基于themoTRPs介導(dǎo)冷痛敏對(duì)“溫經(jīng)活血、截?cái)嗯まD(zhuǎn)”外治膝骨關(guān)節(jié)炎的機(jī)理研究
發(fā)布時(shí)間：2019-05-09 18:06
【摘要】：膝骨關(guān)節(jié)炎(Knee Osteoarthritis,KOA)是最常見的骨與關(guān)節(jié)退行性疾病,因其發(fā)病機(jī)制一直未能明確,至今沒有特效的治療藥物。KOA疼痛癥狀的出現(xiàn)很早,影響也最深遠(yuǎn)。KOA疼痛對(duì)冷溫刺激非常敏感,近年來研究逐步揭示這是一類冷刺激痛敏。TRPA1和TRPM8是人體對(duì)低溫刺激所致疼痛信號(hào)轉(zhuǎn)遞的介導(dǎo)者,膝骨關(guān)節(jié)炎中是否存在TRPA1、TRPM8的參與,對(duì)于認(rèn)識(shí)KOA疼痛和開發(fā)靶向藥物意義重大。"易層"貼敷膏劑是我院專利成方,以"溫經(jīng)活血"立法,通過"截?cái)? KOA疼痛,"扭轉(zhuǎn)" KOA病情進(jìn)展,具有良好的效果,其藥效機(jī)制是否與此有關(guān),也是我們本課題研究的關(guān)注點(diǎn)。目的:探索TRPA1和TRPM8與KOA冷刺激痛敏之間的聯(lián)系,以及溫經(jīng)活血外治("易層"貼敷膏劑)通過截?cái)郖OA冷痛敏扭轉(zhuǎn)其病情進(jìn)展的療效機(jī)制。方法:1.對(duì)比KOA的人滑膜組織(全膝關(guān)節(jié)置換手術(shù)術(shù)中提取廢棄滑膜)和非KOA的人滑膜組織(半月板損傷關(guān)節(jié)鏡清理修補(bǔ)手術(shù)中所獲滑膜碎屑)中TRPA1和TRPM8的蛋白和mRNA含量;2.對(duì)比KOA大鼠模型冷刺激痛閾、滑膜組織TRPA1和TRPM8的蛋白和mRNA含量變化,以及選擇性TRPA1、TRPM8阻斷劑對(duì)冷痛閾的影響和滑膜細(xì)胞TRPA1、TRPM8電生理特性的改變。3.觀察"易層"貼敷膏劑對(duì)KOA大鼠模型冷刺激痛閾、滑膜組織TRPA1和TRPM8蛋白和mRNA含量的影響。4.TRPA1和TRPM8活化的維持尚受到炎性細(xì)胞因子的調(diào)節(jié),進(jìn)一步觀察"易層"貼敷膏劑對(duì)KOA炎性細(xì)胞因子含量的影響。結(jié)果:1.KOA的人滑膜組織對(duì)比非KOA的人滑膜組織,TRPA1、TRPM8的蛋白和mRNA含量水平顯著上調(diào),差異有統(tǒng)計(jì)學(xué)意義(P0.05);2.KOA大鼠對(duì)比空白對(duì)照組健康大鼠冷刺激痛閾顯著下降,TRPA1、TRPM8的蛋白和mRNA含量水平顯著上調(diào),差異有統(tǒng)計(jì)學(xué)意義(P0.05);選擇性TRPA1、TRPM8阻斷劑通過阻斷滑膜細(xì)胞上TRPA1、TRPM8的鈣離子內(nèi)流,能夠上調(diào)KOA大鼠的冷刺激痛閾,差異有統(tǒng)計(jì)學(xué)意義(P0.05);3."易層"貼敷膏劑能夠上調(diào)KOA大鼠模型冷刺激痛閾,下調(diào)KOA大鼠滑膜組織中TRPA1和TRPM8蛋白和mRNA含量,差異有統(tǒng)計(jì)學(xué)意義(P0.05);4."易層"貼敷膏劑能夠下調(diào)KOA大鼠促炎細(xì)胞因子含量水平,上調(diào)抑炎細(xì)胞因子含量水平,這與其能夠抑制TRPA1、TRPM8的通道活化有關(guān)。結(jié)論:TRPA1和TRPM8是KOA冷刺激痛敏的重要介導(dǎo)者,"易層"貼敷膏劑可能通過下調(diào)TRPA1、TRPM8表達(dá)和抑制TRPA1、TRPM8通道活性,緩解KOA冷刺激痛敏,發(fā)揮其療效。"溫經(jīng)活血、截?cái)嗯まD(zhuǎn)"作為KOA治療理論有其臨床價(jià)值。
[Abstract]:Knee osteoarthritis (Knee Osteoarthritis,KOA) is the most common degenerative disease of bone and joint, because its pathogenesis has not been clear, so far there is no special therapeutic drug. KOA pain symptoms appeared very early. KOA pain is also the most far-reaching. KOA pain is very sensitive to cold stimulation. In recent years, studies have gradually revealed that this is a kind of cold stimulation pain sensitivity. TRPA1 and TRPM8 are the mediators of pain signal transmission caused by hypothermia stimulation in human body, and whether there is TRPA1, in knee osteoarthritis. The involvement of TRPM8 is important for understanding KOA pain and developing targeted drugs. " Yi layer "paste is a patented prescription in our hospital. With the legislation of" warming meridians and activating blood circulation ", it has a good effect by" cutting off "KOA pain and" reversing "the progress of KOA. Whether its efficacy mechanism is related to this. It is also the focus