人脑胶质瘤性脑水肿与AQP4的关系

目的检测人脑胶质细胞瘤组织中的水通道4（AQP4）的表达，探讨水通道在胶质瘤性脑水肿中的表达规律，阐述胶质瘤性脑水肿的发生、发展机制。方法对24例胶质细胞瘤组织进行逆转录-聚合酶链式反应（RT．PCR）和免疫印迹（Westernblot），检测胶质细胞瘤组织中AQP4mRNA和AQP4蛋白的表达。结果RT-PCR经半定量分析和Westernblot结果表明，胶质细胞瘤组织中AQP4表达高于对照组，二组之间存在显著差异（P〈0．01）。结论胶质细胞瘤组织中AQP4mRNA和蛋白质的表达与胶质细胞瘤的恶性程度呈高度正相关，证明了AQP4参与了胶质瘤性脑水肿的发生和发展过程，在胶质瘤性脑水肿的形成过程中起重要作用。     

水通道蛋白4：缺血后脑水肿的靶分子

卒中后1周内，脑水肿引发的水快速流动导致脑组织膨胀是引起患者死亡的主要原因之一。对这个过程治疗的困难主要还是因为其机制仍然不是很清楚。1988年第一个水通道蛋白的发现，似乎为认识和治疗缺血后脑水肿开辟了一条崭新的道路。水通道蛋白（aquaporin,AQP），又称水孔蛋白，是一个同源水通道蛋白家族，在许多上皮和内皮细胞丰富表达，参与液体的转运。目前已发现的AQP有11种，其分布有相对的组织特异性，主要存在于脑内并且研究较多的是AQP1和AQP4。     

AQP-4、VEGF表达与脑膜瘤术后脑水肿加重的相关性分析

目的 探讨水通道蛋白4（AQP-4）、血管内皮生长因子（VEGF）表达与脑膜瘤术后脑水肿加重的相关性。方法 收集2019年1月至2020年1月手术切除并经术后病理确诊的脑膜瘤组织105例,免疫组化染色检测AQP-4和VEGF的表达。术后2~15 d复查头部MRI判断脑水肿。结果 105例中,术后脑水肿加重30例（28.57%）,未加重75例。术后脑水肿加重组AQP-4阳性表达率（63.3%）和VEGF阳性表达率（30.0%）较未加重组明显增加（分别为30.7%和16.0%;P<0.05）。多因素logistic回归分析显示,AQP-4和VEGF阳性表达是脑膜瘤术后脑水肿加重的独立危险因素（P<0.05）。结论 AQP-4和VEGF表达上调与脑膜瘤术后脑水肿加重有关。     

AQP4在高血压脑出血周围水肿组织中表达的临床研究

目的研究水通道蛋白-4（AQP4）与高血压脑出血（HICH）患者血肿周围组织水肿的相关性，并观察其在脑水肿形成过程中表达变化的规律。方法对32例HICH患者行开颅血肿清除术，对术中所取得的血肿周围水肿脑组织标本（实验组）分别应用免疫组化方法测定AQP4的表达，并与对照组（为手术人路中皮层造瘘所获取的皮层标本）进行对比分析。结果实验组各时间段血肿周围水肿脑组织AQP4的表达均明显高于对照组（P〈0．01）；脑出血后24h周围水肿脑组织中的AQP4含量显著升高，直到72h仍在较高水平。结论HICH血肿周围脑水肿的形成和发展与AQP4的异常表达密切相关。     

水通道蛋白4在颅脑损伤组织的表达及临床意义

目的检测颅脑损伤脑水肿组织中AQP4的表达,探讨水通道在颅脑损伤性脑水肿中的表达规律,阐述脑水肿的发生、发展机制。方法对8例颅脑损伤的脑水肿组织和8例对照组织进行逆转录-聚合酶链式反应(RT-PCR)和免疫印迹(Western-Blot),检测颅脑损伤水肿组织中AQP4 mRNA的表达和AQP4蛋白的表达情况。结果RT-PCR经半定量分析和Western-Blot结果显示:颅脑损伤组AQP4表达比正常组明显升高,两组之间有统计学意义。结论颅脑损伤组织中,损伤周围的脑水肿组织AQP4 mRNA和蛋白质的表达与颅脑损伤组织中脑水肿的严重程度呈高度正相关,证明了AQP4参与了颅脑损伤组织中脑水肿的发生和发展过程,在脑水肿的形成过程中起重要作用。     

