摘要:炎癥性腸?。↖BD)目前無法治愈,只能通過藥物、手術(shù)等手段緩解癥狀,延緩和減少?gòu)?fù)發(fā),因此對(duì)疾病活動(dòng)度的監(jiān)測(cè)至關(guān)重要。糖萼是覆蓋于血管內(nèi)皮細(xì)胞管腔側(cè)的多糖蛋白復(fù)合物,對(duì)于維持腸道黏膜屏障具有支持作用,而炎癥會(huì)導(dǎo)致其結(jié)構(gòu)受損。該文介紹了目前臨床上IBD在實(shí)驗(yàn)室檢測(cè)中的無創(chuàng)性生物標(biāo)志物,并分析了血清糖萼損傷標(biāo)志物多配體蛋白聚糖1、硫酸乙酰肝素、透明質(zhì)酸對(duì)IBD的診斷和監(jiān)測(cè)價(jià)值。
關(guān)鍵詞:炎性腸疾?。荒c黏膜;多配體蛋白聚糖1;硫酸乙酰肝素;透明質(zhì)酸;糖萼損傷
中圖分類號(hào):R446.1,R574.6 文獻(xiàn)標(biāo)志碼:A DOI:10.11958/20231646
Advances in the diagnostic and monitoring value of glycocalyx injury in
inflammatory bowel disease
ZHANG Ledan1, JIN Mingxing2, LIU Yandi2△
1 School of Medicine, Nankai University, Tianjin 300071, China; 2 Department of Gastroenterology,
Tianjin Union Medical Center
△Corresponding Author E-mail: liuyandi66@163.com
Abstract: Inflammatory bowel disease (IBD) is no cure at present, and only drugs and surgery can relieve symptoms, delay and reduce recurrence. Therefore, it is very important to monitor the disease activity." Glycocalyx, a polyglycoprotein complex covering luminal side of vascular endothelial cells, is supportive in maintaining the intestinal mucosal barrier, and inflammation leads to its structural damage. This review introduces currently available non-invasive biomarkers of clinical importance for IBD in laboratory testing, and analyzes the value of serum glycocalyx injury markers (syndecan-1, HS and HA) in the diagnosis or monitoring of IBD.
Key words: inflammatory bowel diseases; intestinal mucosa; syndecan-1; heparitin sulfate; hyaluronic acid; glycocalyx damage
