, including heart, kidney, liver, lung, brain, bone and so on. Also they play a very important role in some physiological and pathophysiological process, such as urine producing.
Respiratory system is an important system in the body, which includes trachea, bronchia and alveoli. Respiratory system takes part in gas exchange; immunological defense and air hydration. Among AQPs, AQP1, AQP3, AQP4, and AQP5 are expressed in the respiratory system. Studies show that AQP1 first appears in the lung of rats on the embryonic day 19 and subsequently increases until birth. However, AQP3, AQP4, and AQP5 appear in the lung after birth. The changed expression of AQPs is relative to the changed function of lung before and after birth.
It was proposed that clearance of excess fluid from the alveolar space might be decreased with aging. However, its reason is unknown clearly. The purpose of the present study was to examine whether AQPs of lung change in aged mice, whether lung water transport changes and whether the change of lung water transport is associated with the change of AQPs. Since alveolar endothelial water channel AQP1 and alveolar epithelial water channel AQP5 are expressed in peripheral lung and they take part in the process of water transport between alveolar and capillary compartments, they become the main subject in this study. Western blot and RT-PCR analysis was used to detect the expression of AQP1 and AQP5. Both mRNA expression and protein expression of AQP1 and AQP5 are decreased compared with young mice. By a modified gravimetric method, we knew that osmotically and hydrostatically driven water transport rates (Jw) between the airspace and capillary compartments were reduced in aged mice compared with young mice. However, there was no remarkable difference in lung histology between young and aged mice. Subsequently, since corticosteroids can induce expression of AQP1 in the lung, we compared the level of serum glucocorticoid in young mice and aged mice. As expected, there was a dramatic decrease of serum glucocorticoid in aged mice compared with young mice. In vivo administration of dexamethasone (4mg/Kg) to aged mice increased lung AQP1 mRNA and protein expression by about 2 fold, respectively. In addition, decreased water transport rate in the lung also can be increased partially for increased AQP1 expression. However, AQP5 mRNA and protein expression in aged lung was not affected by dexamethasone administration.
The present study provided the first evidence of reduced lung water transport rate associated with down-regulation of AQP1 and AQP5 in aged mice. Corticosteroid hormone may accelerate edema clearance in aged lung by stimulating AQP1 expression, providing a new mechanism for using corticosteroid in acute lung edema.
呼吸系统的主要功能是提供呼吸通路、发声,同时具有免疫防御功能。其另外的一个作用是参与吸入气体的加温加湿,参与液体的吸收和分泌。水通道中的AQP1、AQP3、AQP4和AQP5在呼吸系统表达:AQP1主要在毛细血管内皮细胞和胸膜上表达;AQP3主要在气道基细胞的基底边膜表达;AQP4只在气道上皮细胞表达;AQP5在I型肺泡顶膜上高表达。此外,纤毛柱状细胞、支气管腺体细胞中也有表达。
肺在出生前为液体分泌器官,而在出生后则迅速转为液体吸收器官,从而为肺泡呼吸做好准备。研究表明,大鼠胎肺在孕19天时首先出现AQP1的表达,且这种表达水平持续升高,从孕21天到出生后1天内可以增加5倍,而且这种高水平表达可以持续到成年以后。而AQP3、AQP4、AQP5的表达则发生在出生后2周内。水通道蛋白这种在出生前后的表达变化主要是与其出生前后的功能变化相适应的。
已有研究显示,肺泡腔内过量的液体清除随年龄的老化而下降,其确切机制尚不十分明确。本研究的目的是探讨小鼠肺内水通道蛋白的表达在老年状态下的变化及其与老年鼠肺泡水转运功能的关系。由于AQP1和AQP5在外周肺组织表达,直接参与肺泡腔和血管室之间的水转运过程,因此他们成为本研究的主要研究对象。Western blot和RT-PCR的结果提示了AQP1和AQP5在老年鼠肺组织内的表达有明显下调。通过一种改造的重力测定方法,对肺泡腔和肺毛细血管腔之间的渗透性和压力性水转运率进行了测量,结果显示,两种方法测定的老年鼠肺泡水转运率均较青年鼠显著下降,而组织形态学分析提示老年鼠和青年鼠之间的肺组织结构无显著差异,这说明老年鼠肺泡水转运率的下降与其肺组织结构变化无关,而与AQP1和AQP5在老年鼠肺组织内的下调表达有关。以往的研究表明,糖皮质激素可以上调AQP1表达,因此,我们比较了老年鼠和青年鼠血清糖皮质激素水平,与预期结果一致,老年鼠的糖皮质激素水平明显低于青年鼠的糖皮质激素水平,肌肉注射糖皮质激素可以上调AQP1的表达,并能够提高老年鼠肺泡水转运率,然而糖皮质激素对AQP5的表达并无作用。
本研究首次证明了老年鼠肺内水转运率下降、以及这种下降的功能改变与老年鼠AQP1和AQP5的下调表达有关。此外,糖皮质激素能够上调老年鼠肺内AQP1的表达、并改善肺水转运功能,为糖皮质激素应用于急性肺水肿的治疗提供了一条新的作用机制。
Aquaporins (AQPs) are a family of small and integral membrane proteins that facilitate water transport across cell membranes in response to osmotic gradients. Discovery of AQPs has provided a molecular explanation for rapid water transport across the membranes of many types of cells. AQPs are expressed extensively in the body, including heart, kidney, liver, lung, brain, bone and so on. Also they play a very important role in some physiological and pathophysiological process, such as urine producing.
Respiratory system is an important system in the body, which includes trachea, bronchia and alveoli. Respiratory system takes part in gas exchange; immunological defense and air hydration. Among AQPs, AQP1, AQP3, AQP4, and AQP5 are expressed in the respiratory system. Studies show that AQP1 first appears in the lung of rats on the embryonic day 19 and subsequently increases until birth. However, AQP3, AQP4, and AQP5 appear in the lung after birth. The changed expression of AQPs is relative to the changed function of lung before and after birth.
It was proposed that clearance of excess fluid from the alveolar space might be decreased with aging. However, its reason is unknown clearly. The purpose of the present study was to examine whether AQPs of lung change in aged mice, whether lung water transport changes and whether the change of lung water transport is associated with the change of AQPs. Since alveolar endothelial water channel AQP1 and alveolar epithelial water channel AQP5 are expressed in peripheral lung and they take part in the process of water transport between alveolar and capillary compartments, they become the main subject in this study. Western blot and RT-PCR analysis was used to detect the expression of AQP1 and AQP5. Both mRNA expression and protein expression of AQP1 and AQP5 are decreased compared with young mice. By a modified gravimetric method, we knew that osmotically and hydrostatically driven water transport rates (Jw) between the airspace and capillary compartments were reduced in aged mice compared with young mice. However, there was no remarkable difference in lung histology between young and aged mice. Subsequently, since corticosteroids can induce expression of AQP1 in the lung, we compared the level of serum glucocorticoid in young mice and aged mice. As expected, there was a dramatic decrease of serum glucocorticoid in aged mice compared with young mice. In vivo administration of dexamethasone (4mg/Kg) to aged mice increased lung AQP1 mRNA and protein expression by about 2 fold, respectively. In addition, decreased water transport rate in the lung also can be increased partially for increased AQP1 expression. However, AQP5 mRNA and protein expression in aged lung was not affected by dexamethasone administration.
The present study provided the first evidence of reduced lung water transport rate associated with down-regulation of AQP1 and AQP5 in aged mice. Corticosteroid hormone may accelerate edema clearance in aged lung by stimulating AQP1 expression, providing a new mechanism for using corticosteroid in acute lung edema.
引文
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