張東東，尚德靜

(遼寧師范大學(xué) 生命科學(xué)學(xué)院，遼寧 大連 116081)

抗菌肽作為新型抗感染藥物的潛力及應(yīng)用前景

張東東，尚德靜Δ

(遼寧師范大學(xué) 生命科學(xué)學(xué)院，遼寧 大連 116081)

抗菌肽廣泛存在于各種生物中，是先天免疫反應(yīng)的保守組分，對(duì)革蘭氏陰性細(xì)菌、革蘭氏陽性細(xì)菌、真菌、原蟲等有廣泛地殺滅作用，尤其對(duì)耐藥性細(xì)菌有抗菌活性，有希望成為新型的抗生素治療性藥物。近年來發(fā)現(xiàn)抗菌肽具有免疫調(diào)節(jié)活性，是一種新興的治療理念，它的選擇性調(diào)節(jié)是一種新型抗感染策略?？咕哪艽龠M(jìn)先天性免疫應(yīng)答和選擇性地調(diào)節(jié)致病菌引起的炎癥反應(yīng)。本文主要闡述了抗菌肽作為先天性免疫調(diào)節(jié)因子的作用機(jī)制，它們?cè)谙忍煨悦庖吆瓦m應(yīng)性免疫界面的作用，以及它們作為新型抗感染和免疫調(diào)節(jié)藥物的潛力及應(yīng)用前景。

抗菌肽；免疫調(diào)節(jié)；抗感染

抗菌肽是天然廣譜抗菌藥物，它們廣泛分布于自然界，從原核生物到脊椎動(dòng)物都有分布[1]。這些分子是先天免疫系統(tǒng)的保守組分，能選擇性地激活體內(nèi)先天免疫應(yīng)答，對(duì)敗血癥等感染性疾病有良好的預(yù)防和保護(hù)作用?？咕囊部梢哉{(diào)節(jié)細(xì)胞的功能，例如趨化作用、基因轉(zhuǎn)錄、細(xì)胞因子產(chǎn)生和釋放，增強(qiáng)抗菌免疫力，同時(shí)減少炎癥引起的組織損傷。另外，抗菌肽能參與傷口愈合和血管生成過程[2-3]。因此，抗菌肽有希望成為新型抗生素，幫助治療由致病菌引起的感染性疾病。

抗菌肽的抗菌活性作為最早已知特性之一，已被廣泛討論。它們不僅是抗菌分子(甚至對(duì)傳統(tǒng)抗生素耐藥菌株)，而且對(duì)真菌、包膜病毒(如HIV、流感)、寄生性原蟲及癌細(xì)胞等具有直接的殺滅活性[4-6]?？咕目勺饔糜谥|(zhì)雙分子層通過不同的機(jī)制使細(xì)菌細(xì)胞死亡：①改變膜電勢[7]；②形成跨膜孔[8-9]；③修改膜脂電流分布，導(dǎo)致膜結(jié)構(gòu)的去穩(wěn)定性[7, 10]；④觸發(fā)致死程序，如誘導(dǎo)自溶酶[11]；透膜后作用于細(xì)胞內(nèi)的重要靶點(diǎn)[12]。

然而，不是所有的抗菌肽都是通過直接殺菌，而是通過參與免疫調(diào)節(jié)發(fā)揮保護(hù)作用。例如，人抗菌肽LL-37可預(yù)防體內(nèi)細(xì)菌感染，在磷酸鹽緩沖液中可顯示出抑菌活性，但在生理學(xué)相關(guān)組織培養(yǎng)基中卻不能減少細(xì)菌負(fù)荷[13]。此外，已證明合成的抗菌肽沒有直接抑菌活性，但卻能有效的防止組織損傷和體內(nèi)細(xì)菌感染[1, 2, 14, 15, 7, 13]。雖然這些免疫調(diào)節(jié)功能不是產(chǎn)生直接的抗菌活性，而是補(bǔ)充和增強(qiáng)身體抗感染能力，但是它們可以影響感染的結(jié)果。本綜述認(rèn)為抗菌肽的選擇性免疫調(diào)節(jié)活性對(duì)于它們的保護(hù)機(jī)制而言與直接抗菌活性一樣重要，甚至更重要。本文主要就這類肽的免疫調(diào)節(jié)活性及它們?cè)诳垢腥绢I(lǐng)域的應(yīng)用前景作一綜述。

