盐酸多西环素刺激诱导型一氧化氮合酶和精氨酸酶失衡，加剧血吸虫病中的炎症和氧化肺损伤。
Doxycycline hyclate stimulates inducible nitric oxide synthase and arginase imbalance, potentiating inflammatory and oxidative lung damage in schistosomiasis.
机构信息
Institute of Biomedical Sciences, Department of Structural Biology, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil.
Department of Animal Biology, Federal University of Viçosa, Viçosa, Minas Gerais, Brazil.
出版信息
Biomed J. 2022 Dec;45(6):857-869. doi: 10.1016/j.bj.2021.12.007. Epub 2021 Dec 28.
BACKGROUND
We investigated the relationship between inducible nitric oxide synthase (iNOS) and arginase pathways, cytokines, macrophages, oxidative damage and lung granulomatous inflammation in S. mansoni-infected and doxycycline-treated mice.
METHODS
Swiss mice were randomized in four groups: (i) uninfected, (ii) infected with S. mansoni, (iii) infected + 200 mg/kg praziquantel (Pzt), (iv) and (v) infected + 5 and 50 mg/kg doxycycline. Pzt (reference drug) was administered in a single dose and doxycycline for 60 days.
RESULTS
S. mansoni-infection determined extensive lung inflammation, marked recruitment of M2 macrophages, cytokines (IL-4, IL-5, IFN-γ, TNF-α) upregulation, intense eosinophil peroxidase (EPO) levels, arginase expression and activity, reduced iNOS expression and nitric oxide (NO) production. The higher dose of doxycycline aggravated lung granulomatous inflammation, downregulating IL-4 levels and M2 macrophages recruitment, and upregulating iNOS expression, EPO, NO, IFN-γ, TNF-α, M1 macrophages, protein carbonyl and malondialdehyde tissue levels. The number and size of granulomas in doxycycline-treated animals was higher than untreated and Pzt-treated mice. Exudative/productive granulomas were predominant in untreated and doxycycline-treated animals, while fibrotic/involutive granulomas were more frequent in Pzt-treated mice. The reference treatment with Pzt attenuated all these parameters.
CONCLUSION
Our findings indicated that doxycycline aggravated lung granulomatous inflammation in a dose-dependent way. Although Th1 effectors are protective against several intracellular pathogens, effective schistosomicidal responses are dependent of the Th2 phenotype. Thus, doxycycline contributes to the worsening of lung granulomatous inflammation by potentiating eosinophils influx and downregulating Th2 effectors, reinforcing lipid and protein oxidative damage in chronic S. mansoni infection.
背景
我们研究了诱导型一氧化氮合酶（iNOS）和精氨酸酶途径、细胞因子、巨噬细胞、氧化损伤与曼氏血吸虫感染和强力霉素治疗的小鼠肺部肉芽肿性炎症之间的关系。
方法
瑞士小鼠被随机分为四组：（i）未感染，（ii）感染曼氏血吸虫，（iii）感染+ 200mg/kg 吡喹酮（Pzt），（iv）和（v）感染+ 5 和 50mg/kg 强力霉素。吡喹酮（参考药物）一次性给药，强力霉素治疗 60 天。
结果
曼氏血吸虫感染导致广泛的肺部炎症，大量 M2 巨噬细胞募集，细胞因子（IL-4、IL-5、IFN-γ、TNF-α）上调，嗜酸性粒细胞过氧化物酶（EPO）水平升高，精氨酸酶表达和活性增强，iNOS 表达和一氧化氮（NO）生成减少。较高剂量的强力霉素加重了肺部肉芽肿性炎症，下调了 IL-4 水平和 M2 巨噬细胞募集，上调了 iNOS 表达、EPO、NO、IFN-γ、TNF-α、M1 巨噬细胞、蛋白质羰基和丙二醛组织水平。强力霉素治疗动物的肉芽肿数量和大小均高于未治疗和吡喹酮治疗的动物。未经治疗和强力霉素治疗的动物中渗出/产生产性肉芽肿占主导地位，而吡喹酮治疗的动物中纤维化/退行性肉芽肿更为常见。参考治疗吡喹酮减轻了所有这些参数。
结论
我们的研究结果表明，强力霉素以剂量依赖的方式加重了肺部肉芽肿性炎症。虽然 Th1 效应物对多种细胞内病原体具有保护作用，但有效的血吸虫杀伤反应依赖于 Th2 表型。因此，强力霉素通过增强嗜酸性粒细胞浸润和下调 Th2 效应物，加重慢性曼氏血吸虫感染中的脂质和蛋白质氧化损伤，加剧肺部肉芽肿性炎症。
Zotero 插件