Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder

Neuromyelitis optica is an autoimmune inflammatory disorder of the central nervous system that preferentially targets the spinal cord and optic nerve. Following the discovery of circulating antibodies against the astrocytic aquaporin 4 (AQP4) water channel protein, recent studies have expanded our knowledge of the unique complexities of the pathogenesis of neuromyelitis optica and its relationship with the immune response. This review describes and summarizes the recent advances in our understanding of the molecular mechanisms underlying neuromyelitis optica disease pathology and examines their potential as therapeutic targets. Additionally, we update the most recent research by proposing major unanswered questions regarding how peripheral AQP4 antibodies are produced and their entry into the central nervous system, the causes of AQP4-IgG-seronegative disease, why peripheral AQP4-expressing organs are spared from damage, and the impact of this disease on pregnancy.     

水通道蛋白4基因多态性与陕西地区高血压脑 出血患者迟发性脑水肿的相关性研究

目的：探讨水通道蛋白4（AQP4）基因多态性与高血压脑出血（HICH）患者迟发性脑水肿的关系。方 法：137例HICH患者按照是否合并迟发性脑水肿分为病例组42例和对照组95例,采用聚合酶链反应-直接 测序分型法检测 AQP4基因 rs1058424,rs3763043 和 rs335931 多态性,并收集患者临床资料进行统计学分 析。结果：与对照组比较,病例组患者年龄较大,糖尿病、持续发热患者比例较高,基线血肿体积较大,基线 NIHSS评分较高（均P＜0.05）。病例组rs3763043位点TT基因型和T等位基因分布频率较对照组均显著增 加（均P＜0.05）。回归分析结果显示,对于HICH患者,携带AQP4基因rs3763043位点T等位基因、发热、血 肿体积偏大及NIHSS评分偏高可能是发生迟发型脑水肿的危险因素。结论：携带AQP4基因rs3763043位点 T等位基因、发热、血肿体积偏大及NIHSS评分偏高可能是HICH患者发生迟发型脑水肿的危险因素。     

Postmortem immunohistochemical alterations following cerebral lesions: A possible pathohistological importance of the β‐dystroglycan immunoreactivity

The frequency of cerebrovascular injuries raises the importance of their immunohistological investigation in postmortem materials. Most injuries involve the impairment of the blood–brain barrier. The barrier is maintained by the glio‐vascular connections which break up following injuries. Some immunohistochemical alterations may refer to the impairment of the gliovascular connections. Laminin and the components of the dystroglycan complex show characteristic immunohistochemical alterations following various experimental injuries (stab wound, cryogenic lesion, arterial occlusions): immunoreactivity of β‐dystroglycan, α‐dystrobrevin and aquaporin 4 disappeared while that of utrophin and laminin appeared along the vessels, whereas α‐syntrophin visualized the reactive astrocytes but not the resting ones. The aims of the present study were to investigate whether these post‐lesion alterations: (i) are reproducible with immersive fixation, which is used in postmortem histology; (ii) are resistant to a postmortem delay before fixation; and (iii) are to be attributed to a direct effect of the lesion, or are mediated by processes occurring only in the living brain. Three models were investigated: (i) following lesions, some brains were fixed by transcardial perfusion, others by immersion; (ii) following lesions, the animals were decapitated and stored at room temperature for 8 or 16 h before fixation; and (iii) the lesions were performed after decapitation. Cryogenic lesions were performed by applying a dry ice cooled copper rod to the brain surface of ketamine‐xylazine anesthetized rats. The immunohistochemical reactions were performed on free‐floating sections cut with vibratome. Both immunoperoxidase and immunofluorescence methods were used. The fixation method – perfusive or immersive – did not change the post‐lesion phenomena investigated. The postmortem delay did not influence the β‐dystroglycan immunoreactivity, that is its lack delineated the area of the lesion. However, in the case of the other substances, various lengths of postmortem delay rendered the immunohistochemistry uninterpretable. The results suggest β‐dystroglycan immunostaining could be applied in the neuropathology to detect cerebrovascular impairments.     

尿液中水孔蛋白-2的检测及其与肾组织中表达的相关性

目的 研究尿液ＡＱＰ２水孔蛋白检测的方法及其与肾脏ＡＱＰ２水孔蛋白表达量之间的相关性,为应用尿液ＡＱＰ２蛋白监测机体的水重吸收状况提供理论依据。方法 用Ｗｅｓｔｅｒｎ印迹分析法测定自由进水和禁水２４ｈ大鼠肾脏ＡＱＰ２的表达量及尿液ＡＱＰ２的含量,并分析两者之间的相关性。结果 ＡＱＰ２蛋白可在尿液中检测到。尿液ＡＱＰ２与肾脏ＡＱＰ２吴正相关（ｒ＝０．７９９）。结论：尿液ＡＱＰ２水平可以反映肾脏集合管     

醛固酮对豚鼠耳蜗水通道及离子通道蛋白的作用

目的检测醛固酮作用后早期（6h）及远期（1月）豚鼠耳蜗水通道及离子通道蛋白基因与蛋白质的表达改变情况。方法使用RT-PCR方法检测醛固酮腹腔注射后6h豚鼠耳蜗中Na-K ATP酶β1、β3亚单位及钠离子通道蛋白仅亚单位（ENaCα Subunit）基因表达的改变情况：使用免疫组织化学染色的方法检测醛固酮作用后1月耳蜗水通道蛋白1（AQP1）蛋白的表达情况。结果醛固酮作用后早期,在豚鼠耳蜗中Na-KATP酶β1、β3亚单位的表达情况无明显改变,钠离子通道蛋白仅亚单位则出现明显上调（P〈0．05）;远期则出现AQP1表达的下调（P〈0．05）。结论醛固酮在豚鼠耳蜗中可能通过基因组作用方式发挥作用．并且醛固酮引起膜迷路积水可能是由于其对离子浓度的改变所引起的。     

