INSERM U,1049 Neuroinflammation, Imagerie et Thérapie de la Sclérose en Plaques, F-33076 Bordeaux, France.
J Neuroinflammation. 2011 Oct 19;8:143. doi: 10.1186/1742-2094-8-143.
Vasogenic edema dynamically accumulates in many brain disorders associated with brain inflammation, with the critical step of edema exacerbation feared in patient care. Water entrance through blood-brain barrier (BBB) opening is thought to have a role in edema formation. Nevertheless, the mechanisms of edema resolution remain poorly understood. Because the water channel aquaporin 4 (AQP4) provides an important route for vasogenic edema resolution, we studied the time course of AQP4 expression to better understand its potential effect in countering the exacerbation of vasogenic edema.
Focal inflammation was induced in the rat brain by a lysolecithin injection and was evaluated at 1, 3, 7, 14 and 20 days using a combination of in vivo MRI with apparent diffusion coefficient (ADC) measurements used as a marker of water content, and molecular and histological approaches for the quantification of AQP4 expression. Markers of active inflammation (macrophages, BBB permeability, and interleukin-1β) and markers of scarring (gliosis) were also quantified.
This animal model of brain inflammation demonstrated two phases of edema development: an initial edema build-up phase during active inflammation that peaked after 3 days (ADC increase) was followed by an edema resolution phase that lasted from 7 to 20 days post injection (ADC decrease) and was accompanied by glial scar formation. A moderate upregulation in AQP4 was observed during the build-up phase, but a much stronger transcriptional and translational level of AQP4 expression was observed during the secondary edema resolution phase.
We conclude that a time lag in AQP4 expression occurs such that the more significant upregulation was achieved only after a delay period. This change in AQP4 expression appears to act as an important determinant in the exacerbation of edema, considering that AQP4 expression is insufficient to counter the water influx during the build-up phase, while the second more pronounced but delayed upregulation is involved in the resolution phase. A better pathophysiological understanding of edema exacerbation, which is observed in many clinical situations, is crucial in pursuing new therapeutic strategies.
血管源性水肿在许多与脑炎症相关的脑部疾病中动态积累，水肿加剧是患者护理中令人担忧的关键步骤。人们认为水通过血脑屏障（BBB）开放进入脑内与水肿形成有关。然而，水肿消退的机制仍知之甚少。由于水通道蛋白 4（AQP4）为血管源性水肿消退提供了重要途径，因此我们研究了 AQP4 表达的时间过程，以更好地了解其在对抗血管源性水肿加剧方面的潜在作用。
通过卵磷脂注射在大鼠脑内诱导局灶性炎症，并通过组合使用体内 MRI 和表观扩散系数（ADC）测量作为水含量标志物，以及分子和组织学方法来评估炎症在第 1、3、7、14 和 20 天的变化，以评估 AQP4 表达的定量。还定量了活性炎症（巨噬细胞、BBB 通透性和白细胞介素-1β）和瘢痕形成（神经胶质增生）标志物。
这种脑炎症动物模型显示出水肿发展的两个阶段：在主动炎症期间的初始水肿积聚阶段，在第 3 天达到高峰（ADC 增加），随后是水肿消退阶段，从注射后 7 天持续到 20 天（ADC 减少），并伴有神经胶质瘢痕形成。在积聚阶段观察到 AQP4 的适度上调，但在继发性水肿消退阶段观察到 AQP4 表达的转录和翻译水平更高上调。
我们得出结论，AQP4 表达存在时间滞后，只有在延迟期后才能实现更显著的上调。这种 AQP4 表达的变化似乎是水肿加剧的重要决定因素，因为在积聚阶段 AQP4 表达不足以对抗水的流入，而第二次更明显但延迟的上调则参与了消退阶段。更好地了解水肿加剧的病理生理学，这在许多临床情况下都有观察到，对于寻求新的治疗策略至关重要。
