Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, MG, Brazil.
Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31270-901, MG, Brazil.
Viruses. 2023 Oct 4;15(10):2049. doi: 10.3390/v15102049.
Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme involved in the production of several inflammatory/pro-resolving lipid mediators. Herein, we investigated the effect of Zi treatment in a severe acute respiratory syndrome (SARS) model. Mouse hepatitis virus (MHV)3-infected mice treated with Zi significantly improved the clinical score, weight loss, cardiopulmonary function, and survival rates compared with infected untreated animals. The protection observed in Zi-treated mice was associated with a lower inflammatory score, reduced dendritic cell-producing tumor necrosis factor (TNF), and increased neutrophil-producing interleukin (IL)-10 in the lungs three days after infection (dpi). At 5 dpi, the lungs of treated mice showed an increase in Th2-, Treg CD4-, and Treg CD8-producing IL-10 and reduced Th1 infiltrating cells. Furthermore, similar results were found upon Zi treatment after SARS-CoV-2 infection in transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2), significantly improving the clinical score, weight loss, and lung inflammatory score compared with untreated animals. Our data suggest that Zi protects against developing severe lung disease during SARS induced by betacoronavirus without affecting the host's capacity to deal with infection.
炎症反应加剧是严重 2019 年冠状病毒病（COVID-19）的标志。齐留通（Zi）是 5-脂氧合酶的选择性抑制剂，5-脂氧合酶参与几种炎症/促解决脂质介质的产生。在此，我们研究了 Zi 治疗在严重急性呼吸综合征（SARS）模型中的作用。与未感染未治疗的动物相比，感染鼠肝炎病毒（MHV）3 的 Zi 治疗小鼠的临床评分、体重减轻、心肺功能和存活率显著改善。Zi 治疗小鼠的保护作用与肺部感染后三天炎症评分降低、树突状细胞产生的肿瘤坏死因子（TNF）减少以及中性粒细胞产生的白细胞介素（IL）-10 增加有关。在 5dpi 时，治疗小鼠的肺部显示 Th2、Treg CD4 和 Treg CD8 产生的 IL-10 增加，Th1 浸润细胞减少。此外，在表达人血管紧张素 I 转换酶 2（ACE2）受体的转基因小鼠中，用丝氨酸蛋白酶抑制剂 3（SERPINB3）基因启动子（K18）驱动的人丝氨酸蛋白酶抑制剂 3（SERPINB3）基因治疗后，也发现了类似的结果，与未治疗的动物相比，临床评分、体重减轻和肺部炎症评分显著改善。我们的数据表明，Zi 可防止在β冠状病毒引起的 SARS 中发生严重的肺部疾病，而不影响宿主对抗感染的能力。