1 抗菌肽抗內(nèi)毒素活性

內(nèi)毒素是革蘭氏陰性細(xì)菌外膜的主要分子組分脂多糖(lipopolysaccharide，LPS)，在細(xì)菌外圍作為一種物理屏障為其提供保護(hù)。內(nèi)毒素能被免疫系統(tǒng)識(shí)別作為檢測細(xì)菌病原體入侵的一個(gè)標(biāo)志，是炎性反應(yīng)發(fā)展的原因，在極端情況下會(huì)導(dǎo)致內(nèi)毒素性休克。不同來源的抗菌肽，例如來自昆蟲的天蠶抗菌肽-蜂毒肽雜合肽CEMA[16]、人抗菌肽LL-37(human antibacterial peptide LL-37，LL-37)[17]、?？咕腂MAP-27(bovine antimicrobial peptides BMAP-27，BMAP-27)及小分子的合成肽[18]能顯著降低內(nèi)毒素誘導(dǎo)的炎癥反應(yīng)，并且可以預(yù)防內(nèi)毒素性休克[2, 13]。因此，研究者推測這些肽顯示出的抗內(nèi)毒素活性在不同物種之間可能是守恒的。

抗菌肽在炎癥反應(yīng)的微妙平衡和調(diào)節(jié)中發(fā)揮著重要作用，它們會(huì)抑制內(nèi)毒素誘導(dǎo)的促炎基因表達(dá)(例如內(nèi)毒素誘導(dǎo)的NF-κB亞基核易位)和炎癥介質(zhì)蛋白的分泌(例如腫瘤壞死因子(tumor necrosis factor，TNF-α)；白細(xì)胞介素-6(interleukin-6，IL-6)和一氧化氮(NO)，同時(shí)維持其他促炎反應(yīng)(例如幾種趨化因子的產(chǎn)生和釋放)，導(dǎo)致促炎癥反應(yīng)的整體選擇性抑制[2, 16, 19]。例如，人抗菌肽LL-37在各種哺乳動(dòng)物體內(nèi)能選擇性地抑制由革蘭氏陰性菌細(xì)胞壁特有成分LPS及其他Toll樣受體(toll like receptors，TLRs)激動(dòng)劑(例如革蘭氏陽性特有的脂磷壁酸)引起的促炎性反應(yīng)[16-17, 20 ]。另一方面，當(dāng)用一種來源于鱟的抗LPS因子的合成肽預(yù)防性給藥時(shí)能顯著增加小鼠內(nèi)毒素休克模型存活率，顯然這種肽是通過一種與LPS直接結(jié)合無關(guān)的方式調(diào)節(jié)細(xì)胞因子的表達(dá)[21]。通過對(duì)抗菌肽與LPS的相互作用進(jìn)一步研究，提出了2種作用機(jī)制：①抗菌肽直接結(jié)合于LPS，使其無法與脂多糖結(jié)合蛋白(lipopolysaccharide-binding protein，LBP)結(jié)合，因此無法將其傳送到其初級(jí)受體CD14[22]。②通過調(diào)節(jié)內(nèi)毒素誘導(dǎo)的TLRs到核因子-κB(nuclear factor-κB，NF-κB)通路的信號(hào)傳遞。目前研究表明，這些肽通過多方面機(jī)制經(jīng)由多點(diǎn)干預(yù)起保護(hù)作用[16, 19, 23, 24]。根據(jù)抗菌肽的總體抗內(nèi)毒素效應(yīng)可以推測，它們不僅能在致病菌感染中抑制炎癥，而且可能在維持內(nèi)環(huán)境的穩(wěn)定中發(fā)揮至關(guān)重要的作用。