β--七叶皂甙钠对实验性脑出血后AQP4表达及脑水肿的影响

目的研究β--七叶皂甙钠对大鼠脑出血后水通道蛋白4（AQP4）表达及脑水肿的影响,探讨β--七叶皂甙钠治疗出血性脑水肿的作用机制。方法在大鼠苍白球注射胶原酶制作脑出血模型,采用干湿重法观察脑水肿的变化;应用免疫组织化学方法检测脑组织AQP4表达。结果脑出血模型大鼠病灶侧脑含水量、血肿周围AQP4的表达水平均明显高于假手术组（均P〈0．01）;各个时间点β--七叶皂甙钠治疗组病灶侧脑含水量以及血肿周围AQP4的表达水平均明显低于对照组（均P〈0．05）;AQP4表达水平与脑含水量呈正相关（r=0.976,P〈0．01）。结论β--七叶皂甙钠能明显减轻脑出血后脑水肿及AQP4的表达,β--七叶皂甙钠可能抑制AQP4的表达而减轻脑水肿。     

颅脑损伤后AQP-4在脑组织中表达与脑水肿的关系

目的探讨水通道蛋白-4（AQP-4）在急性颅脑损伤早期脑水肿发生中的作用。方法应用免疫组织化学方法检测人脑组织中AQP-4的表达。创伤组标本取自28例急性颅脑损伤患者急诊开颅血肿清除时所获挫伤灶周围脑组织；对照组取自8例原发性癫痫患者手术切除的相对正常脑组织。结果急性颅脑损伤后早期挫伤灶周围脑组织有明显的脑水肿发生，AQP-4的表达水平明显高于对照组（P〈0．01），且其表达主要见于小血管及神经胶质细胞。结论AQP-4表达的早期上调与急性颅脑损伤后脑水肿的发生有密切的关系。     

水通道蛋白-4与脑水肿

水通道蛋白(aquaporins，AQPs)的主要功能是转运水，其中AQP4主要分布于中枢神经系统。AQP4分布特点是胶质细胞与脑脊液以及血管之间的水调节和运输的重要结构基础，与脑脊液重吸收、渗透压调节、脑水肿形成等生理、病理过程密切相关。近期研究表明，AQP4与脑水肿密切相关，参与了脑创伤、脑肿瘤及脑缺血继发的脑水肿的过程，提示抑制AQP4可能为减轻各种脑疾病所致脑水肿提供新的治疗方法．     

AQP4与中枢神经系统生理和病理的研究进展

AQP4属水通道蛋白（AQP）家族中仅对水具有通透性的亚类，主要分布于中枢神经系统的胶质界膜和血管周围的星形细胞足突．受多种生理和病理因素调节，在维持中枢神经系统水、电解质平衡和多种病理状况下脑水肿的发生、发展中具有重要作用。本文综述了近年来AQP4有关方面的研究进展。     

Aquaporin-4 expression is increased in edematous meningiomas

Peritumoral edema is frequently present in meningiomas and can result in serious morbidity and mortality. The aquaporins (AQPs) are a family of membrane protein water channels with an integral role in water transport and maintenance of fluid balance. AQP4, increased in edematous human brain tumors such as astrocytomas and metastases, is present in the astrocytic foot processes adjacent to endothelial cells and may therefore have a role in cerebral edema formation. The objective of this study is to investigate the expression of AQP4 in meningiomas and to correlate their expression with peritumoral edema. Fresh human meningioma specimens (17) were obtained and immunohistochemical staining and Western blot analysis was performed for AQP4. The peritumoral edema index (EI) was calculated based on MRI post-processed to calculate the tumor and edema volume. Overexpression of AQP4 was associated with significant peritumoral edema. Immunohistochemistry showed upregulation of AQP4 throughout the specimens. Therefore, we conclude that increased expression of AQP4 is associated with peritumoral edema in meningiomas. This suggests that AQP4 overexpression can lead to abnormal water transport and edema formation in meningiomas. The inhibition of AQP4 water channels is a potential therapeutic option to reduce the adverse effects of peritumoral edema in meningiomas.     

脑出血患者血肿周围脑组织水通道蛋白-4的表达变化

目的：探讨脑出血血肿周围脑组织水通道蛋白-4（AQP4）的表达规律及其与脑水肿形成的关系。方法：32例行颅内血肿清除术患者，按发病至手术时间不同分为〈6h、6～24h、24～72h和〉72h组。取术中获得的脑组织做病理标本，检测AQP4的表达变化，并观察其组织病理及超微结构变化。结果：〈6h组脑组织轻微水肿，AQP4表达呈弱阳性，6h后水肿逐渐加重，AQP4表达开始增强，至24～72h达高峰。此后，AQP4表达下降，水肿减轻。结论：脑出血后AQP4表达呈动态变化与脑组织水肿程度一致，提示AQP4在脑出血患者脑水肿的发生、发展中起着重要作用。     

Aquaporins in brain: distribution, physiology, and pathophysiology.

