本文選題：ASIC3 + 瘙癢��； 參考：《南方醫(yī)科大學(xué)》2017年碩士論文

【摘要】：瘙癢是皮膚疾病和一些系統(tǒng)疾病的常見臨床癥狀之一,嚴(yán)重影響睡眠,降低患者生活質(zhì)量。急性瘙癢主要由某些致癢物質(zhì)引起的,慢性瘙癢主要由皮膚疾病和某些系統(tǒng)性疾病引起。臨床上治療瘙癢以傳統(tǒng)的抗組胺治療為主,但對(duì)于大多數(shù)的慢性瘙癢,效果往往不佳。瘙癢的發(fā)病機(jī)制至今不是很清楚,目前普遍認(rèn)為瘙癢并不是由單一因素引起的,而是由致癢物質(zhì)、皮膚神經(jīng)纖維、角質(zhì)形成細(xì)胞、皮膚屏障、外周中樞神經(jīng)系統(tǒng)間的復(fù)雜相互作用的結(jié)果。常用的完全弗氏佐劑(complete Freund' S adjuvant,CFA)炎癥模型進(jìn)行觸誘發(fā)癢實(shí)驗(yàn)發(fā)現(xiàn),炎癥皮損區(qū)出現(xiàn)癢覺敏化,并且緩激肽受體(bradykinin receptor,BR)在其中起到關(guān)鍵作用。緩激肽(bradykinin,BK)是目前已知的最強(qiáng)的致痛物質(zhì)也是重要的致炎因子。緩激肽及其代謝產(chǎn)物des-Arg(9)-bradykinin,des-Arg(10)-kallidin通過結(jié)合細(xì)胞膜上的特異性緩激肽受體發(fā)揮生物作用。緩激肽受體是一種九肽段蛋白耦聯(lián)受體(G.protein.coupled receptor,GPCR)受體。正常生理情況下B1R除中樞神經(jīng)系統(tǒng)組少量表達(dá)外其他組織幾乎不表達(dá),而在細(xì)菌脂多糖(lipopolysaccharide,LPS)、炎癥、創(chuàng)傷等情況誘導(dǎo)下迅速表達(dá),是一種誘導(dǎo)性表達(dá)受體。皮內(nèi)注射B1R受體激動(dòng)劑可引起CFA炎癥模型小鼠產(chǎn)生搔抓行為,但B1R受體激動(dòng)劑引起瘙癢的下游機(jī)制至今不是很清楚。有研究指出機(jī)體炎癥,對(duì)應(yīng)的背根神經(jīng)節(jié)(dorsal root ganglion,DRG)酸敏感性離子通道(Acid-sensing ion channels,ASICs)表達(dá)上升,干皮癥小鼠ASIC3基因敲除或使用特異阻斷劑均可使搔抓行為減弱。B1R激動(dòng)劑引起瘙癢是否與背根神經(jīng)節(jié)上ASIC3表達(dá)增加有關(guān)值得進(jìn)一步深入探討。研究方法:模型制備:C57BL/6J鼠七氟醚麻醉后頸背部皮膚剃毛,皮內(nèi)注射CFA,96h后進(jìn)行行為學(xué)觀察。實(shí)驗(yàn)前置于Plexiglas盒內(nèi)適應(yīng)30 min,麻醉后腹腔預(yù)注射ASIC3阻斷劑APETx2,對(duì)照組腹腔注射生理鹽水,腹腔注射后立即放入Plexiglas盒內(nèi)。30min后,于七氟醚麻醉后頸背部炎性皮損區(qū)皮內(nèi)注射BIR激動(dòng)劑,放入Plexiglas盒內(nèi)觀察小鼠后肢搔抓藥物注射部位的次數(shù),每只小鼠的觀察時(shí)間為30 min。觀察結(jié)束后處死取相應(yīng)節(jié)段DRG,western blot檢測(cè)DRG中ASIC3表達(dá)情況。為進(jìn)一步探討ASIC3參與瘙癢是否具有選擇性,本研究檢驗(yàn)了 APETx2是否能抑制DCP模型小鼠自發(fā)癢以及急性致癢物質(zhì):氯喹(chloroquine,CQ),內(nèi)皮素-1(endothelin-1,ET-1)、48/80 混合物(48/80 compound)誘發(fā)的瘙癢。結(jié)果:1.抑制ASIC3通路顯著減弱小鼠B1R激動(dòng)劑誘發(fā)的炎性皮損區(qū)瘙癢行為。較對(duì)照組,實(shí)驗(yàn)組腹腔預(yù)注射APETx2明顯減弱小鼠的搔抓行為(Figl-1,*P0.05),表明ASIC3參與B1R激動(dòng)劑誘發(fā)的瘙癢。2.抑制ASIC3通路只能減弱某些致癢物質(zhì)引起的瘙癢。腹腔預(yù)注射APETx2明顯減弱氯喹引起的瘙癢(Fig2-2,*P0.05),但對(duì)48/80compound,ET-I引起的搔抓行為無(wú)明顯減弱作用(Fig2-2,*P0.05).3.抑制ASI3通路減弱DCP自發(fā)癢模型小鼠的搔抓行為。實(shí)驗(yàn)組腹腔注射APETx2小鼠30min內(nèi)搔抓次數(shù)顯著較對(duì)照組減少(Fig2-1,*P0.05)。4.皮膚炎癥刺激引起DRG上ASIC3表達(dá)增加。CFA引起的炎癥皮損區(qū)對(duì)應(yīng)節(jié)段的DRG上ASIC3表達(dá)較正常鼠有明顯的增加(Figl-2)。結(jié)論:炎癥刺激引起DRG上ASIC3表達(dá)上調(diào)。ASIC3通路參與B1R激動(dòng)劑及CQ引起的瘙癢,但不參與ET-1、48/80compound引起的瘙癢。結(jié)論ASIC3可能參與B1R激活引起瘙癢的下游機(jī)制ASIC3參與瘙癢的調(diào)節(jié)具有選擇性
[Abstract]:Itching is one of the common clinical symptoms of skin diseases and some systemic diseases, which seriously affect sleep and reduce the quality of life of the patients. Acute itching is mainly caused by some itchy substances. Chronic itching is mainly caused by skin diseases and some systemic diseases. The pathogenesis of chronic pruritus is often poor. The pathogenesis of itching is not very clear. It is generally believed that itching is not caused by a single factor, but is the result of the complex interaction between the itching, skin nerve fibers, keratinocytes, skin barrier, and the peripheral nervous system. C Omplete Freund'S adjuvant, CFA) an itching experiment of the inflammatory model found that there was a tickling sensitization in the inflammatory zone and the key role of the bradykinin receptor (bradykinin receptor, BR). Bradykinin (bradykinin, BK) is the strongest pain causing substance known at present and an important inflammatory factor. Bradykinin and its metabolite Des-Arg (9) -bradykinin, des-Arg (10) -kallidin plays biological action by binding the specific bradykinin receptor on the cell membrane. The bradykinin receptor is a G.protein.coupled receptor