2 抗菌肽具有趨化活性

抗菌肽能選擇性地上調(diào)趨化因子和細(xì)胞因子的產(chǎn)生，召集單核細(xì)胞、巨噬細(xì)胞及嗜中性粒細(xì)胞到感染部位發(fā)揮保護(hù)作用[7, 9, 13]。細(xì)菌入侵的同時(shí)，受感染部位的局部組織細(xì)胞會(huì)分泌趨化因子吸引包括中性粒細(xì)胞在內(nèi)的其他免疫效應(yīng)細(xì)胞，導(dǎo)致抗菌肽的釋放量增加[25]。分泌的抗菌肽又可以反過來直接或間接地促進(jìn)效應(yīng)細(xì)胞的召集，如嗜中性粒細(xì)胞、單核細(xì)胞/巨噬細(xì)胞、未成熟的樹突細(xì)胞和T細(xì)胞。例如，LL-37和IL-1β一起作用誘導(dǎo)外周血單個(gè)核細(xì)胞合成趨化物如單核細(xì)胞趨化蛋白1(monocyte chemotactic protein 1，MCP-1) 和單核細(xì)胞趨化蛋白3(monocyte chemotactic protein 3，MCP-3)[26]。此外，LL-37是中性粒細(xì)胞、單核細(xì)胞、T淋巴細(xì)胞及肥大細(xì)胞的一種趨化物[27]。另外，小鼠β-防御素(β-defensin，HBD)和HBD-123是未成熟樹突狀細(xì)胞和記憶T細(xì)胞的趨化物，與細(xì)胞內(nèi)的CCR6相互作用[28]。因此，抗菌肽的一個(gè)重要特性是它們能有選擇性地誘導(dǎo)基因表達(dá)和產(chǎn)生趨化因子或細(xì)胞因子，這種能力對(duì)免疫效應(yīng)功能至關(guān)重要。

此外，抗菌肽通過趨化活性促進(jìn)傷口愈合有助于緩解損傷或感染[3]。LL-37在表皮細(xì)胞再生和血管再生過程中具有重要的作用，可直接作用于上皮細(xì)胞促進(jìn)細(xì)胞增殖和血管樣結(jié)構(gòu)形成[29]。LL-37通過反式激活表皮生長因子受體誘導(dǎo)角化細(xì)胞發(fā)生顯著的遷移[30]。在小鼠體內(nèi)，通過局部使用LL-37的合成重組肽P-LL-37可治療由地塞米松誘導(dǎo)損傷的血管形成恢復(fù)[31]。LL-37 和HNP1-3通過與表皮生長因子相互作用和激活細(xì)胞外MAPK通路,有助于呼吸道上皮的愈合[32-33]。HNP-1作用于成纖維細(xì)胞能增加I型膠原蛋白的表達(dá)及下調(diào)間質(zhì)膠原酶的合成[34]。此外，HBD-2和HBD-3能通過誘導(dǎo)細(xì)胞因子的合成激活角化細(xì)胞并促進(jìn)其遷移和增殖[35]。

3 抗菌肽調(diào)節(jié)炎癥反應(yīng)

抗菌肽是先天免疫系統(tǒng)的一部分，在感染或炎癥中許多的肽的表達(dá)量增加，例如被細(xì)菌感染期間在不同類型的細(xì)胞中人β-防御素2的表達(dá)被上調(diào)，并且用不同的細(xì)菌組分刺激后能夠激活Toll樣受體到NF-κB通路，而人抗菌肽LL-37似乎僅通過內(nèi)源性炎癥分子上調(diào)[14, 36]。在轉(zhuǎn)基因小鼠模型中增加這些肽的表達(dá)，對(duì)細(xì)菌感染的抵抗力隨之增強(qiáng)[37]。與此相反，對(duì)小鼠模型的體內(nèi)研究結(jié)果表明，在這些防御肽缺失的情況下將導(dǎo)致感染的易感性增加[1]。同樣地，如果人體內(nèi)缺乏或低表達(dá)某些防御肽也會(huì)導(dǎo)致對(duì)感染的易感性增加。例如，特應(yīng)性皮炎與防御素和抗菌肽LL-37的缺乏有關(guān)[15]。通過利用實(shí)驗(yàn)系統(tǒng)模擬生理學(xué)相關(guān)條件以及在動(dòng)物模型中體內(nèi)感染的研究[1, 38]，充分證明了抗菌肽能夠抑制或清除細(xì)菌感染和調(diào)節(jié)相關(guān)炎癥，在宿主免疫系統(tǒng)中發(fā)揮著重要作用。

