Keeble Julie, Russell Fiona, Curtis Bradley, Starr Anna, Pinter Erika, Brain Susan D
Cardiovascular Division, New Hunt's House, King's College London, Guy's Campus, London, UK.
Arthritis Rheum. 2005 Oct;52(10):3248-56. doi: 10.1002/art.21297.
To investigate the endogenous involvement of transient receptor potential vanilloid 1 (TRPV1) in a model of knee joint inflammation in the mouse.
Following characterization of wild-type (WT) and TRPV1-knockout mice, inflammation was induced via intraarticular (IA) injection of Freund's complete adjuvant (CFA). Knee swelling was assessed as diameter, and inflammatory heat hyperalgesia was determined using the Hargreaves technique, for up to 3 weeks. At 18 hours, acute hyperpermeability was measured with 125I-albumin, and cytokines and myeloperoxidase activity, a marker of neutrophils, were assayed in synovial fluid extracts. The possibility that exogenous tumor necrosis factor alpha (TNFalpha) was involved in influencing TRPV1 activation was investigated in separate experiments.
Increased levels of knee swelling, hyperpermeability, leukocyte accumulation, and TNFalpha were found in WT mice 18 hours after IA CFA treatment compared with saline treatment. Significantly less knee swelling and hyperpermeability were found in TRPV1-/- mice, but leukocyte accumulation and TNFalpha levels were similar in WT and TRPV1-/- mice. Knee swelling in response to CFA remained significantly higher for a longer period in WT mice compared with TRPV1-/- mice, with thermal hyperalgesic sensitivity observed at 24 hours and at 1 week in WT, but not TRPV1-/-, mice. Knee swelling was attenuated (P < 0.05) in TRPV1-/- compared with WT mice 4 hours after IA administration of TNFalpha.
Our findings indicate that TRPV1 has a role in acute and chronic inflammation in the mouse knee joint. Thus, selective antagonism of TRPV1 should be considered as a potential target for treatment of acute and chronic joint inflammation.
研究瞬时受体电位香草酸亚型1（TRPV1）在小鼠膝关节炎症模型中的内源性作用。
对野生型（WT）和TRPV1基因敲除小鼠进行特征鉴定后，通过关节内（IA）注射弗氏完全佐剂（CFA）诱导炎症。以直径评估膝关节肿胀情况，采用哈格里夫斯技术测定炎症性热痛觉过敏，观察期长达3周。在18小时时，用125I-白蛋白测量急性通透性，并检测滑膜液提取物中的细胞因子和中性粒细胞标志物髓过氧化物酶活性。在单独实验中研究外源性肿瘤坏死因子α（TNFα）是否参与影响TRPV1激活。
与生理盐水处理相比，IA注射CFA处理18小时后，WT小鼠膝关节肿胀、通透性增加、白细胞聚集和TNFα水平升高。TRPV1基因敲除小鼠的膝关节肿胀和通透性明显减轻，但WT小鼠和TRPV1基因敲除小鼠的白细胞聚集和TNFα水平相似。与TRPV1基因敲除小鼠相比，WT小鼠对CFA的膝关节肿胀在更长时间内仍显著更高，WT小鼠在24小时和1周时出现热痛觉过敏敏感性，而TRPV1基因敲除小鼠未出现。IA注射TNFα 4小时后，与WT小鼠相比，TRPV1基因敲除小鼠的膝关节肿胀减轻（P < 0.05）。
我们的研究结果表明，TRPV1在小鼠膝关节的急性和慢性炎症中起作用。因此，TRPV1的选择性拮抗作用应被视为治疗急性和慢性关节炎症的潜在靶点。
