消退素是一種具有抗炎作用的長(zhǎng)鏈多不飽和脂肪酸衍生物家族[1,2]，可分為來(lái)源于ω3-20碳5烯酸(EPA)的消退素E(RvE)、來(lái)源于ω3-22碳6烯酸(DHA)的消退素D(RvD)及阿司匹林觸發(fā)型消退素D(AT-RvD)等[3]。據(jù)報(bào)道，消退素有抑制中性粒細(xì)胞募集[1,4]、調(diào)節(jié)趨化因子和細(xì)胞因子產(chǎn)生、減少炎細(xì)胞浸潤(rùn)、抑制非自主疼痛及高血壓[5]、促進(jìn)瘢痕修復(fù)等作用[6]。在腹膜炎、炎性腸病、關(guān)節(jié)炎、哮喘及膿毒癥等動(dòng)物模型中，消退素表現(xiàn)出良好的抗炎效果。近年發(fā)現(xiàn)消退素對(duì)于缺血再灌注腎損傷、梗阻性腎病、內(nèi)毒素血癥相關(guān)腎損傷及腎移植排斥反應(yīng)等具有保護(hù)作用[7]。本文就消退素在腎臟疾病領(lǐng)域的研究現(xiàn)狀作一綜述。

消退素的合成與受體

消退素合成的前體是EPA和DHA兩種人體必須脂肪酸，分別通過(guò)阿司匹林化環(huán)氧酶2(Aspirin-COX2)和脂氧酶(LO)的催化。目前已發(fā)現(xiàn)2種E類消退素(RvE1、 RvE2)、4種D類消退素(RvD1～ RvD4)、4種阿司匹林觸發(fā)型消退素D(AT-RvD1～AT-RvD4)，共10種消退素。消退素的合成及分類如圖1所示。高表達(dá)Aspirin-COX2的血管內(nèi)皮細(xì)胞、高表達(dá)LO的多形核細(xì)胞(PMN)均能夠產(chǎn)生相應(yīng)種類的消退素。多種動(dòng)物組織或器官(如血液、脂肪、大腦、視網(wǎng)膜、呼吸道、腹膜、腎臟)可檢出消退素的天然表達(dá)[8]。有研究顯示，白色念珠菌可通過(guò)細(xì)胞色素P450單氧化酶途徑產(chǎn)生RevE1[9]。

目前，RvE1和RvD1的受體已經(jīng)得到分離確認(rèn)。RvE1受體包括趨化樣因子受體1(CMKLR1，又稱ChemR23)和白三烯B4受體1(BLT1)，而RvD1則由G蛋白偶聯(lián)脂氧素A4受體(ALX/FPR2) 和G蛋白偶聯(lián)受體32(GPR32)所介導(dǎo)[10]。ChemR23和ALX/FPR2在免疫反應(yīng)中發(fā)揮重要作用，可表達(dá)于單核細(xì)胞、樹(shù)突狀細(xì)胞、巨噬細(xì)胞、中性粒細(xì)胞及T細(xì)胞等多種免疫細(xì)胞表面。研究發(fā)現(xiàn)ChemR23還見(jiàn)于人血管平滑肌細(xì)胞、脂肪細(xì)胞、神經(jīng)膠質(zhì)細(xì)胞等表面[11]。ALX和GPR32在呼吸道上皮、多形核細(xì)胞、脂肪細(xì)胞、血管平滑肌、巨噬細(xì)胞表面分布較廣泛[12]，而其他種類的消退素的受體尚未得到確認(rèn)。消退素受體在腎組織中除分布在非固有的免疫細(xì)胞表面外，還被證實(shí)分布于腎間質(zhì)成纖維細(xì)胞，消退素主要作用于免疫細(xì)胞、腎間質(zhì)纖維細(xì)胞等對(duì)腎臟起間接保護(hù)作用[13]。目前消退素受體在腎小球內(nèi)皮、腎小管上皮等細(xì)胞表面的分布情況尚不十分清楚，亦有研究發(fā)現(xiàn)RvD并不直接保護(hù)體外培養(yǎng)的豬腎小管上皮細(xì)胞[3]。消退素對(duì)腎臟損傷是否有直接作用尚需要進(jìn)一步闡明。

圖1 消退素的合成及分類

EPA：ω3-20碳5烯酸；DHA：ω3-22碳6烯酸；LO：脂氧酶；Aspirin-COX2：阿司匹林化環(huán)氧酶2；RvE：E類消退素；RvD：D類消退素；AT-RvD：阿司匹林觸發(fā)消退素

