Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.
Pharmacology Division, Institute Butantan, São Paulo, Brazil.
Toxicology. 2018 Sep 1;408:22-30. doi: 10.1016/j.tox.2018.06.010. Epub 2018 Jun 21.
Robust correlation between the severity of rheumatoid arthritis (RA) and cigarette smoking has been clinically demonstrated. Nevertheless, cigarette compounds responsible for this toxic effect and their mechanisms have not been described. Considering that hydroquinone (HQ) is an abundant, pro-oxidative compound of the matter particle phase of cigarette smoke, we investigated whether HQ exposure during the initial phase of collagen-induced arthritis (CIA) could aggravate the disease. For this purpose, male Wistar rats were exposed to aerosolized HQ (25 ppm), saline or 5% ethanol solution (HQ vehicle) for 1 h per day during 14 days. CIA was induced through s.c. injection of bovine collagen Type II (0.4 mg/100 μL) at days seven and 14 of exposure. Clinical signs of disease and the cell profile and chemical mediators in the synovial fluid and membrane were analysed at day 35 after the beginning of exposure. HQ exposure aggravated CIA-related paw edema and increased the cell infiltrate and interleukin-6 (IL-6) levels in the synovial fluid, promoted intense tissue collagen deposition and enhanced synoviocyte proliferation and higher frequency of aryl hydrocarbon receptor (AhR) and interleukin (IL-17) neutrophils in the synovial membrane. in vitro data also highlighted that neutrophils expressed increased levels of AhR, IL-17 and reactive oxygen species (ROS) generation. However, only AhR expression and ROS generation were blocked by in vitro treatment with AhR antagonist. Therefore, we conclude that in vivo HQ exposure at the early phase of AR onset worsens RA, leading to high frequency of AhR/IL-17 neutrophils into the joint.
已经在临床上证明，类风湿关节炎（RA）的严重程度与吸烟之间存在很强的相关性。然而，导致这种毒性作用的香烟化合物及其机制尚未描述。考虑到对苯二酚（HQ）是香烟烟尘颗粒相中的一种丰富的促氧化化合物，我们研究了在胶原诱导性关节炎（CIA）的初始阶段暴露于 HQ 是否会加重疾病。为此，雄性 Wistar 大鼠每天暴露于雾化 HQ（25ppm）、生理盐水或 HQ 载体 5%乙醇溶液中 1 小时，共 14 天。在暴露的第 7 天和第 14 天通过 sc 注射牛胶原蛋白 II（0.4mg/100μL）诱导 CIA。在暴露开始后的第 35 天分析疾病的临床症状以及滑液和膜中的细胞谱和化学介质。HQ 暴露加重了 CIA 相关的爪肿胀，并增加了滑液中的细胞浸润和白细胞介素-6（IL-6）水平，促进了组织胶原的强烈沉积，并增强了滑膜细胞的增殖和滑膜中芳香烃受体（AhR）和白细胞介素（IL-17）中性粒细胞的高频率。体外数据还强调，中性粒细胞表达了增加的 AhR、IL-17 和活性氧（ROS）生成。然而，只有 AhR 拮抗剂的体外处理才能阻断 AhR 表达和 ROS 生成。因此，我们得出结论，在 AR 发病早期体内 HQ 暴露会加重 RA，导致大量 AhR/IL-17 中性粒细胞进入关节。