of our research. Objective: to explore the relationship between TRPA1 and TRPM8 and KOA cold stimulation hyperalgesia, and the therapeutic mechanism of warming meridians and activating blood circulation to reverse the progress of KOA cold hyperalgesia by cutting off KOA cold hyperalgesia. Methods: 1. The protein and mRNA contents of TRPA1 and TRPM8 in human synovial tissue of KOA (discarded synovium extracted during total knee arthroplasty) and non-KOA synovial tissue (synovial debris obtained during meniscus injury arthroscopic repair) were compared. 2. The changes of protein and mRNA content of TRPA1 and TRPM8 in synovial tissue, the effect of selective TRPA1,TRPM8 blocker on cold pain threshold and the changes of TRPA1,TRPM8 electrophysiological characteristics of synovial cells were compared with those of cold stimulation pain threshold, synovial tissue protein and mRNA content. To observe the effect of "Yi layer" paste on the pain threshold of cold stimulation and the content of TRPA1 and TRPM8 protein and mRNA in synovial tissue of KOA rats. 4. The maintenance of TRPA1 and TRPM8 activation is still regulated by inflammatory cytokines. Further observe the effect of "Yi layer" paste on the content of inflammatory cytokines in KOA. Results: the content of TRPA1,TRPM8 protein and mRNA in human synovial tissue of 1.KOA was significantly higher than that of non-KOA synovial tissue, and the difference was statistically significant (P 0.05). Compared with the blank control group, the cold stimulation pain threshold of 2.KOA rats was significantly decreased, and the levels of TRPA1,TRPM8 protein and mRNA were significantly up-regulated (P 0.05). Selective TRPA1,TRPM8 blockers can up-regulate the cold stimulation pain threshold of KOA rats by blocking the calcium influx of TRPA1,TRPM8 on synovial cells, the difference is statistically significant (P 0.05). " Yi layer "paste can up-regulate the pain threshold of cold stimulation in KOA rat model and down-regulate the contents of TRPA1 and TRPM8 protein and mRNA in synovial tissue of KOA rats, the difference is statistically significant (P 0.05)." Yi layer "paste can down-regulate the content of pro-inflammatory cytokines and up-regulate the level of anti-inflammatory cytokines in KOA rats, which is related to the inhibition of TRPA1,TRPM8 channel activation. Conclusion: TRPA1 and TRPM8 are important mediators of KOA cold stimulation hyperalgesia. "Yi layer" paste may relieve KOA cold stimulation pain sensitivity and exert its curative effect by down-regulating the expression of TRPA1,TRPM8 and inhibiting the activity of TRPA1,TRPM8 channel. " Wenjing Huoxue, truncated torsion "as the treatment of KOA theory has its clinical value."
