許宏蓉, 周曉燕, 呂農(nóng)華
(南昌大學(xué) 1第一附屬醫(yī)院消化內(nèi)科, 2醫(yī)學(xué)院病理生理學(xué)教研室, 江西 南昌 330006)
脂氧素(lipoxins,LXs)是Serhan等[1]在1984年首次發(fā)現(xiàn)的一類具有三羥四烯結(jié)構(gòu)的花生四烯酸代謝產(chǎn)物,已被證實(shí)是炎癥反應(yīng)的強(qiáng)大的“停止信號(hào)”[2]。LXs參與很多疾病,尤其是消化系統(tǒng)疾病的病理生理過程,其多種生物學(xué)作用,尤其是抗炎促消退作用為消化系統(tǒng)疾病的治療提供了新的思路。現(xiàn)就LXs在消化系統(tǒng)疾病中的作用綜述如下。
感染、創(chuàng)傷或炎癥刺激、缺血再灌注等引起的多細(xì)胞宿主反應(yīng)導(dǎo)致了LXs的合成[3-4]。LXs是花生四烯酸(arachidonic acid,AA)在2種或2種以上的脂氧合酶(lipoxygenases,LOs)的連續(xù)性作用下生成的,主要通過跨細(xì)胞途徑合成。LXs的跨細(xì)胞合成途徑主要有以下3種:(1)15-LO和5-LO途徑。在噬酸性粒細(xì)胞、巨噬細(xì)胞、單核細(xì)胞、樹突狀細(xì)胞及呼吸道上皮細(xì)胞中,15-LO催化AA生成15S-過氧羥基二十四碳四烯酸(15S-hydroperoxyeicosatetraenoic acid,15S-HpETE),通過細(xì)胞之間的黏附作用,中間產(chǎn)物15S-HpETE被轉(zhuǎn)移到白細(xì)胞或多形核白細(xì)胞(polymorphonuclear,PMN)中并由其細(xì)胞內(nèi)的5-LO催化生成LXA4及其位置異構(gòu)體LXB4[3]。(2)5-LO和12-LO途徑。AA在PMN中由5-LO催化生成促炎介質(zhì)白三烯A4(leukotriene A4,LTA4),黏附到PMN上的血小板攝取了LTA4,其在12-LO的作用生成LXA4和LXB4[3]。(3)阿司匹林(aspirin;即乙酰水楊酸,acetylsalicylic acid,ASA)誘生的脂氧素(aspirin-triggered lipoxins,ATL)途徑。當(dāng)暴露于細(xì)胞因子如IL-β、LPS或TNF時(shí),上皮細(xì)胞或內(nèi)皮細(xì)胞上表達(dá)的環(huán)氧酶2(cyclooxygenase 2,COX-2)被ASA乙?;?,乙?;腃OX-2失去催化前列腺素生成的能力,但可以催化AA生成15R-羥基二十四碳四烯酸(15R-hydroxyeicosatetraenoic acid,15R-HETE)。通過細(xì)胞黏附作用,上皮細(xì)胞或內(nèi)皮細(xì)胞將15R-HETE傳遞給PMN并受5-LO催化合成15-epi-LXA4和15-epi-LXB4[5-6]。除了上述跨細(xì)胞合成途徑外,LXs還有單細(xì)胞合成途徑,即患哮喘等炎性疾病的個(gè)體在暴露于細(xì)胞因子或炎癥刺激時(shí),接觸了抗原的白細(xì)胞可合成LXs[5]。
LXs的生物學(xué)作用主要包括:(1)抗炎促消退作用。一方面,LXs通過抑制促炎信號(hào)通路(如NF-κB及激活蛋白-1等)及抑制PMN趨化、滾動(dòng)、黏附、轉(zhuǎn)移、脫顆粒等,抑制PMN滲出引起的炎癥反應(yīng),從而抑制PMN誘導(dǎo)的組織損傷。另一方面,LXs 可促進(jìn)巨噬細(xì)胞向炎癥部位聚集并增強(qiáng)其非炎性吞噬作用,促進(jìn)凋亡PMN的清除及炎癥消退[3,5-6]。(2)抗氧化作用。通過促進(jìn)核因子E2相關(guān)因子2(nuclear factor E2-related factor 2,Nrf2)的核轉(zhuǎn)運(yùn),上調(diào)抗氧化酶超氧化物歧化酶(superoxide dismutase,SOD)和谷胱甘肽過氧化物酶(glutathione peroxidase,GPx)的表達(dá),從而發(fā)揮抗氧化應(yīng)激及抗凋亡的作用[7]。(3)抗纖維化作用。