Minocycline prevents retinal inflammation and vascular permeability following ischemia-reperfusion injury.
Minocycline prevents retinal inflammation and vascular permeability following ischemia-reperfusion injury.
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DOI：
10.1186/1742-2094-10-149
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发表时间：
2013-12-10
影响因子：
9.3
通讯作者：
Antonetti DA
中科院分区：
文献类型：
--
作者：
Abcouwer SF;Lin CM;Shanmugam S;Muthusamy A;Barber AJ;Antonetti DA
许多视网膜疾病与伴随神经炎症的血管功能障碍有关。我们研究了米诺环素（Mino），一种具有抗炎和神经保护特性的四环素衍生物，在视网膜缺血-再灌注（IR）损伤（一种伴有血-视网膜屏障（BRB）破坏的视网膜神经变性模型）后预防血管通透性和炎症的能力。雄性Sprague-Dawley大鼠经受45分钟的压力诱导的视网膜缺血，对侧眼作为对照。在再灌注后48 h，测定视网膜基因表达、细胞炎症、伊文思蓝染料渗漏、紧密连接蛋白组织、caspase-3活化和DNA片段化。通过使用髓系标志物CD 11b和白细胞共同抗原CD 45对视网膜组织进行流式细胞术评价，以区分和定量CD 11b +/CD 45 low小胶质细胞、CD 11b +/CD 45 hi髓系白细胞和CD 11bneg/CD 45 hi淋巴细胞，从而定量细胞炎症。使用主要组织相容性复合物II类（MHCII）免疫反应性来确定这些细胞的炎症状态。米诺治疗显着抑制IR诱导的视网膜血管通透性和紧密连接组织的破坏。视网膜IR损伤显著改变了25个炎症和神经胶质增生相关基因中21个的mRNA表达。其中，Mino处理有效地减弱了IR诱导的脂质运载蛋白2（LCN 2）、丝氨酸蛋白酶抑制剂肽酶抑制剂进化枝A成员3 N（SERPINA 3 N）、TNF受体超家族成员12 A（TNFRSF 12 A）、单核细胞趋化因子-1（MCP-1、CCL 2）和细胞间粘附分子-1（ICAM-1）的表达。白细胞停滞的髓系白细胞和淋巴细胞的显着增加后IR观察。米诺治疗显着减少视网膜白细胞数量后IR和减少MHCII+炎性白细胞的出现特别有效。令人惊讶的是，Mino在该模型中没有显著抑制视网膜细胞死亡。IR在再灌注数小时内诱导视网膜神经炎症，其特征在于炎症基因表达、白细胞粘附和侵袭以及血管通透性。尽管Mino显著抑制了这些反应，但它未能阻止神经变性。
Many retinal diseases are associated with vascular dysfunction accompanied by neuroinflammation. We examined the ability of minocycline (Mino), a tetracycline derivative with anti-inflammatory and neuroprotective properties, to prevent vascular permeability and inflammation following retinal ischemia-reperfusion (IR) injury, a model of retinal neurodegeneration with breakdown of the blood-retinal barrier (BRB). Male Sprague–Dawley rats were subjected to 45 min of pressure-induced retinal ischemia, with the contralateral eye serving as control. Rats were treated with Mino prior to and following IR. At 48 h after reperfusion, retinal gene expression, cellular inflammation, Evan’s blue dye leakage, tight junction protein organization, caspase-3 activation, and DNA fragmentation were measured. Cellular inflammation was quantified by flow-cytometric evaluation of retinal tissue using the myeloid marker CD11b and leukocyte common antigen CD45 to differentiate and quantify CD11b+/CD45low microglia, CD11b+/CD45hi myeloid leukocytes and CD11bneg/CD45hi lymphocytes. Major histocompatibility complex class II (MHCII) immunoreactivity was used to determine the inflammatory state of these cells. Mino treatment significantly inhibited IR-induced retinal vascular permeability and disruption of tight junction organization. Retinal IR injury significantly altered mRNA expression for 21 of 25 inflammation- and gliosis-related genes examined. Of these, Mino treatment effectively attenuated IR-induced expression of lipocalin 2 (LCN2), serpin peptidase inhibitor clade A member 3 N (SERPINA3N), TNF receptor superfamily member 12A (TNFRSF12A), monocyte chemoattractant-1 (MCP-1, CCL2) and intercellular adhesion molecule-1 (ICAM-1). A marked increase in leukostasis of both myeloid leukocytes and lymphocytes was observed following IR. Mino treatment significantly reduced retinal leukocyte numbers following IR and was particularly effective in decreasing the appearance of MHCII+ inflammatory leukocytes. Surprisingly, Mino did not significantly inhibit retinal cell death in this model. IR induces a retinal neuroinflammation within hours of reperfusion characterized by inflammatory gene expression, leukocyte adhesion and invasion, and vascular permeability. Despite Mino significantly inhibiting these responses, it failed to block neurodegeneration.
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影响因子：
82.9
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