Water homeostasis in the brain is of central physiologic and clinical importance. Neuronal activity and ion water homeostasis are inextricably coupled. For example, the clearance of K+ from areas of high neuronal activity is associated with a concomitant water flux. Furthermore, cerebral edema, a final common pathway of numerous neurologic diseases, including stroke, may rapidly become life threatening because of the rigid encasement of the brain. A water channel family, the aquaporins, facilitates water flux through the plasma membrane of many cell types. In rodent brain, several recent studies have demonstrated the presence of different types of aquaporins. Aquaporin 1 (AQP1) was detected on epithelial cells in the choroid plexus whereas AQP4, AQP5 and AQP9 were localized on astrocytes and ependymal cells. In rodent brain, AQP4 is present on astrocytic end-feet in contact with brain vessels, and AQP9 is found on astrocytic processes and cell bodies. In basal physiologic conditions, AQP4 and AQP9 appear to be implicated in brain homeostasis and in central plasma osmolarity regulation. Aquaporin 4 may also play a role in pathophysiologic conditions, as shown by the reduced edema formation observed after water intoxication and focal cerebral ischemia in AQP4-knockout mice. Furthermore, pathophysiologic conditions may modulate AQP4 and AQP9 expression. For example, AQP4 and AQP9 were shown to be upregulated after ischemia or after traumatic injuries. Taken together, these recent reports suggest that water homeostasis in the brain is maintained by regulatory processes that, by control of aquaporin expression and distribution, induce and organize water movements. Facilitation of these movements may contribute to the development of edema formation after acute cerebral insults such as ischemia or traumatic injury.     

脂多糖诱发兔颅内压增高后脑组织水通道蛋白-4mRNA的表达

目的观察脂多糖(LPS)诱发兔颅内压增高后脑组织内水通道蛋白-4(aquaporin-4,AQP4)表达水平的动态变化,研究其在脑水肿形成中的作用机制。方法应用经皮穿刺枕大池内注入LPS的方法建立兔颅内高压症模型,通过干湿重法测定脑组织含水量,HE染色观察脑组织的病理变化,RT-PCR技术测定脑组织内 AQP4-mRNA的表达。结果模型组脑组织含水量较假手术组显著增高,在6h达高峰。模型组动物脑组织神经元固缩,血管周围间隙增加,血管周围可见炎性细胞浸润,在6h病理改变最明显。造模3h后AQP4-mRNA表达开始增强,至6h达高峰,随后表达显著降低。结论颅内高压下AQP4参与了脑水肿的发生发展,在脑水肿的形成过程中起重要作用。     

Sulforaphane enhances aquaporin-4 expression and decreases cerebral edema following traumatic brain injury

Brain edema, the infiltration and accumulation of excess fluid causing an increase in brain tissue volume, often leads to a rise in intracranial pressure and is a key contributor to the morbidity and mortality associated with traumatic brain injury (TBI). The cellular and molecular mechanisms contributing to the development/resolution of TBI-associated brain edema are poorly understood. Aquaporin-4 (AQP4) water channel is expressed at high levels in brain astrocytes, and the bidirectional transport of water through these channels is critical for the maintenance of brain water homeostasis. By using a rodent injury model, we show that TBI decreased AQP4 level in the injury core and modestly increased it in the penumbra region surrounding the core. Postinjury administration of sulforaphane (SUL), an isothiocyanate present in abundance in cruciferous vegetables such as broccoli, attenuated AQP4 loss in the injury core and further increased AQP4 levels in the penumbra region compared with injured animals receiving vehicle. These increases in AQP4 levels were accompanied by a significant reduction in brain edema (assessed by percentage water content) at 3 days postinjury. These findings suggest that the reduction of brain edema in response to SUL administration could be due, in part, to water clearance by AQP4 from the injured brain.     