具體包括:①激活轉(zhuǎn)錄生長因子β(transforming growth factor β,TGF-β)誘導(dǎo)的包括JNK、p38及ERK的促分裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)途徑、減少COL1A2 mRNA的表達(dá)[8];②抑制血小板來源的生長因子(platelet-derived growth factor,PDGF)[9],上調(diào)microRNA let-7c以抑制TGFβR1[10];③刺激甲酰肽受體2(formyl peptide receptor 2,FPR2)/脂氧素A4受體(lipoxin A4 receptor,ALX),激活KATP鉀通道及ERK磷酸化[11]等。(4)抗腫瘤作用。LXs通過抑制血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)[12-13]、抑制巨噬細(xì)胞活化[12]、缺氧誘導(dǎo)因子1α(hypoxia-inducible factor 1α,HIF-1α)[13]及NF-κB/COX-2信號(hào)通路[14],調(diào)控調(diào)節(jié)性T細(xì)胞(regulatory T cells,Tregs)[15]等途徑抑制腫瘤生長。(5)雌激素受體調(diào)節(jié)劑作用。LXA4是一種雌激素受體調(diào)節(jié)劑,其通過作用于人子宮內(nèi)膜和蛻膜上的FPR2/ALX啟動(dòng)信號(hào)通路,這給控制經(jīng)期及妊娠期炎癥、治療子宮內(nèi)膜異位及子宮內(nèi)膜癌等婦科疾病的提供了新思路[16-17]。(6)鎮(zhèn)痛作用。LXs及其類似物對(duì)于炎癥性疼痛及中樞神性疼痛有較好的鎮(zhèn)痛作用,其具體機(jī)制與抑制促炎細(xì)胞因子(IL-1β和TNF-α)[18]、抑制NALP1(NACHT, leucine rich repeat and PYD containing protein 1)[19]炎癥體有關(guān)。
LXA4通過作用于FPR2/ALX及芳烴受體(aryl hydrocarbon receptor, AhR)[20]等并激活由前角鯊烯二磷酸(presqualene diphosphate,PSDP)介導(dǎo)的多萜醇磷酸(polyisoprenyl phosphates ,PIPP)途徑[6]、p38途徑[8]、ERK途徑[8,11]、JNK途徑[8,12]等信號(hào)通路及調(diào)節(jié)NF-κB)[6,14]等轉(zhuǎn)錄因子的活性來發(fā)揮不同的生物學(xué)作用。
2.1LXs與肝臟疾病 近年來,LXs在肝損傷中的抗炎、護(hù)肝作用愈加凸顯。El-Agamy等[21]研究發(fā)現(xiàn)BML-111(LXs受體激動(dòng)劑)對(duì)于對(duì)乙酰氨基酚(acetaminophen,APAP)誘導(dǎo)的肝損傷具有保護(hù)作用。主要表現(xiàn)在BML-111可減少丙二醛并增加SOD及谷胱甘肽。更重要的是,BML-111減少了NO2-/NO3-及TNF-α的水平。相似的,Xia等[22]在APAP誘導(dǎo)肝損傷的兔模型中發(fā)現(xiàn),LXA4可上調(diào)IL-10并下調(diào)TNF-α和NF-κB p65的表達(dá),以減少炎癥細(xì)胞因子的滲出及肝細(xì)胞壞死和凋亡。值得注意的是,LXA4在大鼠肝移植排斥反應(yīng)中顯示出較好的肝保護(hù)作用。Liao等[23]在肝移植急性排斥反應(yīng)的大鼠模型中發(fā)現(xiàn),LXA4是通過調(diào)節(jié)IFN-γ(Th1細(xì)胞因子)向IL-10(Th2細(xì)胞因子)的轉(zhuǎn)化減少大鼠肝移植的急性排斥反應(yīng)。上述研究表明:LXA4在藥物、手術(shù)及創(chuàng)傷等引起的肝損傷中發(fā)揮了重要的肝保護(hù)作用。因?yàn)楦螕p傷是多種肝病的基本病理改變,因此LXA4可能在多種肝臟疾病的治療中發(fā)揮著重要的作用。
