Driving β(2)- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis.
Driving β(2)- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis.
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DOI：
10.3389/fimmu.2021.628065
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发表时间：
2021
影响因子：
7.3
通讯作者：
Lorton D
中科院分区：
文献类型：
--
作者：
Bellinger DL;Wood C;Wergedal JE;Lorton D
交感神经活动亢进在类风湿性关节炎中很突出，约80%的患者在发病前有主要的生活压力。这些发现和其他研究结果支持压力、交感神经系统和疾病发作和进展之间的联系。在这里，我们通过评估选择性外周作用α/β2-肾上腺素能药物如何影响关节炎诱导的关节炎的关节破坏来扩展先前的研究。完全弗氏佐剂诱导雄性刘易斯大鼠的炎性关节炎。对照组未接受治疗。然后，关节炎大鼠从疾病发作（D12）至急性（D21）和重度疾病（D28）的第（D）天接受溶媒或α-肾上腺素能拮抗剂酚妥拉明（0.5 mg/天）和β2-肾上腺素能激动剂特布他林（1200 µg/天，统称为SH 1293）每日两次治疗。在免疫后D14、D21和D28，使用背跖宽度、X射线分析、显微计算机断层扫描和常规组织学评估后肢的疾病进展。在D21，基于减少的淋巴细胞浸润、保留软骨和骨体积，SH 1293显著减轻了后肢中的关节炎。血管翳形成和交感神经损失不受SH 1293的影响。骨面积和破骨细胞数量显示高和低治疗反应组。在高反应大鼠中，SH 1293治疗显著保留了骨面积并减少了破骨细胞数量，这些数据与药物介导的关节保护相关。SH 1293抑制基于骨赘产生减少的异常骨形成。在D28，SH 1293对淋巴细胞浸润、软骨和骨保留的关节炎保留作用以骨髓脂肪化为代价得以维持。然而，交感神经从距小腿关节缩回。我们的研究结果支持用SH 1293治疗显著延迟早期关节炎进展。靶向交感神经传递可能提供减缓疾病进展的策略。
Hypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/β2-adrenergic drugs affect joint destruction in adjuvant-induced arthritis. Complete Freund’s adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the β2-adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization. On D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint. Our findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression.
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影响因子：
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