消退素對(duì)缺血再灌注腎損傷的保護(hù)作用

缺血再灌注損傷是組織或器官一段時(shí)間缺血或缺氧后恢復(fù)供血引起的組織損傷，其損傷機(jī)制與炎癥反應(yīng)部分相關(guān)[14]。Keyes等[15]曾報(bào)道，RvE1可直接作用于心肌細(xì)胞，通過(guò)抑制心肌凋亡，對(duì)抗大鼠心臟缺血再灌注損傷。缺血再灌注腎損傷可能是很多進(jìn)展性腎臟疾病的中心環(huán)節(jié)[16,17]。缺血再灌注損傷時(shí)，RvD可抑制小鼠腎組織中白細(xì)胞聚集和白細(xì)胞浸潤(rùn)、降低白細(xì)胞活性，并可阻斷Toll樣受體介導(dǎo)的巨噬細(xì)胞激活[3]。在腎缺血再灌注小鼠模型中，RvD前體DHA內(nèi)源性合成增多，RvD1和RvD3的血漿濃度也輕度增加。缺血腎損傷后外源性補(bǔ)充DHA，血漿中RvD1、RvD2、RvD3水平明顯濃度上升[3]，提示在缺血再灌注腎損傷時(shí)，機(jī)體不僅能內(nèi)源性分泌消退素及前體，外源性補(bǔ)充DHA也能促進(jìn)各種RvD的合成。研究還發(fā)現(xiàn)，腎臟缺血再灌注前和損傷后注射RvD均可發(fā)揮保護(hù)作用。在夾閉腎動(dòng)脈前對(duì)小鼠進(jìn)行尾靜脈注射RvD，可減少功能性和器質(zhì)性腎臟損傷；即使在夾閉腎動(dòng)脈10 min后進(jìn)行RvD干預(yù)，48h時(shí)小鼠的血漿肌酐已恢復(fù)正常，而對(duì)照組中肌酐仍顯著升高。此外，PAS染色發(fā)現(xiàn)，RvD可提高腎小管上皮細(xì)胞生存率、降低炎癥反應(yīng)、減少毛細(xì)血管阻塞。因此，外源性補(bǔ)充消退素可以保護(hù)缺血再灌注引起的腎臟損傷，其機(jī)制可能與減少炎性細(xì)胞浸潤(rùn)、抑制腎間質(zhì)纖維化[3]、防止微血栓形成[18]等有關(guān)。

消退素對(duì)梗阻性腎病的保護(hù)作用

纖維化是器官或組織中代償性或反應(yīng)性纖維結(jié)締組織增生，為急性和慢性炎癥反應(yīng)結(jié)局之一[19]。2006年，Duffield等[3]發(fā)現(xiàn)治療小鼠腎臟缺血再灌注損傷時(shí)，RvD能顯著減少膠原沉積，對(duì)腎臟纖維化起保護(hù)作用。Qu等[13]在單側(cè)輸尿管結(jié)扎(UUO)模型中發(fā)現(xiàn)，RvE1可抑制造模2d、4d、6d小鼠腎臟肌成纖維細(xì)胞增生及平滑肌肌動(dòng)蛋白和Ⅳ型膠原沉積，起早期對(duì)抗纖維化的作用。血小板源性生長(zhǎng)因子B(PDGF-BB)在腎間質(zhì)成纖維細(xì)胞增生中起重要作用[20,21]；Qu等[13]體外實(shí)驗(yàn)發(fā)現(xiàn)，RvE1可抑制細(xì)胞外調(diào)節(jié)蛋白激酶(ERK)、蛋白激酶B(AKT)信號(hào)通路的持續(xù)性活化、對(duì)抗PDGF-BB誘導(dǎo)的小鼠腎纖維母細(xì)胞增生；對(duì)ChemR23進(jìn)行敲除后，RvE1的抗纖維化作用被部分逆轉(zhuǎn)，提示ChemR23可能介導(dǎo)RvE1的抗纖維化作用。纖維化可繼發(fā)于炎癥，消退素的抗纖維化作用也可能繼發(fā)于抗炎作用。但UUO模型的炎性反應(yīng)較輕，巨噬細(xì)胞等免疫細(xì)胞浸潤(rùn)不明顯。因此，消退素可能擁有直接抗纖維化的效果，在梗阻性腎病等領(lǐng)域有一定應(yīng)用前景。

