O'Shaughnessy M C, Vetsika E-K, Inglis J J, Carleson J, Haigh R, Kidd B L, Winyard P G
Bone and Joint Research Unit, Barts and the London, Queen Mary's School of Medicine and Dentistry, London, EC1M 6BQ, UK.
Inflamm Res. 2006 Jun;55(6):236-40. doi: 10.1007/s00011-006-0079-8.
The inflammatory mediator substance P (SP) acts principally through the neurokinin (NK1) receptor. We assessed the influence of SP on production of NO and its possible role in the pathogenesis of rheumatoid arthritis (RA).
The effect of SP (0.1-100 nM) on concentrations of the NO metabolite, nitrite, produced by synovial fibroblasts from RA patients was studied. For comparison, the effects of TNF-alpha (0.57 pM-5.7 nM) and IL-1beta (0.57 pM-5.7 nM) were also studied. In parallel studies, footpad inflammation was induced in NK1 receptor knock-out (KO) and wild-type (WT) mice, and swelling and NO metabolite levels were measured.
In cultured synoviocytes, SP, TNF-alpha and IL-1beta induced significantly increased nitrite concentrations. Consistent with a role for NO in SP-mediated inflammatory reactions, the plasma NO metabolite level in WT mice was significantly increased at 3 days following an injection of 10 mg/ml Mycobacterium tuberculosis, but there was no significant change in NK1 KO mice. These results were paralleled by the changes in footpad swelling in WT mice compared to NK1 KO mice.
SP, like TNF-alpha and IL-1beta, induces NO in both rheumatoid synoviocytes and experimental models of inflammation. Treatments directed against SP may have important and hitherto unrecognised anti-inflammatory effects.
炎症介质P物质（SP）主要通过神经激肽（NK1）受体发挥作用。我们评估了SP对一氧化氮（NO）产生的影响及其在类风湿关节炎（RA）发病机制中的可能作用。
研究了SP（0.1 - 100 nM）对类风湿关节炎患者滑膜成纤维细胞产生的NO代谢产物亚硝酸盐浓度的影响。为作比较，还研究了肿瘤坏死因子-α（TNF-α，0.57 pM - 5.7 nM）和白细胞介素-1β（IL-1β，0.57 pM - 5.7 nM）的作用。在平行研究中，在NK1受体敲除（KO）小鼠和野生型（WT）小鼠中诱导足垫炎症，并测量肿胀和NO代谢产物水平。
在培养的滑膜细胞中，SP、TNF-α和IL-1β均显著诱导亚硝酸盐浓度升高。与NO在SP介导的炎症反应中起作用一致，在注射10 mg/ml结核分枝杆菌后3天，WT小鼠血浆中NO代谢产物水平显著升高，但NK1 KO小鼠无显著变化。与NK1 KO小鼠相比，WT小鼠足垫肿胀的变化与此结果相似。
与TNF-α和IL-1β一样，SP在类风湿滑膜细胞和炎症实验模型中均诱导产生NO。针对SP的治疗可能具有重要且迄今未被认识到的抗炎作用。
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