Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Londrina State University, Londrina, Paraná, Brazil.
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States.
Front Immunol. 2023 Jun 14;14:949407. doi: 10.3389/fimmu.2023.949407. eCollection 2023.
Lipoxin A4 (LXA) has anti-inflammatory and pro-resolutive roles in inflammation. We evaluated the effects and mechanisms of action of LXA4 in titanium dioxide (TiO) arthritis, a model of prosthesis-induced joint inflammation and pain.
Mice were stimulated with TiO (3mg) in the knee joint followed by LXA (0.1, 1, or 10ng/animal) or vehicle (ethanol 3.2% in saline) administration. Pain-like behavior, inflammation, and dosages were performed to assess the effects of LXA .
LXA reduced mechanical and thermal hyperalgesia, histopathological damage, edema, and recruitment of leukocytes without liver, kidney, or stomach toxicity. LXA reduced leukocyte migration and modulated cytokine production. These effects were explained by reduced nuclear factor kappa B (NFκB) activation in recruited macrophages. LXA improved antioxidant parameters [reduced glutathione (GSH) and 2,2-azino-bis 3-ethylbenzothiazoline-6-sulfonate (ABTS) levels, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and Nrf2 protein expression], reducing reactive oxygen species (ROS) fluorescent detection induced by TiO2 in synovial fluid leukocytes. We observed an increase of lipoxin receptor (ALX/FPR2) in transient receptor potential cation channel subfamily V member 1 (TRPV1) DRG nociceptive neurons upon TiO inflammation. LXA reduced TiO-induced TRPV1 mRNA expression and protein detection, as well TRPV1 co-staining with p-NFκB, indicating reduction of neuronal activation. LXA down-modulated neuronal activation and response to capsaicin (a TRPV1 agonist) and AITC [a transient receptor potential ankyrin 1 (TRPA1) agonist] of DRG neurons.
LXA might target recruited leukocytes and primary afferent nociceptive neurons to exert analgesic and anti-inflammatory activities in a model resembling what is observed in patients with prosthesis inflammation.
脂氧素 A4（LXA4）在炎症中具有抗炎和促解决作用。我们评估了 LXA4 在二氧化钛（TiO）关节炎中的作用和作用机制，该模型为假体诱导的关节炎症和疼痛模型。
在膝关节中用 TiO（3mg）刺激小鼠，然后给予 LXA（0.1、1 或 10ng/动物）或载体（生理盐水 3.2%乙醇）。进行疼痛样行为、炎症和剂量评估以评估 LXA 的作用。
LXA 减轻了机械性和热痛觉过敏、组织病理学损伤、水肿和白细胞募集，而无肝、肾或胃毒性。LXA 减少了白细胞迁移并调节了细胞因子的产生。这些作用是通过减少募集的巨噬细胞中核因子 kappa B（NFκB）的激活来解释的。LXA 改善了抗氧化参数[还原型谷胱甘肽（GSH）和 2,2-偶氮-双-3-乙基苯并噻唑啉-6-磺酸（ABTS）水平、核因子红细胞 2 相关因子 2（Nrf2）mRNA 和 Nrf2 蛋白表达]，减少了 TiO2 在滑膜液白细胞中诱导的活性氧（ROS）荧光检测。我们观察到在 TiO 炎症时，瞬时受体电位阳离子通道亚家族 V 成员 1（TRPV1）DRG 伤害性神经元中转录因子 NF-κB 相关因子 2（Nrf2）mRNA 和 Nrf2 蛋白表达增加。LXA 降低了 TiO 诱导的 TRPV1 mRNA 表达和蛋白检测，以及 TRPV1 与 p-NFκB 的共染色，表明神经元激活减少。LXA 下调了神经元的激活和对辣椒素（TRPV1 激动剂）和 AITC[瞬时受体电位锚蛋白 1（TRPA1）激动剂]的反应性DRG 神经元。
LXA 可能靶向募集的白细胞和初级传入伤害性神经元，在类似于假体炎症患者中观察到的模型中发挥镇痛和抗炎作用。
