在年龄相关性黄斑变性小鼠模型中，热刺激和视网膜色素上皮（RPE）再生激光疗法对炎症过程的调节作用
Modulation of inflammatory processes by thermal stimulating and RPE regenerative laser therapies in age related macular degeneration mouse models.
作者信息
Richert Elisabeth, von der Burchard Claus, Klettner Alexa, Arnold Philipp, Lucius Ralph, Brinkmann Ralf, Roider Johann, Tode Jan
机构信息
Christian-Albrechts-University of Kiel, Department of Ophthalmology, University Medical Center, Kiel, Germany.
Christian-Albrechts-University of Kiel, Institute of Anatomy, Kiel, Germany.
出版信息
Cytokine X. 2020 Jun 20;2(3):100031. doi: 10.1016/j.cytox.2020.100031. eCollection 2020 Sep.
PURPOSE
Inflammatory processes play a major role within the multifactorial pathogenesis of age-related macular degeneration (AMD). Neuroretina sparing laser therapies, thermal stimulation of the retina (TSR) and selective retina therapy (SRT), are known to reduce AMD-like pathology in vitro and in vivo. We investigated the effect of TSR and SRT on inflammatory processes in AMD mouse models.
METHODS
One randomized eye of 8 months old apolipoprotein (Apo)E and 9 months old nuclear factor (erythroid-derived 2) -like 2 (NRF2) knock out mice were treated by TSR (10 ms, 532 nm, 50 µm spot size, mean 4.5 W, 200 spots) or SRT (1.4 µs pulses, 532 nm, 50 µm spot size, 100 Hz over 300 ms, mean 2.5 µJ per pulse, ~200 spots). Fellow eyes, untreated knock out mice and wild-type BL/6J mice acted as controls. All mice were examined funduscopically and by optical coherence tomography (OCT) at the day of laser treatment. Mice were euthanized and enucleated either 1 day or 7 days after laser treatment and examined by gene expression analysis of 84 inflammatory genes.
RESULTS
The inflammatory gene expression profile of both knock out models compared to healthy BL/6J mice suggests a regulation of pro- and anti-inflammatory processes especially concerning T-cell activity and immune cell recruitment. TSR resulted in downregulation of several pro-inflammatory cell-mediators both in ApoE -/- and NRF2-/- mice compared to treatment naïve litter mates one day after treatment. In contrast, SRT induced pro-inflammatory cell-mediators connected with necrosis one day after treatment as expected following laser-induced selective RPE cell death. Seven days after laser treatment, both findings were reversed.
CONCLUSIONS
Both TSR and SRT influence inflammatory processes in AMD mouse models. However, they act conversely. TSR leads to anti-inflammatory processes shortly after laser therapy and induces immune-cell recruitment one week after treatment. SRT leads to a quick inflammatory response to laser induced RPE necrotic processes. One week after SRT inflammation is inhibited. It remains unclear, if and to what extent this might play a role in a therapeutic or preventive approach of both laser modalities on AMD pathology.
目的
炎症过程在年龄相关性黄斑变性（AMD）的多因素发病机制中起主要作用。已知保留神经视网膜的激光疗法，即视网膜热刺激（TSR）和选择性视网膜疗法（SRT），在体外和体内均可减轻AMD样病变。我们研究了TSR和SRT对AMD小鼠模型炎症过程的影响。
方法
对8个月大的载脂蛋白（Apo）E基因敲除小鼠和9个月大的核因子（红细胞衍生2）样2（NRF2）基因敲除小鼠的一只随机选取的眼睛进行TSR（10毫秒，532纳米，光斑大小50微米，平均4.5瓦，约200个光斑）或SRT（约1.4微秒脉冲，532纳米，光斑大小50微米，300毫秒内100赫兹，每个脉冲平均2.5微焦，约200个光斑）治疗。对侧眼、未治疗的基因敲除小鼠和野生型BL/6J小鼠作为对照。在激光治疗当天，对所有小鼠进行眼底镜检查和光学相干断层扫描（OCT）。在激光治疗后1天或7天对小鼠实施安乐死并摘除眼球，通过对84个炎症基因的表达分析进行检查。
结果
与健康的BL/6J小鼠相比，两种基因敲除模型的炎症基因表达谱表明促炎和抗炎过程存在调节，特别是与T细胞活性和免疫细胞募集有关。与治疗前的同窝小鼠相比，治疗后1天，TSR导致ApoE -/-和NRF2-/-小鼠中几种促炎细胞介质的下调。相反，正如激光诱导的视网膜色素上皮（RPE）细胞死亡后所预期的那样，SRT在治疗后1天诱导了与坏死相关的促炎细胞介质。激光治疗7天后，这两种结果均发生逆转。
结论
TSR和SRT均影响AMD小鼠模型中的炎症过程。然而，它们的作用相反。TSR在激光治疗后不久导致抗炎过程，并在治疗1周后诱导免疫细胞募集。SRT对激光诱导的RPE坏死过程产生快速炎症反应。SRT治疗1周后炎症受到抑制。目前尚不清楚这在这两种激光治疗方式对AMD病理的治疗或预防方法中是否以及在多大程度上起作用。
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