Several retinal pathologies exhibit both inflammation and breakdown of the inner blood-retinal barrier (iBRB) resulting in vascular permeability, suggesting that treatments that trigger resolution of inflammation may also promote iBRB restoration. Using the mouse retinal ischemia-reperfusion (IR) injury model, we followed the time course of neurodegeneration, inflammation, and iBRB disruption and repair to examine the relationship between resolution of inflammation and iBRB restoration and to determine if minocycline, a tetracycline derivative shown to reverse microglial activation, can hasten these processes. A 90-min ischemic insult followed by reperfusion in the retina induced cell apoptosis and inner retina thinning that progressed for approximately 2 weeks. IR increased vascular permeability within hours, which resolved between 3 and 4 weeks after injury. Increased vascular permeability coincided with alteration and loss of endothelial cell tight junction (TJ) protein content and disorganization of TJ protein complexes. Shunting of blood flow away from leaky vessels and dropout of leaky capillaries were eliminated as possible mechanisms for restoring the iBRB. Repletion of TJ protein contents occurred within 2 days after injury, long before restoration of the iBRB. In contrast, the eventual re-organization of TJ complexes at the cell border coincided with restoration of the barrier. A robust inflammatory response was evident a 1 day after IR and progressed to resolution over the 4-week time course. The inflammatory response included a rapid and transient infiltration of granulocytes and Ly6C+ classical inflammatory monocytes, a slow accumulation of Ly6Cneg monocyte/macrophages, and activation, proliferation, and mobilization of resident microglia. Extravasation of the majority of CD45+ leukocytes occurred from the superficial plexus. The presence of monocyte/macrophages and increased numbers of microglia were sustained until the iBRB was eventually restored. Intervention with minocycline to reverse microglial activation at 1 week after injury promoted early restoration of the iBRB coinciding with decreased expression of mRNAs for the microglial M1 markers TNF-α, IL-1β, and Ptgs2 (Cox-2) and increased expression of secreted serine protease inhibitor Serpina3n mRNA. These results suggest that iBRB restoration occurs as TJ complexes are reorganized and that resolution of inflammation and restoration of the iBRB following retinal IR injury are functionally linked.

中文翻译：

---

视网膜缺血再灌注损伤后炎症消退和血管屏障恢复

几种视网膜病变表现出炎症和内部血视网膜屏障 (iBRB) 的破坏，导致血管通透性，这表明触发炎症消退的治疗也可能促进 iBRB 恢复。使用小鼠视网膜缺血再灌注 (IR) 损伤模型，我们跟踪神经变性、炎症和 iBRB 破坏和修复的时间过程，以检查炎症消退与 iBRB 恢复之间的关系，并确定米诺环素（一种四环素衍生物）是否显示逆转小胶质细胞的激活，可以加速这些过程。90 分钟的缺血性损伤，随后视网膜再灌注诱导细胞凋亡和视网膜内层变薄，持续约 2 周。IR 在数小时内增加血管通透性，在受伤后 3 到 4 周内消退。血管通透性增加与内皮细胞紧密连接 (TJ) 蛋白含量的改变和丢失以及 TJ 蛋白复合物的解体相吻合。作为恢复 iBRB 的可能机制，消除了从渗漏血管中分流血流和渗漏毛细血管脱落。TJ 蛋白含量的补充发生在受伤后 2 天内，远在 iBRB 恢复之前。相比之下，细胞边界处 TJ 复合物的最终重组与屏障的恢复相吻合。IR 后 1 天明显出现强烈的炎症反应，并在 4 周的时间过程中逐渐消退。炎症反应包括粒细胞和 Ly6C+ 经典炎症单核细胞的快速和短暂浸润，Ly6Cneg 单核细胞/巨噬细胞的缓慢积累，以及常驻小胶质细胞的活化、增殖和动员。大多数 CD45+ 白细胞外渗发生在浅丛。单核细胞/巨噬细胞的存在和小胶质细胞数量的增加一直持续到 iBRB 最终恢复。在损伤后 1 周用米诺环素逆转小胶质细胞活化促进 iBRB 的早期恢复，同时小胶质细胞 M1 标志物 TNF-α、IL-1β 和 Ptgs2 (Cox-2) 的 mRNA 表达降低，分泌丝氨酸的表达增加蛋白酶抑制剂 Serpina3n mRNA。这些结果表明，iBRB 恢复随着 TJ 复合物的重组而发生，并且炎症的消退和视网膜 IR 损伤后 iBRB 的恢复在功能上是相关的。