消退素對(duì)內(nèi)毒素血癥相關(guān)腎損傷的保護(hù)作用

消退素已經(jīng)在腹膜炎、結(jié)腸炎、膿毒癥等多種感染性疾病小鼠模型中顯示出較好的抗炎作用[8]，其抗炎機(jī)制可能涉及減少炎性細(xì)胞浸潤(rùn)、抑制炎癥因子分泌、促使炎性細(xì)胞凋亡、加速炎性細(xì)胞回流及MicroRNA反饋調(diào)節(jié)等[22]。在脂多糖(LPS)誘導(dǎo)小鼠急性肺損傷模型中，提前30 min經(jīng)腹腔或尾靜脈注射RvD1可顯著降低動(dòng)物死亡率、改善小鼠急性肺損傷癥狀，其機(jī)制可能與絲裂原原活化蛋白激酶(MAPKs)和核因子κB(NF-κB)通路的抑制有關(guān)[23,24]。體外實(shí)驗(yàn)發(fā)現(xiàn)，LPS可刺激巨噬細(xì)胞分泌腫瘤壞死因子α(TNF-α)，而加入DHA或RvD1則能顯著減少TNF-α的表達(dá)，但DHA只在高濃度下才具有抑制細(xì)胞因子分泌的作用，而RvD1在低濃度下即具有抗炎效果，所需濃度僅為其前體DHA的1/100。研究認(rèn)為RvD并不能直接保護(hù)豬腎小管上皮細(xì)胞，但可通過(guò)抑制巨噬細(xì)胞活性、減少細(xì)胞因子分泌等作用實(shí)現(xiàn)對(duì)LPS等所致腎損傷起保護(hù)作用[3]。消退素對(duì)內(nèi)毒素血癥時(shí)腎功能、腎實(shí)質(zhì)細(xì)胞的保護(hù)作用，仍有待研究進(jìn)一步加以闡述。

消退素在腎移植抗排斥反應(yīng)中的應(yīng)用

排斥反應(yīng)是腎移植術(shù)后常見(jiàn)的并發(fā)癥，涉及體液免疫和細(xì)胞免疫中各種抗體、T細(xì)胞、B細(xì)胞、趨化因子、細(xì)胞因子等的交互作用[25]。腎小管上皮細(xì)胞是產(chǎn)生細(xì)胞因子和趨化因子的主要部位之一；浸潤(rùn)性白細(xì)胞和上皮細(xì)胞共同決定間質(zhì)炎癥反應(yīng)和局部組織損傷的程度。研究證實(shí)RvE1等消退素可加強(qiáng)小鼠、人的巨噬細(xì)胞對(duì)凋亡白細(xì)胞、趨化因子、細(xì)胞因子和微生物產(chǎn)物的清掃，是多形核白細(xì)胞活化趨化、浸潤(rùn)的抑制劑[26,27]。Levy等[28]在腎移植前向小鼠靜脈注射RvE1發(fā)現(xiàn)，RvE1可通過(guò)下調(diào)固有免疫而延遲排異反應(yīng)發(fā)生的時(shí)間。白細(xì)胞介素17等是異體移植排斥反應(yīng)的重要介質(zhì)[29]，消退素能夠下調(diào)這些細(xì)胞因子的表達(dá)[30]，也是消退素抑制移植排斥反應(yīng)的可能機(jī)制之一。白三烯1受體在移植炎性反應(yīng)白三烯4介導(dǎo)的傳導(dǎo)途徑中發(fā)揮重要作用，因此，RvE1在異體腎移植后發(fā)揮器官保護(hù)作用也可能通過(guò)其受體水平與白三烯1的拮抗[28,31]。此外，移植排斥反應(yīng)時(shí)，腎臟組織易因免疫反應(yīng)引發(fā)缺血再灌注損傷[32]；如前文所述，消退素可保護(hù)小鼠缺血再灌注腎損傷，其減輕腎移植排斥反應(yīng)的作用或與此有關(guān)。

小結(jié)：消退素是人體內(nèi)EPA或DHA的衍生物，是生物效能強(qiáng)大的炎癥自限因子，可通過(guò)阻止炎性細(xì)胞浸潤(rùn)、抑制炎癥因子生成等發(fā)揮作用。Hellmann等[33]研究發(fā)現(xiàn)消退素具有緩解疼痛、抗纖維化、改善胰島素抵抗等多種生物效應(yīng)，NF-κB、MAPK、AKT等通路可能在其中發(fā)揮了關(guān)鍵作用。消退素是目前腎臟疾病研究中較新的領(lǐng)域，已有的報(bào)道提示消退素對(duì)小鼠缺血再灌注損傷腎損傷、梗阻性腎病、內(nèi)毒素血癥相關(guān)腎損傷及腎移植排斥反應(yīng)等疾病動(dòng)物模型具有保護(hù)作用，為相關(guān)疾病的藥物研發(fā)提供了新思路，但仍需進(jìn)一步明確消退素對(duì)各種腎臟疾病模型及腎固有細(xì)胞的保護(hù)作用，并深入闡述相關(guān)作用機(jī)制，為臨床應(yīng)用提供證據(jù)。

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