炎癥性腸?。╥nflammatory bowel disease,IBD)是一組以胃腸道反復(fù)慢性炎癥反應(yīng)為主要表現(xiàn)的自身免疫性疾病。在發(fā)達(dá)國(guó)家,IBD患病率超過0.3%,一些新興工業(yè)化國(guó)家的IBD患病率亦持續(xù)上升[1]。IBD的癥狀大多為非特異性,而診斷又缺乏金標(biāo)準(zhǔn),且尚無治愈的方法,因此對(duì)疾病活動(dòng)度的監(jiān)測(cè)至關(guān)重要[2]。因內(nèi)鏡檢查具有有創(chuàng)性,無法作為常規(guī)的監(jiān)測(cè)手段[3]。目前尚缺乏高特異性的生物標(biāo)志物作為其診斷和監(jiān)測(cè)工具。腸道黏膜是位于消化道內(nèi)的一層薄膜,是防止有害微生物、毒素和抗原進(jìn)入血液的屏障,糖萼在維持這一功能中起到重要支持作用[4]。糖萼是覆蓋于血管內(nèi)皮細(xì)胞管腔側(cè)的多糖蛋白復(fù)合物,其在調(diào)節(jié)血管通透性、炎癥以及剪應(yīng)力的機(jī)械傳導(dǎo)等生理功能中起重要作用[5]。血清多配體蛋白聚糖1(Syndecan-1)、硫酸乙酰肝素(heparin sulfate,HS)、透明質(zhì)酸(hyaluronic acid,HA)可作為內(nèi)皮糖萼損傷的標(biāo)志物[6]。研究表明,腸道黏膜免疫失衡與IBD發(fā)生發(fā)展有關(guān)[7],且IBD患者伴有明顯的腸道炎癥、組織水腫、充血及腸黏膜創(chuàng)面潰瘍,由此可推測(cè)IBD的發(fā)生發(fā)展與糖萼損傷有關(guān)。本文對(duì)IBD常見的生物標(biāo)志物及IBD患者血清糖萼損傷標(biāo)志物對(duì)IBD的診斷和監(jiān)測(cè)價(jià)值進(jìn)行綜述。
1 IBD常見的生物標(biāo)志物
IBD目前在臨床上使用的診斷和監(jiān)測(cè)指標(biāo)主要包括C反應(yīng)蛋白(C-reactive protein,CRP)、紅細(xì)胞沉降率(erythrocyte sedimentation rate,ESR)和糞便鈣衛(wèi)蛋白(fecal calprotectin,F(xiàn)C),敏感度和特異度均有限。CRP是一種五聚體蛋白,由肝細(xì)胞應(yīng)對(duì)各種急慢性炎癥時(shí)產(chǎn)生,其水平在機(jī)體發(fā)生炎癥時(shí)升高,廣泛用于IBD篩查和疾病活動(dòng)度的評(píng)估,也可通過重復(fù)測(cè)量來評(píng)估治療效果,尤其是在克羅恩病中[8]。CRP對(duì)炎癥敏感,半衰期較短,但不具有特異性,其表達(dá)受多種因素影響[9]。
ESR即紅細(xì)胞在1 h內(nèi)通過血漿遷移的速率,可快速粗略地評(píng)估一般急性炎癥。與CRP不同,ESR的峰值速度下調(diào)較慢[8],且ESR值在潰瘍性結(jié)腸炎和克羅恩病中相差不大。ESR是診斷和監(jiān)測(cè)IBD的生物標(biāo)志物之一,其較CRP持續(xù)時(shí)間更長(zhǎng),但敏感度和特異度均較低[10-11]。
FC是一種鈣結(jié)合蛋白,其水平升高與腸道炎癥有關(guān),與IBD的疾病活動(dòng)度呈正相關(guān)[12],可區(qū)分IBD與腸易激綜合征,評(píng)估疾病活動(dòng)及對(duì)治療的反應(yīng),并預(yù)測(cè)疾病復(fù)發(fā)[13],因此FC在IBD的診斷和監(jiān)測(cè)中具有重要作用。FC的敏感度和陰性預(yù)測(cè)值高,且穩(wěn)定性較好,但特異度較低[14]。
2 血管內(nèi)皮糖萼
2.1 糖萼的結(jié)構(gòu)及功能 糖萼主要由糖胺聚糖(glycosaminoglycans,GAGs)和蛋白聚糖(proteoglycans,PGs)組成。其中GAGs主要包括HS、HA和硫酸軟骨素(chondroitin sulfate,CS)[15];PGs主要包括Syndecans、磷脂酰肌醇蛋白聚糖(glypican)等[16]。糖萼作為血管內(nèi)皮屏障,除了調(diào)節(jié)血管通透性,還參與生長(zhǎng)因子和趨化因子等的信號(hào)傳導(dǎo)、抗炎、抗血栓形成以及剪應(yīng)力的機(jī)械傳導(dǎo)[15]。有研究表明,炎癥反應(yīng)時(shí)內(nèi)皮糖萼結(jié)構(gòu)受損,促炎因子主要是通過刺激內(nèi)皮細(xì)胞產(chǎn)生金屬蛋白酶及透明質(zhì)酸,并刺激肥大細(xì)胞分泌肝素酶,從而導(dǎo)致糖萼的損傷[17]。
