Suganuma Eisuke, Niimura Fumio, Matsuda Shinichi, Ukawa Toshiko, Nakamura Hideaki, Sekine Kaori, Kato Masahiko, Aiba Yuji, Koga Yasuhiro, Hayashi Kuniyoshi, Takahashi Osamu, Mochizuki Hiroyuki
Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan.
Division of Infectious Diseases and Immunology, Saitama Children's Medical Center, Saitama, Japan.
Pediatr Res. 2017 Apr;81(4):593-600. doi: 10.1038/pr.2016.266. Epub 2016 Dec 20.
Kawasaki disease is a common systemic vasculitis that leads to coronary artery lesions. Besides its antihypertensive effects, losartan can modulate inflammation in cardiovascular disease. We examined whether losartan can attenuate coronary inflammation in a murine model of Kawasaki disease.
Five-wk-old C57/BL6J male mice were intraperitoneally injected with Lactobacillus casei cell wall extract to induce coronary inflammation and divided into four groups: placebo, intravenous immunoglobulin (IVIG), losartan, and IVIG+losartan. After 2 wk, mice were harvested. The coronary perivasculitis was significantly attenuated by losartan but not by IVIG alone, and further dramatic attenuation by IVIG+losartan was observed. The frequency of Lactobacillus casei cell wall extract-induced myocarditis (80%) was markedly lowered by losartan (22%) and IVIG+losartan (0%). Furthermore, interleukin (IL)-6 mRNA was markedly attenuated by IVIG+losartan. Serum levels of IL-6, TNF-α, MCP-1, and IL-10 after Lactobacillus casei cell wall extract injection were slightly decreased by IVIG or losartan. Moreover, IL-1β, IL-10, and MCP-1 levels were significantly decreased by IVIG+losartan.
The addition of losartan to IVIG strongly attenuated the severity of coronary perivasculitis and the incidence of myocarditis, along with suppressing systemic/local cytokines as well as the activated macrophage infiltration. Therefore, losartan may be a potentially useful additive drug for the acute phase of Kawasaki disease to minimize coronary artery lesions.
川崎病是一种常见的导致冠状动脉病变的系统性血管炎。除了具有降压作用外，氯沙坦还可调节心血管疾病中的炎症反应。我们研究了氯沙坦是否能减轻川崎病小鼠模型中的冠状动脉炎症。
对5周龄的C57/BL6J雄性小鼠腹腔注射干酪乳杆菌细胞壁提取物以诱导冠状动脉炎症，并将其分为四组：安慰剂组、静脉注射免疫球蛋白（IVIG）组、氯沙坦组和IVIG+氯沙坦组。2周后处死小鼠。氯沙坦可显著减轻冠状动脉周围血管炎，而单独使用IVIG则无此效果，且IVIG+氯沙坦组可进一步显著减轻炎症。氯沙坦（22%）和IVIG+氯沙坦组（0%）可显著降低干酪乳杆菌细胞壁提取物诱导的心肌炎发生率（80%）。此外，IVIG+氯沙坦组可显著降低白细胞介素（IL）-6 mRNA水平。注射干酪乳杆菌细胞壁提取物后，IVIG或氯沙坦可使血清IL-6、肿瘤坏死因子-α、单核细胞趋化蛋白-1和IL-10水平略有下降。此外，IVIG+氯沙坦组可显著降低IL-1β、IL-10和单核细胞趋化蛋白-1水平。
IVIG联合氯沙坦可显著减轻冠状动脉周围血管炎的严重程度和心肌炎的发生率，同时抑制全身/局部细胞因子以及活化巨噬细胞浸润。因此，氯沙坦可能是川崎病急性期一种潜在有用的辅助药物，可将冠状动脉病变降至最低。
