Walker Mary E, Souza Patricia R, Colas Romain A, Dalli Jesmond
Lipid Mediator Unit, Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
Lipid Mediator Unit, Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
FASEB J. 2017 Aug;31(8):3636-3648. doi: 10.1096/fj.201700268. Epub 2017 May 2.
Rheumatoid arthritis is an inflammatory condition characterized by overzealous inflammation that leads to joint damage and is associated with an increased incidence of cardiovascular disease. Statins are frontline therapeutics for patients with cardiovascular disease and exert beneficial actions in rheumatoid arthritis. The mechanism that mediates the beneficial actions of statins in rheumatoid arthritis remains of interest. In the present study, we found that the administration of 2 clinically relevant statins-atorvastatin (0.2 mg/kg) or pravastatin (0.2 mg/kg)-to mice during inflammatory arthritis up-regulated systemic and tissue amounts of a novel family of proresolving mediators, termed 13-series resolvins (RvTs), and significantly reduced joint disease. Of note, administration of simvastatin (0.2 mg/kg) did not significantly up-regulate RvTs or reduce joint inflammation. We also found that atorvastatin and pravastatin each reduced systemic leukocyte activation, including platelet-monocyte aggregates (∼25-60%). These statins decreased neutrophil trafficking to the joint as well as joint monocyte and macrophage numbers. Atorvastatin and pravastatin produced significant reductions (∼30-50%) in expression of CD11b and major histocompatibility complex class II on both monocytes and monocyte-derived macrophages in joints. Administration of an inhibitor to cyclooxygenase-2, the initiating enzyme in the RvT pathway, reversed the protective actions of these statins on both joint and systemic inflammation. Together, these findings provide evidence for the role of RvTs in mediating the protective actions of atorvastatin and pravastatin in reducing local and vascular inflammation, and suggest that RvTs may be useful in measuring the anti-inflammatory actions of statins.-Walker, M. E., Souza, P. R., Colas, R. A., Dalli, J. 13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis.
类风湿性关节炎是一种炎症性疾病，其特征是过度炎症反应导致关节损伤，并与心血管疾病发病率增加有关。他汀类药物是心血管疾病患者的一线治疗药物，对类风湿性关节炎也有有益作用。介导他汀类药物在类风湿性关节炎中有益作用的机制仍备受关注。在本研究中，我们发现，在炎症性关节炎期间给小鼠施用两种临床相关的他汀类药物——阿托伐他汀（0.2毫克/千克）或普伐他汀（0.2毫克/千克）——可上调一种新的促消退介质家族（称为13-系列消退素，RvTs）的全身和组织含量，并显著减轻关节疾病。值得注意的是，施用辛伐他汀（0.2毫克/千克）并未显著上调RvTs或减轻关节炎症。我们还发现，阿托伐他汀和普伐他汀均可降低全身白细胞活化，包括血小板-单核细胞聚集体（约25%-60%）。这些他汀类药物减少了中性粒细胞向关节的迁移以及关节单核细胞和巨噬细胞数量。阿托伐他汀和普伐他汀使关节中单核细胞和单核细胞衍生巨噬细胞上CD11b和主要组织相容性复合体II类分子的表达显著降低（约30%-50%）。施用环氧化酶-2（RvT途径中的起始酶）抑制剂可逆转这些他汀类药物对关节和全身炎症的保护作用。总之，这些发现为RvTs在介导阿托伐他汀和普伐他汀减轻局部和血管炎症的保护作用中的作用提供了证据，并表明RvTs可能有助于衡量他汀类药物的抗炎作用。——沃克，M.E.，苏扎，P.R.，科拉斯，R.A.，达利，J. 13-系列消退素介导阿托伐他汀和普伐他汀在炎症性关节炎中的白细胞-血小板作用