2.2 糖萼損傷標(biāo)志物 糖萼結(jié)構(gòu)具有易損性,在急性損傷、炎癥等病理?xiàng)l件下會(huì)導(dǎo)致其結(jié)構(gòu)受損,通常表現(xiàn)為糖萼層變薄,組分破壞、脫落[18]。目前臨床上常用血清中的糖萼損傷脫落物進(jìn)行定量分析,從而進(jìn)行糖萼厚度與損傷程度的無創(chuàng)可視化研究[19]。糖萼的降解通常伴隨著一種或多種糖萼成分(Syndecan-1、HS和HA)脫落至血液中,其脫落代表著內(nèi)皮糖萼的健康狀況[20]。
3 糖萼損傷在IBD中的診斷和監(jiān)測(cè)價(jià)值
3.1 腸道黏膜屏障 腸道是一個(gè)動(dòng)態(tài)而復(fù)雜的生態(tài)系統(tǒng),腸道黏膜屏障在維持其穩(wěn)定方面發(fā)揮了重要作用。腸道黏膜屏障由物理屏障、化學(xué)屏障、免疫屏障和微生物屏障組成,腸道物理屏障是腸道黏膜屏障的重要組成部分[21],是維持化學(xué)屏障、免疫屏障和其他屏障功能的結(jié)構(gòu)基礎(chǔ),其中最重要的是黏液層和糖萼[22]。黏蛋白(Mucins,MUC)根據(jù)結(jié)構(gòu)和功能特征可大致分為分泌型和跨膜型,其中分泌型黏蛋白包括MUC2、MUC5AC和MUC6等,是黏液層的主要成分;跨膜型黏蛋白包括MUC1、MUC3、MUC4、MUC13和MUC17等,其延伸結(jié)構(gòu)域形成致密的腸細(xì)胞糖萼[7],可以阻擋細(xì)菌等病原體的入侵。
正常情況下,腸道內(nèi)微生物的數(shù)量和種類處于動(dòng)態(tài)平衡中,這對(duì)維持和調(diào)節(jié)腸黏膜屏障的功能至關(guān)重要[23]。一方面,腸道微生物通過釋放抗菌物質(zhì)或提高對(duì)有害及致病菌定植的抵抗力來防止病原體入侵;另一方面,腸道微生物可以限制腸道免疫系統(tǒng)的過度反應(yīng),從而維持免疫耐受性和穩(wěn)態(tài)。
3.2 從腸道黏膜屏障功能不全探討糖萼損傷與IBD的關(guān)系 腸道黏膜屏障的完整性和功能對(duì)維持免疫穩(wěn)態(tài)至關(guān)重要。一旦腸道黏膜屏障受損,外界抗原就會(huì)通過受損的腸道黏膜侵入體內(nèi),誘發(fā)和加重全身炎癥反應(yīng),導(dǎo)致自身免疫耐受破壞和免疫穩(wěn)態(tài)失衡,加劇IBD等自身免疫性疾病的進(jìn)展[24]。因此,腸道黏膜屏障功能障礙是導(dǎo)致IBD發(fā)展的重要因素。一方面,糖萼對(duì)維持腸道黏膜物理屏障具有重要作用,當(dāng)有細(xì)菌入侵或機(jī)械應(yīng)激等刺激時(shí),會(huì)引起腸道糖萼層受損,從而導(dǎo)致腸道通透性增加[25],各種毒素、炎性介質(zhì)和抗原產(chǎn)物等會(huì)侵入腸壁深層,從而異常激活多種炎癥和免疫細(xì)胞,產(chǎn)生大量促炎因子,這些異常因子亦會(huì)加劇腸道糖萼層的破壞[21],導(dǎo)致屏障功能喪失,并啟動(dòng)黏膜維持所涉及的信號(hào)通路[26],進(jìn)一步導(dǎo)致IBD的急性發(fā)作。另一方面,細(xì)菌性脂多糖(lipopolysaccharide,LPS)與慢性腸道炎癥有關(guān),LPS是革蘭陰性菌外膜的組成部分。有研究表明,LPS會(huì)損傷糖萼結(jié)構(gòu)[27]。