Trevisan Gabriela, Hoffmeister Carin, Rossato Mateus Fortes, Oliveira Sara Marchesan, Silva Mariane Arnoldi, Silva Cássia Regina, Fusi Camilla, Tonello Raquel, Minocci Daiana, Guerra Gustavo Petri, Materazzi Serena, Nassini Romina, Geppetti Pierangelo, Ferreira Juliano
Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil; Laboratory of Cellular and Molecular Biology, Graduate Program in Health Science, University of Southern Santa Catarina, Criciúma, SC, Brazil.
Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
Free Radic Biol Med. 2014 Jul;72:200-9. doi: 10.1016/j.freeradbiomed.2014.04.021. Epub 2014 Apr 26.
Acute gout attacks produce severe joint pain and inflammation associated with monosodium urate (MSU) crystals leading to oxidative stress production. The transient potential receptor ankyrin 1 (TRPA1) is expressed by a subpopulation of peptidergic nociceptors and, via its activation by endogenous reactive oxygen species, including hydrogen peroxide (H2O2), contributes to pain and neurogenic inflammation. The aim of this study was to investigate the role of TRPA1 in hyperalgesia and inflammation in a model of acute gout attack in rodents. Inflammatory parameters and mechanical hyperalgesia were measured in male Wistar rats and in wild-type (Trpa1(+/+)) or TRPA1-deficient (Trpa1(-/-)) male mice. Animals received intra-articular (ia, ankle) injection of MSU. The role of TRPA1 was assessed by receptor antagonism, gene deletion or expression, sensory fiber defunctionalization, and calcitonin gene-related peptide (CGRP) release. We found that nociceptor defunctionalization, TRPA1 antagonist treatment (via ia or oral administration), and Trpa1 gene ablation abated hyperalgesia and inflammatory responses (edema, H2O2 generation, interleukin-1β release, and neutrophil infiltration) induced by ia MSU injection. In addition, we showed that MSU evoked generation of H2O2 in synovial tissue, which stimulated TRPA1 producing CGRP release and plasma protein extravasation. The MSU-elicited responses were also reduced by the H2O2-detoxifying enzyme catalase and the reducing agent dithiothreitol. TRPA1 activation by MSU challenge-generated H2O2 mediates the entire inflammatory response in an acute gout attack rodent model, thus strengthening the role of the TRPA1 receptor and H2O2 production as potential targets for treatment of acute gout attacks.
急性痛风发作会产生严重的关节疼痛和炎症，与尿酸钠（MSU）晶体相关，导致氧化应激产生。瞬时电位受体锚蛋白1（TRPA1）由肽能伤害感受器亚群表达，并且通过其被包括过氧化氢（H2O2）在内的内源性活性氧激活，促成疼痛和神经源性炎症。本研究的目的是在啮齿动物急性痛风发作模型中研究TRPA1在痛觉过敏和炎症中的作用。在雄性Wistar大鼠以及野生型（Trpa1(+/+)）或TRPA1缺陷型（Trpa1(-/-)）雄性小鼠中测量炎症参数和机械性痛觉过敏。动物接受关节内（ia，踝关节）注射MSU。通过受体拮抗、基因缺失或表达、感觉纤维去功能化以及降钙素基因相关肽（CGRP）释放来评估TRPA1的作用。我们发现伤害感受器去功能化、TRPA1拮抗剂治疗（通过关节内或口服给药）以及Trpa1基因敲除减轻了由关节内注射MSU诱导的痛觉过敏和炎症反应（水肿、H2O2生成、白细胞介素-1β释放以及中性粒细胞浸润）。此外，我们表明MSU诱导体液组织中H2O2的生成，其刺激TRPA1产生CGRP释放和血浆蛋白外渗。H2O2解毒酶过氧化氢酶和还原剂二硫苏糖醇也降低了MSU引发的反应。MSU激发产生的H2O2激活TRPA1介导了急性痛风发作啮齿动物模型中的整个炎症反应，从而强化了TRPA1受体和H2O2生成作为急性痛风发作治疗潜在靶点的作用。