肝星狀細(xì)胞(hepatic stellate cell,HSC)是細(xì)胞外基質(zhì)的主要來源,PDGF和TGF-β是HSC活化和膠原合成中最重要的生長因子[24]。Zhou等[9]通過觀察BML-111對(duì)四氯化碳誘導(dǎo)的肝纖維化大鼠模型的影響時(shí)發(fā)現(xiàn),BML-111減少了α-平滑肌肌動(dòng)蛋白的表達(dá)及膠原沉積。此外,BML-111明顯下調(diào)了TGF-β1和PDGF的表達(dá),提示BML-111抑制TGF-β1和PDGF可能是BML-111抗纖維化作用的重要機(jī)制。除此之外,LXs及其類似物在系統(tǒng)性硬化癥[8]、腎纖維化[10]、囊胞性纖維癥[11]等疾病中也被證實(shí)了有較好的抗纖維化作用,提示LXs具備成為治療纖維化疾病新物的潛質(zhì)。
非酒精性脂肪肝(non-alcoholic fatty liver disease,NAFLD)中Δ5和Δ6去飽和酶活性減弱,因此飲食中的必需脂肪酸不能代謝為抗炎分子(如LXs)的前體物質(zhì)。NAFLD中抗炎分子(如LXs、消退素、保護(hù)素、IL-4和IL-10)的減少導(dǎo)致了IL-6、TNF-α、PGE2水平升高及胰島素抵抗[25]。有趣的是,Gangemi等[26]首次發(fā)現(xiàn)運(yùn)動(dòng)誘導(dǎo)產(chǎn)生的LXA4可以在尿中檢測出來,提示運(yùn)動(dòng)具有抗炎作用且有益于NAFLD患者。
腫瘤是慢性炎癥持續(xù)作用的結(jié)果且肝癌與慢性肝炎關(guān)系密切,作為炎癥反應(yīng)的“剎車信號(hào)”,LXs表現(xiàn)出較好的抗腫瘤作用。Hao等[12]在脂多糖(lipopolysaccharide,LPS)或激活的巨噬細(xì)胞條件培養(yǎng)基(activated macrophage-conditioned media,ACM)刺激的HepG2肝癌細(xì)胞中發(fā)現(xiàn),LXA4促進(jìn)HepG2細(xì)胞的凋亡,并抑制其增殖、擴(kuò)散和血管形成。
LXA4的抑癌機(jī)制受到了越來越多學(xué)者的關(guān)注。Zhou等[14]在肝癌HepG2細(xì)胞系中檢測到LXs受體的表達(dá),發(fā)現(xiàn)LXA4通過抑制NF-κB/COX-2信號(hào)通路而抑制HGF誘導(dǎo)的HepG2細(xì)胞的生長。具體而言,LXs抑制HGF誘導(dǎo)HepG2肝癌細(xì)胞表達(dá)血管生成相關(guān)細(xì)胞因子,包括VEGF、COX-2、TNF-α、IL-1β、TGF-β、MMP-2及MMP-9而抑制肝癌血管新生[27]。最新的研究表明,LXA4通過引起G0/G1期阻滯而抑制LPS誘導(dǎo)的RAW264.7巨噬細(xì)胞增殖[28]。因巨噬細(xì)胞在炎癥和腫瘤的發(fā)展中具有重要作用,故該研究為分析LXs的抑癌機(jī)制提供了新視角。
其他學(xué)者也闡述了LXs的抑癌機(jī)制。Chen等[13]在小鼠肝癌細(xì)胞系H22中發(fā)現(xiàn)LXA4通過抑制腫瘤相關(guān)的血管生成而抑制H22腫瘤的生長。Zhang等[15]在小鼠肝癌模型中發(fā)現(xiàn)Tregs,髓源性抑制細(xì)胞及LXA4的互相作用可調(diào)節(jié)腫瘤相關(guān)性炎癥。Li等[29]研究發(fā)現(xiàn)通過調(diào)節(jié)信號(hào)轉(zhuǎn)導(dǎo)子及轉(zhuǎn)錄激活子3(signal transducer and activator of transcription 3,STAT3)的磷酸化,LXA4誘導(dǎo)單核細(xì)胞分化為M2a+M2c-樣細(xì)胞,顯示出抗腫瘤基因活性。
2.2LXA4與重癥急性胰腺炎(severe acute pancreatitis,SAP) 胰腺壞死和炎癥產(chǎn)生的細(xì)胞因子可使SAP迅速發(fā)展為系統(tǒng)性炎癥反應(yīng)綜合征或多器官功能障礙,所以有效抗炎是治療SAP的關(guān)鍵。Zhou等[30]經(jīng)大鼠胰管內(nèi)注射5%?;悄懰徕c建立SAP模型,發(fā)現(xiàn)LXA4通過抑制NF-κB信號(hào)通路,減少促炎細(xì)胞因子的產(chǎn)生而起到了SAP的保護(hù)作用。另一項(xiàng)研究也得出相似的結(jié)論,即LXA4對(duì)SAP大鼠的保護(hù)機(jī)制可能與減少NF-κB的激活有關(guān)[31]。