抗菌肽不僅能抑制某些促炎癥反應(yīng)，同時(shí)也能增強(qiáng)某些其他免疫反應(yīng)(通常認(rèn)為是促炎性的)，這有利于將細(xì)胞召集到感染部位并影響隨后的免疫反應(yīng)。例如，LL-37作為促炎和抗炎抗菌肽在調(diào)節(jié)調(diào)節(jié)炎癥方面具有雙重作用，在保持其動(dòng)態(tài)平衡中起重要作用。LL-37在LPS和IFN-γ極化的小鼠骨髓巨噬細(xì)胞中能下調(diào)TNF-α和NO等炎性因子產(chǎn)生[39]。相反，LL-37和HBD通過召集、激活和脫粒肥大細(xì)胞促進(jìn)炎癥[40]，例如LL-37和HBD-4誘導(dǎo)促炎細(xì)胞因子IL-18和IL-31的合成[41-42]?？咕哪苷T導(dǎo)產(chǎn)生一些細(xì)胞因子和趨化因子或作為某些類型細(xì)胞(例如單核細(xì)胞、嗜中性粒細(xì)胞、T細(xì)胞和嗜酸性粒細(xì)胞)定向趨化的趨化因子，影響未成熟樹突狀細(xì)胞的細(xì)胞分化[13, 43]。由此可見，抗菌肽對(duì)免疫反應(yīng)中功能的調(diào)節(jié)或調(diào)控具有明顯的矛盾性。本綜述認(rèn)為這些肽在炎癥環(huán)境中表現(xiàn)出的這種特性有利于選擇性地抑制或促進(jìn)炎癥反應(yīng)在宿主中的綜合平衡，從而產(chǎn)生一種適度、純粹的抗感染反應(yīng)。

此外，抗菌肽還能影其他免疫調(diào)節(jié)功能，包括細(xì)胞分化和增殖，通過抑制細(xì)胞凋亡延長嗜中性粒細(xì)胞的壽命，肥大細(xì)胞的活化和脫粒，傷口修復(fù)，刺激血管再生，以及增強(qiáng)樹突狀細(xì)胞攝取、加工處理和遞呈抗原的能力[44-47]。在炎癥環(huán)境下，這些肽顯示能與其他免疫效應(yīng)分子(如粒細(xì)胞巨噬細(xì)胞刺激因子或白介素-1β)協(xié)同作用。因此，由抗菌肽所介導(dǎo)的免疫調(diào)節(jié)功能并不是獨(dú)立于其他免疫反應(yīng)，而是形成一個(gè)復(fù)雜的免疫介質(zhì)網(wǎng)絡(luò)和下游信號(hào)通路，這也是防御機(jī)制整體有效運(yùn)作所必需的。在與抗菌肽反應(yīng)過程中，調(diào)節(jié)下游先天免疫基因功能的關(guān)鍵信號(hào)通路不同程度地被激活和調(diào)節(jié)。例如，在肥大細(xì)胞、角質(zhì)形成細(xì)胞和單核細(xì)胞中，人抗菌肽LL-37和β-防御素可以激活絲裂原活化蛋白激酶p38和細(xì)胞外信號(hào)調(diào)節(jié)激酶-1/2[41, 46]。此外，在角質(zhì)形成細(xì)胞中LL-37通過STAT3信號(hào)通路反式激活表皮生長因子受體[47]。這些結(jié)果表明，抗菌肽可以直接影響轉(zhuǎn)錄因子的激活，參與先天免疫基因的調(diào)節(jié)和表達(dá)，符合功能基因組學(xué)研究[ 16-17]。