Expression of aquaporin 5 during murine palatine glands development: a light and electron microscopic immunocytochemical study

Although aquaporin 5 (AQP5) seems to play a role in cytodifferentiation and cell proliferation during the development of salivary glands, its distribution during minor salivary glands development has been scarcely reported. This study examined the temporal-spatial distribution of AQP5 in the developing rat palatine glands using light and electron microscopy. At embryonic (E) age E18, AQP5 labeling was observed on the cell membranes of some terminal bulb cells. After lumenization at E20, AQP5 labeled the apical membrane in acini where a lumen existed, in addition to displaying positive diffuse cytoplasmic and cell membrane staining. At the electron microscopic level, AQP5 labeled the supranuclear cytoplasm and the luminal microvilli along the apical membrane. At birth, AQP5 was also localized to the lateral membranes associated ultrastructurally with the microvilli of intercellular canaliculi. After postnatal (PN) day PN7, mucous acini and serous demilunes showed reactivity. AQP5 reached peak reactivity around PN13 with a similar staining pattern in all acini, but had reduced dramatically by PN21. Thereafter, AQP5 reactivity was mainly associated with serous cells in adults. In conclusion, the transitory expression of AQP5 during palatine glands development may reflect changing physiological functions of the secretory cells and/or AQP5 throughout the maturation of the glands.     

大鼠出血性脑水肿水通道蛋白4表达的研究

目的 :探讨大鼠脑出血后血肿周围水通道蛋白 4(AQP4)的表达变化。方法 :采用定量胶原酶注入大鼠尾状核建立脑出血模型 ,用干湿重法和免疫组织化学法分别检测脑出血后不同时间段脑含水量和 AQP4蛋白的表达。结果 :脑出血后 6h,脑含水量和血肿周围 AQP4蛋白表达增加 ;出血后 72 h达到高峰 ,出血 1周后仍高于正常 ;AQP4蛋白的表达和脑含水量呈显著正相关 (r=0 .985 7,P<0 .0 1)。结论 :AQP4与出血性脑水肿的形成密切相关     

Time course of aquaporin expression after transient focal cerebral ischemia in mice

Cerebral edema contributes to morbidity and mortality in stroke. Aquaporins (AQPs)-1, -4, and -9 have been identified as the three main water channels in the brain. To clarify their role in water movement, we have compared their expression patterns with brain swelling after transient focal brain ischemia. There were two peaks of maximal hemispheric swelling at 1 hr and at 48 hr after ischemia, coinciding with two peaks of AQP4 expression. At 1 hr after occlusion, AQP4 expression was significantly increased on astrocyte endfeet in the core and in the border of the lesion. At 48 hr, AQP4 expression was increased in astrocytes in the border of the lesion over the whole cell. AQP9 showed a significant induction at 24 hr that increased gradually with time, without correlation with the swelling. The expression of AQP1 remained unchanged. These results suggest that AQP4, but not AQP1 or AQP9, may play an important role in water movement associated with the pathophysiology of edema after transient cerebral ischemia in the mouse.     

水通道蛋白-1及其在心脏中作用的研究进展

水通道蛋白-1(AQP1)是水通道蛋白(AQPs)家族中发现最早且分布最广泛的成员,具有特殊的分子结构,受多种因素的调节。除转运水分子外,AQP1还能转运多种气体分子并参与细胞游走过程。心脏组织中AQP1主要在红细胞、毛细血管内皮细胞以及心肌细胞中表达。心肌细胞内AQP1定位于细胞质膜,可能参加兴奋—收缩偶联过程以及水分子的转运,调节心脏的各种生理和病理过程的水代谢。体外循环心脏手术可以影响AQPs的表达及活性,导致术后心肌水肿。心脏中AQPs的研究对临床工作有重要的指导意义。     

七叶皂苷对心肺复苏后大鼠脑水肿期脑水通道蛋白4 mRNA变化的作用

目的：观察大鼠心肺复苏后脑水肿期大脑皮质水通道蛋白4（AQP4）mRNA表达的变化及七叶皂苷的治疗作用。方法：采用窒息法制备心搏骤停大鼠模型，制备成功后进行相应复苏（复苏组）；达到自主循环恢复（ROSC）标准后，药物组即刻经颈动脉插管推注七叶皂苷（药物组）；对照组除不进行窒息／复苏外，其余操作同复苏组。于ROSC后0．5、3、6和12h用干／湿比重法测定各组脑组织含水量；用半定量逆转录一聚合酶链反应（RT—PCR）测定各组大脑皮质AQP4mRNA变化。结果：复苏组ROSC后AQP4mRNA表达随脑组织含水量的增加而上升，与对照组比较差异均有显著性（P〈O．05或P〈O．01），且两者呈正直线相关（r=0．681，P〈0．01）；药物组脑组织含水量和AQP4mRNA表达在ROSC后0．5h和3h显著增高（P〈O．05或P〈O．01），但在6h和12h明显回落，与对照组比较差异均无显著性（P均〉0．05）。结论：心肺复苏后脑水肿的发生与AQP4mRNA表达上调有关；七叶皂苷具有减轻复苏后脑水肿、调节AQP4mRNA表达的作用，可能是其抗脑水肿作用的机制之一。