2.3LXA4與胃疾病 藥物、應(yīng)激及乙醇是引起胃炎的常見病因。近年來,許多研究表明LXs在抑制胃炎的發(fā)展中發(fā)揮了重要作用。Souza等[32]研究發(fā)現(xiàn),在有胃炎的大鼠中,ASA誘導(dǎo)的胃損傷明顯低于正常組,說明ALX在胃炎中發(fā)揮著重要的黏膜防御作用。Hong等[33]研究發(fā)現(xiàn)在服用消炎痛后,老齡組大鼠的胃LXA4明顯低于年輕組,提示LXA4的減少與長期服用NSAID的老齡病人易患胃疾病有關(guān)。
LXA4在應(yīng)激或乙醇引起的胃損傷中也有重要的保護(hù)作用。Peskar等[34]研究發(fā)現(xiàn)5-LO抑制劑A63162、12-LO抑制劑黃芩素、15-LO抑制劑PD146176和LXA4/膜聯(lián)蛋白-1拮抗劑Boc1拮抗了在缺血再灌注條件下水楊酸鈉誘導(dǎo)的胃保護(hù)作用。另外,這些物質(zhì)可以拮抗20%乙醇引起的胃保護(hù)作用。考慮到5-、12- 及15-LO是LXA4生成的關(guān)鍵酶,推測LXA4可能在缺血再灌注及乙醇損傷性胃炎中具有保護(hù)作用。
關(guān)于LXs與胃癌的研究較少。Hong等[33]研究發(fā)現(xiàn)促炎介質(zhì)及氧化劑明顯增加,LXA4及抗凋亡蛋白顯著減少是老齡大鼠胃疾病(包括胃癌)發(fā)生的內(nèi)在機(jī)制。Dai等[35]提出了不同的觀點(diǎn),認(rèn)為補(bǔ)充脂肪酸后胃癌細(xì)胞生成的LXA4與胃癌細(xì)胞凋亡無明顯關(guān)系。目前,LXA4在胃癌發(fā)生中的作用尚無統(tǒng)一的說法,仍需更深入的研究。
2.4LXA4與腸道疾病 炎癥性腸病(inflammatory bowel disease,IBD)包括潰瘍性結(jié)腸炎(ulcerative colitis,UC)和克羅恩病(Crohn disease,CD)。嚴(yán)重UC患者LXA4合成較少或缺乏且有較低的15-LO-2水平,但是仍保有在ASA誘導(dǎo)下合成結(jié)腸15-epi-LXA4的能力,提示UC可能是由于抗炎介質(zhì)合成不足引起的炎癥反應(yīng)[2]。Vong等[36]通過分析LXA4及FPR2/ALX在結(jié)腸黏膜中的表達(dá)發(fā)現(xiàn),UC緩解期時(shí)LXA4明顯提高,伴隨巨噬細(xì)胞滲出增加及FPR2/ALX mRNA的增高,證實(shí)了LXA4在UC緩解期有促進(jìn)黏膜穩(wěn)態(tài)的作用,其機(jī)制可能與抑制NF-κB激活有關(guān)[37]。LXA4及其類似物在IBD中的治療作用已經(jīng)在多個(gè)研究中得到了證實(shí),其治療IBD具有較好的前景。
IBD病人患結(jié)直腸癌(colorectal cancer,CRC)的風(fēng)險(xiǎn)增加[38],而長期服用ASA可減少CRC的發(fā)病率和死亡率[39-40],其內(nèi)在機(jī)制受到了許多學(xué)者的關(guān)注。K?hnke等[41]研究表明,ASA+右旋糖酐硫酸酯鈉(dextran sodium sulfate,DSS)組的15-epi-lipoxin及二十二碳六烯酸來源的17-羥基二十碳六烯酸(17-hydroxydocosahexaenoic acid,17-HDHA)明顯高于DSS組,因此認(rèn)為ASA可增加抗炎脂質(zhì)介質(zhì)的合成,以減輕DSS誘導(dǎo)的結(jié)腸炎的嚴(yán)重程度。Janakiram等[20]更進(jìn)一步的研究發(fā)現(xiàn)LXs或其類似物通過旁分泌或自分泌作用于其特異性七次跨膜的G蛋白偶聯(lián)受體以抑制白細(xì)胞激活,減少促炎介質(zhì)的合成和釋放,從而抑制結(jié)直腸炎癥和腫瘤增殖、生長及侵襲[20]。
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