4 抗菌肽在適應(yīng)性免疫中的作用

先天免疫介質(zhì)在淋巴細(xì)胞特定的發(fā)展過程中起著指導(dǎo)性的作用，能觸發(fā)適應(yīng)性免疫應(yīng)答[48]。先天免疫的細(xì)胞組分被迅速召集到致病菌侵染的部位，誘導(dǎo)產(chǎn)生級(jí)聯(lián)免疫介質(zhì)，包括細(xì)胞因子，趨化因子和抗菌肽。專職的先天性免疫細(xì)胞，包括作為專職抗原呈遞細(xì)胞的未成熟樹突狀細(xì)胞，被免疫介質(zhì)直接激活，隨后導(dǎo)致特異性免疫增強(qiáng)型細(xì)胞因子及T和B淋巴細(xì)胞亞群的激活，導(dǎo)致抗原適應(yīng)性免疫應(yīng)答的開始和發(fā)展。各種各樣的抗菌肽，例如人α-防御素HNP-1和HNP-2、豬抗菌肽PR-39及人抗菌肽LL-37等對(duì)未成熟樹突狀細(xì)胞和T細(xì)胞有趨化作用[49-50]，在這類細(xì)胞中它們作為佐劑通過與不同的受體相互作用影響抗原適應(yīng)性免疫的幅度和分化[51]。

抗菌肽通過與先天免疫橋接能調(diào)節(jié)適應(yīng)性免疫反應(yīng)或與適應(yīng)性免疫細(xì)胞直接相互作用。例如，LL-37不僅能召集肥大細(xì)胞，而且能上調(diào)toll樣受體-4的表達(dá)。這種肽的表達(dá)是通過感染信號(hào)引起，提高了肥大細(xì)胞識(shí)別入侵的細(xì)菌的能力。此外，用LL-37和LPS共刺激肥大細(xì)胞可以下調(diào)Th2細(xì)胞因子分化亞群的表達(dá)[52]。在體外，LL-37通過上調(diào)這些細(xì)胞的內(nèi)吞能力可以促進(jìn)樹突狀細(xì)胞分化以及刺激Th1細(xì)胞因子分化亞群的分泌和Th1反應(yīng)[53]。這些研究證據(jù)表明抗菌肽是在先天和適應(yīng)性免疫反應(yīng)交界面之間起作用的分子[43]，這些肽作為信號(hào)影響適應(yīng)性免疫反應(yīng)的起始、極化和放大。

5 抗菌肽作為有效治療藥物的應(yīng)用前景

目前，市面上所有的常規(guī)抗生素幾乎都出現(xiàn)了相應(yīng)的耐藥性致病菌，致病菌的耐藥性問題日益嚴(yán)重地威脅著人們的健康，因此，亟需尋找一種新型的抗感染藥物作為抗生素的替代治療策略。抗菌肽廣泛的生物學(xué)活性顯示了其在感染醫(yī)學(xué)上良好的應(yīng)用前景。20世紀(jì)80年代以來，隨著人們對(duì)抗菌肽研究的日益深入，對(duì)于這些分子潛在的應(yīng)用前景也已發(fā)生改變。前期，它們主要被考慮作為天然抗生素，潛在用途僅限于感染性疾病的治療。現(xiàn)在，抗菌肽不僅是具有廣譜作用機(jī)制的天然廣譜抗生素，而且還具有廣譜的生理功能，為人類開啟了一個(gè)廣闊的全新應(yīng)用領(lǐng)域。目前，已有多種多肽抗生素進(jìn)入到了臨床前試驗(yàn)階段，其中人胚肺成纖維細(xì)胞1-1(human lung fibroblast，HLF1-1)已進(jìn)入II期臨床試驗(yàn)階段[54]，DiaPep277已進(jìn)入Ⅲ期臨床試驗(yàn)階段，而達(dá)托霉素、Glutoxim(NOV-002)和恩夫韋地(Enfuvirtide)已經(jīng)上市[55]。另外，根據(jù)陽離子宿主防御肽的生物膜滲透能力，可考慮通過工業(yè)生物技術(shù)設(shè)計(jì)新型細(xì)胞內(nèi)的藥物。