Hypoxia-inducible factor-1α contributes to brain edema after stroke by regulating aquaporins and glycerol distribution in brain

Brain edema following stroke is a critical clinical problem due to its association with increased morbidity and mortality. Despite its significance, present treatment for brain edema simply provides symptomatic relief due to the fact that molecular mechanisms underlying brain edema remain poorly understood. The present study investigated the role of hypoxia-inducible factor-1α (HIF-1α) and aquaporins (AQP-4 and -9) in regulating cerebral glycerol accumulation and inducing brain edema in a rodent model of stroke. Two-hours of middle cerebral artery occlusion (MCAO) followed by reperfusion was performed in male Sprague-Dawley rats (250-280 g). Anti-AQP-4 antibody, anti-AQP-9 antibody, or 2-Methoxyestradiol (2ME2, an inhibitor of HIF-1α) was given at the time of MCAO. The rats were sacrificed at 1 and 24 hours after reperfusion and their brains were examined. Extracellular and intracellular glycerol concentration of brain tissue was calculated with an enzymatic glycerol assay. The protein expressions of HIF-1α, AQP-4 and AQP-9 were determined by Western blotting. Brain edema was measured by brain water content. Compared to control, edema (p < 0.01), increased glycerol (p < 0.05), and enhanced expressions of HIF-1α, AQP-4, and AQP-9 (p < 0.05) were observed after stroke. With inhibition of AQP-4, AQP-9 or HIF-1α, edema and extracellular glycerol were significantly (p < 0.01) decreased while intracellular glycerol was increased (p < 0.01) 1 hour after stroke. Inhibition of HIF-1α with 2ME2 suppressed (p < 0.01) the expression of AQP-4 and AQP-9. These findings suggest that HIF-1α serves as an upstream regulator of cerebral glycerol concentrations and brain edema via a molecular pathway involving AQP-4 and AQP-9. Pharmacological blockade of this pathway in stroke patients may provide novel therapeutic strategies.     

高血压脑出血患者血肿周围水肿组织中水通道蛋白-4表达及意义

目的研究高血压脑出血患者血肿周围水肿组织中水通道蛋白-4(aquaporin 4,AQP4)表达及其意义。方法收集2009～2010年高血压脑出血患者血肿周围水肿组织28例,按照脑出血时间分为四组,如<12h,≥12h且<24h,≥24h且<48h和≥48h且<72h,以脑外伤患者术中急性脑膨出行内减压而切除的正常脑组织作为对照,应用Western-Blot方法,以GAPDH为内参,分别检测血肿周围水肿组织及正常脑组织中AQP4的表达水平。结果脑出<12h,≥12h且<24h,≥24h且<48h和≥48h且<72h患者脑内血肿周围水肿组织AQP-4的表达水平明显高于对照组(P<0.05),72h内AQP-4的表达逐渐升高。结论高血压脑出血患者脑内血肿周围水肿组织AQP4的表达增多与脑水肿的形成和发展密切相关。     

Downregulation of NF-κB by Shp-1 Alleviates Cerebral Venous Sinus Thrombosis-Induced Brain Edema Via Suppression of AQP4

Aquaporin 4 (AQP4), a water channel protein, has been well studied in arterial stroke-induced brain edema. However, the role of AQP4 in cerebral venous sinus thrombosis (CVST) has not been reported. Here, we showed that AQP4 expression was increased in the brain of a rat CVST model, whereas inhibition of AQP4 decreased cerebral edema. Subsequent experiments showed that Shp-1 (Src homology 2-containing phosphatase-1) expression and NF-κB phosphorylation were upregulated after CVST. We found that Shp-1 inhibition resulted in enhancement of NF-κB activation and increased AQP4 expression accompanied by aggravated brain edema. We further showed that NF-κB inhibition led to decreased AQP4 expression and subsequent attenuation of brain edema but had no significant effect on Shp-1 expression. These results provide the first evidence suggesting that downregulation of NF-κB by Shp-1 alleviates CVST-induced brain edema through suppression of AQP4.     

Enhanced expression of aquaporin 4 in human brain with infarction

A series of human brains with cerebral infarction obtained at autopsy were investigated to clarify the possible contribution of aquaporin 4 (AQP4) to the development of brain edema. Cellular localization of AQP4 and its relation to ischemic foci were examined with double-labeling immunohistochemistry. AQP4 immunoreactivity (IR) was more intense at the periphery of ischemic foci than at their center. Double-labeling study demonstrated that AQP4 IR was restricted to astrocytes and was localized to their entire processes, including their end feet facing the outer surface of capillaries. Moreover, AQP4 IR, detectable in the subpial and subependymal zone in the normal condition, was more intense in the vicinity of ischemic foci. Accumulation of AQP4 IR may reflect its participation in the development of brain edema in human brains by playing a role in the transport of water not only through blood vessel walls but also through pial and ependymal surface of the brain.