Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
J Med Virol. 2018 Jul;90(7):1192-1198. doi: 10.1002/jmv.25076. Epub 2018 Mar 31.
Encephalopathy is a major cause of influenza-associated child death and severe neurological sequelae in Japan, highlighting the urgent need for new therapeutic strategies. In this study, we evaluated the effects of anti-high mobility group box-1 monoclonal antibody (α-HMGB1) treatment on brain edema induced by influenza A virus (IAV) and lipopolysaccharide in 4-week-old BALB/c female mice. The results showed that administration of 7.5 mg/kg α-HMGB1 1 h after IAV (A/Puerto Rico/8/34) inoculation significantly alleviated brain edema at 48 h after IAV inoculation, as confirmed by the suppression of Evans Blue dye leakage and matrix metallopeptidase-9 mRNA expression in the brain. Moreover, we also observed suppression of oxidative stress and different cytokines in IAV-inoculated mice. The expression of plasminogen activator inhibitor-1 was also attenuated following treatment with α-HMGB1. Notably, α-HMGB1 treatment had no effect on virus propagation in the lung. In summary, anti-HMGB1 treatment may improve the prognosis in cases with influenza-associated encephalopathy by attenuating brain edema and reducing the inflammatory responses induced by HMGB1.
脑病是导致日本流感相关儿童死亡和严重神经后遗症的主要原因，这凸显了迫切需要新的治疗策略。在这项研究中，我们评估了抗高迁移率族蛋白 B1 单克隆抗体（α-HMGB1）治疗对 4 周龄 BALB/c 雌性小鼠流感 A 病毒（IAV）和脂多糖诱导的脑水肿的影响。结果表明，在接种 IAV（A/Puerto Rico/8/34）后 1 小时给予 7.5mg/kg α-HMGB1，可显著减轻接种后 48 小时的脑水肿，这通过脑内 Evans Blue 染料渗漏和基质金属蛋白酶-9mRNA 表达的抑制得到证实。此外，我们还观察到在接种 IAV 的小鼠中氧化应激和不同细胞因子的抑制。纤溶酶原激活物抑制剂-1 的表达在接受 α-HMGB1 治疗后也减弱了。值得注意的是，α-HMGB1 治疗对肺内病毒增殖没有影响。综上所述，抗-HMGB1 治疗通过减轻脑水肿和减少 HMGB1 诱导的炎症反应，可能改善流感相关脑病的预后。