【學(xué)位授予單位】：南京中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R274.9
本文編號(hào)：2472975
[Abstract]:Knee osteoarthritis (Knee Osteoarthritis,KOA) is the most common degenerative disease of bone and joint, because its pathogenesis has not been clear, so far there is no special therapeutic drug. KOA pain symptoms appeared very early. KOA pain is also the most far-reaching. KOA pain is very sensitive to cold stimulation. In recent years, studies have gradually revealed that this is a kind of cold stimulation pain sensitivity. TRPA1 and TRPM8 are the mediators of pain signal transmission caused by hypothermia stimulation in human body, and whether there is TRPA1, in knee osteoarthritis. The involvement of TRPM8 is important for understanding KOA pain and developing targeted drugs. " Yi layer "paste is a patented prescription in our hospital. With the legislation of" warming meridians and activating blood circulation ", it has a good effect by" cutting off "KOA pain and" reversing "the progress of KOA. Whether its efficacy mechanism is related to this. It is also the focus of our research. Objective: to explore the relationship between TRPA1 and TRPM8 and KOA cold stimulation hyperalgesia, and the therapeutic mechanism of warming meridians and activating blood circulation to reverse the progress of KOA cold hyperalgesia by cutting off KOA cold hyperalgesia. Methods: 1. The protein and mRNA contents of TRPA1 and TRPM8 in human synovial tissue of KOA (discarded synovium extracted during total knee arthroplasty) and non-KOA synovial tissue (synovial debris obtained during meniscus injury arthroscopic repair) were compared. 2. The changes of protein and mRNA content of TRPA1 and TRPM8 in synovial tissue, the effect of selective TRPA1,TRPM8 blocker on cold pain threshold and the changes of TRPA1,TRPM8 electrophysiological characteristics of synovial cells were compared with those of cold stimulation pain threshold, synovial tissue protein and mRNA content. To observe the effect of "Yi layer" paste on the pain threshold of cold stimulation and the content of TRPA1 and TRPM8 protein and mRNA in synovial tissue of KOA rats. 4. The maintenance of TRPA1 and TRPM8 activation is still regulated by inflammatory cytokines. Further observe the effect of "Yi layer" paste on the content of inflammatory cytokines in KOA. Results: the content of TRPA1,TRPM8 protein and mRNA in human synovial tissue of 1.KOA was significantly higher than that of non-KOA synovial tissue, and the difference was statistically significant (P 0.05). Compared with the blank control group, the cold stimulation pain threshold of 2.KOA rats was significantly decreased, and the levels of TRPA1,TRPM8 protein and mRNA were significantly up-regulated (P 0.05). Selective TRPA1,TRPM8 blockers can up-regulate the cold stimulation pain threshold of KOA rats by blocking the calcium influx of TRPA1,TRPM8 on synovial cells, the difference is statistically significant (P 0.05). " Yi layer "paste can up-regulate the pain threshold of cold stimulation in KOA rat model and down-regulate the contents of TRPA1 and TRPM8 protein and mRNA in synovial tissue of KOA rats, the difference is statistically significant (P 0.05)." Yi layer "paste can down-regulate the content of pro-inflammatory cytokines and up-regulate the level of anti-inflammatory cytokines in KOA rats, which is related to the inhibition of TRPA1,TRPM8 channel activation. Conclusion: TRPA1 and TRPM8 are important mediators of KOA cold stimulation hyperalgesia. "Yi layer" paste may relieve KOA cold stimulation pain sensitivity and exert its curative effect by down-regulating the expression of TRPA1,TRPM8 and inhibiting the activity of TRPA1,TRPM8 channel. " Wenjing Huoxue, truncated torsion "as the treatment of KOA theory has its clinical value."
【學(xué)位授予單位】：南京中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R274.9
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