在體內(nèi)抗菌肽不直接針對(duì)病原體，而是選擇性調(diào)節(jié)的宿主免疫系統(tǒng)，產(chǎn)生耐藥性的機(jī)率非常低[2, 56]，為治療感染提供了一種新方法。本綜述認(rèn)為根據(jù)抗菌肽呈現(xiàn)的選擇性免疫調(diào)節(jié)生物活性至少可以通過3種途徑對(duì)它們進(jìn)行潛在的開發(fā)利用。①抗菌肽不是直接殺菌，而是通過選擇性的免疫調(diào)節(jié)特性防治感染，據(jù)此可被開發(fā)作為有效的治療藥物預(yù)防多藥耐藥細(xì)菌及新病原體感染。②抗菌肽具有強(qiáng)效的抗炎特性，能選擇性地調(diào)節(jié)或維持某些宿主免疫應(yīng)答，據(jù)此它們可以被開發(fā)用來應(yīng)對(duì)急性、誘發(fā)型或慢性炎性病癥。③抗菌肽影響適應(yīng)性應(yīng)答的起始和分化[43, 53]，因此它們有可能被開發(fā)作為有潛力的佐劑。在上述的所有方法中，抗肽既可以作為獨(dú)立的療法，又能與現(xiàn)有的藥物聯(lián)合使用。

然而，要將抗菌肽作為免疫調(diào)節(jié)藥物應(yīng)用于臨床感染治療仍存在一定的局限性，例如在未知的藥效動(dòng)力學(xué)和毒理學(xué)方面，包括潛在的免疫毒性，以及高昂的商品成本。因此，關(guān)于如何增強(qiáng)其結(jié)構(gòu)穩(wěn)定性，限制相關(guān)細(xì)胞毒性成分，提高療效及降低商品成本等問題成為熱點(diǎn)和難點(diǎn)。相信隨著對(duì)抗菌肽構(gòu)效關(guān)系及藥動(dòng)學(xué)性質(zhì)的深入研究，在此基礎(chǔ)上通過對(duì)抗菌肽進(jìn)行合理的設(shè)計(jì)和人工改造，不僅能夠有效解決傳統(tǒng)抗生素日益嚴(yán)重的耐藥問題，更能以其獨(dú)特的免疫調(diào)節(jié)功能，為抗感染治療提供新的方法，終將對(duì)人類的健康事業(yè)產(chǎn)生深遠(yuǎn)影響。

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(編校：王冬梅)

Potential of antimicrobial peptides as novel anti-infective the rapeutics and application prospect

ZHANG Dong-dong, SHANG De-jingΔ

(Faculty of Life Science, Liaoning Normal University, Dalian 116081, China)

Antimicrobial peptides are conserved components of innate immune response present among all classes of life. These peptides are potent, broad spectrum antimicrobial agents with potential as novel therapeutics. Also, antimicrobial peptides have the ability to modulate immunity and its selective modulation is a novel anti-infective strategy. Antimicrobial peptides represent lead molecules that boost innate immune responses and selectively modulate pathogen-induced inflammatory responses. This review discusss the mechanisms of antimicrobial peptides as innate immune regulators, their role in the interface of innate and adaptive immunity, and their potential application as anti-infective and immunomodulatory therapeutics and application prospect.

antimicrobial peptides; immunomodulatory; anti-infective

張東東，男，碩士在讀，研究方向：生物化學(xué)與分子生物學(xué)，E-mail: dzs-087@163.com；尚德靜，通信作者，女，博士，教授，博士生導(dǎo)師，研究方向：生物化學(xué)與分子生物學(xué)，E-mail: djshang@lnnu.edu.cn。

R96

A

1005-1678(2016)01-0178-05