receptor (G.protein.coupled receptor, GPCR) receptor. Under normal physiological conditions, B1R is almost expressed in a small amount of other tissues except for a small amount of the central deity system. It is an inducible expression receptor that is induced by bacterial lipopolysaccharide (lipopolysaccharide, LPS), inflammation and trauma. Intradermal injection of B1R receptor agonist can cause Scratch behavior in CFA model mice, but the downstream mechanism of pruritus caused by B1R receptor agonists is not very clear. The expression of dorsal root ganglion (DRG) acid sensitive ion channel (Acid-sensing ion channels, ASICs) is increased. The activity of ASIC3 gene knockout in dry skin mice, or using specific blockers, may weaken the scratch behavior of.B1R agonists and whether it is related to the increase of ASIC3 expression on the dorsal root ganglion. Study method: model preparation: model preparation: C57BL/6J rat after sevoflurane anesthesia after the skin shaving, intradermal injection of CFA, 96h after the behavioral observation. The experiment was prepositioned in the Plexiglas box to adapt to 30 min, after the anesthesia, the abdominal preinjection ASIC3 blocker APETx2, the control group intraperitoneal injection of physiological salt water, after intraperitoneal injection into Plexiglas box.30min after immediately after the injection. After sevoflurane anaesthesia, the BIR agonist was injected into the skin of the back of the back of the neck. The times of the injection site of the mouse hind limbs were observed in the Plexiglas box. The observation time of each mouse was 30 min. and the corresponding segment DRG was killed and Western blot was used to detect the expression of ASIC3 in DRG. Whether or not it is selective, this study examined whether APETx2 could inhibit itching in DCP model mice and acute itchy substances: chloroquine (chloroquine, CQ), endothelin -1 (endothelin-1, ET-1), and 48/80 mixture (48/80 compound) induced pruritus. Results: 1. inhibition of ASIC3 pathway significantly diminished the inflammatory skin pruritus induced by mice B1R agonists. Compared with the control group, the preinjection of APETx2 in the experimental group significantly weakened the scratch behavior of mice (Figl-1, *P0.05), indicating that ASIC3 involved in B1R agonist induced pruritus.2. inhibited ASIC3 pathway only to weaken the itching caused by some itchy substances. Peritoneal injection of APETx2 significantly weakened the pruritus (Fig2-2, *P0.05) caused by chloroquine (Fig2-2, *P0.05), but to 48/80compound, The scratch behavior caused by ET-I was not significantly weakened (Fig2-2, *P0.05).3. inhibited the scratch behavior of DCP self itching model mice. In the experimental group, the number of scratching in 30min of APETx2 mice was significantly lower than that of the control group (Fig2-1, *P0.05).4. skin inflammation stimulated the inflammatory skin lesion caused by the increased expression of the DRG. The expression of ASIC3 on the segment of DRG was significantly increased (Figl-2). Conclusion: inflammatory stimulation causes ASIC3 expression on DRG to increase.ASIC3 pathway to participate in B1R agonist and CQ induced pruritus, but does not participate in ET-1,48/80compound induced pruritus. Conclusion ASIC3 may participate in the regulation of pruritus downstream of B1R activation to participate in pruritus. Selectivity

【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R758.31

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本文編號(hào)：1879981