產(chǎn)生LPS的細(xì)菌是健康腸道微生物的正常組成部分。當(dāng)腸道微生物屏障失衡時(shí),LPS會(huì)損害腸道上皮細(xì)胞,從而引起腸道慢性炎癥,其特征是腫瘤壞死因子α(tumor necrosis factor-α,TNF-α)和誘導(dǎo)型一氧化氮合酶(induced nitric oxide synthase,iNOS)炎癥途徑的激活以及氧化應(yīng)激的加重[28]。而IBD患者的腸道通透性和血清LPS水平升高,可能會(huì)激活TNF-α炎癥途徑,導(dǎo)致糖萼脫落,從而破壞糖萼的完整性[29]。MUC17是糖萼中的主要膜黏蛋白之一,在小鼠斷奶期間白細(xì)胞介素(interleukin,IL)-22可特異性上調(diào)MUC17表達(dá),MUC17通過抑制革蘭陰性菌產(chǎn)生LPS,降低革蘭陽性菌的脂磷壁酸水平,從而阻止細(xì)菌進(jìn)入腸細(xì)胞。當(dāng)腸道微生物屏障免疫異常時(shí),細(xì)菌會(huì)導(dǎo)致膜黏蛋白合成減少,從而降低糖萼的屏障作用,進(jìn)一步導(dǎo)致IBD的發(fā)生[30]。
3.3 從炎癥角度探討糖萼損傷與IBD的關(guān)系 IBD的特點(diǎn)是IL和TNF-α等炎性細(xì)胞因子的過度表達(dá)及腸道的高氧化應(yīng)激狀態(tài),糖萼層的損傷是炎癥發(fā)展的初始階段[31]。糖萼在炎癥性疾?。ㄈ鏘BD等)作用下的損傷機(jī)制也逐漸明確。
IBD患者TNF-α、干擾素-γ(interferon-γ,IFN?γ)和IL-17A等促炎細(xì)胞因子表達(dá)上調(diào)。TNF-α的激活可通過多種機(jī)制對(duì)糖萼的完整性產(chǎn)生負(fù)面影響。一方面,TNF-α的激活可誘導(dǎo)活性氧和氮物種(reactive oxygen species/reactive nitrogen species,ROS/RNS)的產(chǎn)生,而某些ROS/RNS會(huì)間接激活基質(zhì)金屬蛋白酶(matrix metalloproteinases,MMPs)的活性[16]。MMPs是一類鋅依賴性內(nèi)肽酶,具有多種亞型,可降解細(xì)胞外基質(zhì)中的膠原蛋白、彈性蛋白以及糖萼中的多配體蛋白聚糖等成分,IBD患者體內(nèi)MMPs表達(dá)上調(diào),可裂解糖萼的核心蛋白,導(dǎo)致糖萼損傷[32]。另一方面,TNF-α?xí)せ詈宿D(zhuǎn)錄因子-κB(nuclear factor-κB,NF-κB)代謝通路,導(dǎo)致肥大細(xì)胞活化,促使肥大細(xì)胞脫顆粒,進(jìn)一步釋放細(xì)胞因子、組胺、硫酸乙酰肝素酶等降解糖萼組分,導(dǎo)致糖萼降解[33]。
氧化應(yīng)激常發(fā)生于IBD等各類疾病,目前氧化應(yīng)激導(dǎo)致糖萼損傷的具體分子生物學(xué)機(jī)制尚未明確。有研究指出,機(jī)體氧化應(yīng)激過程中產(chǎn)生的ROS、RNS等自由基通過獲得具有催化活性的過渡金屬與糖萼相結(jié)合,產(chǎn)生高活性的羥基自由基,從而激活巨噬細(xì)胞,導(dǎo)致糖萼結(jié)構(gòu)的損傷[34]。
綜上,IBD患者炎性因子水平升高,同時(shí)伴有高氧化應(yīng)激狀態(tài),而這些因素均可造成糖萼結(jié)構(gòu)損傷。糖萼結(jié)構(gòu)的損傷又導(dǎo)致組織通透性升高和趨化因子聚集,進(jìn)一步加劇炎癥反應(yīng),形成惡性循環(huán)[35]。
3.4 糖萼裂解標(biāo)志物作為診斷工具 由于IBD會(huì)導(dǎo)致糖萼層損傷,因此建立血液循環(huán)中糖萼裂解物與IBD病情發(fā)展之間的關(guān)系,可能為其在IBD活動(dòng)性及病情發(fā)展評(píng)估提供依據(jù)[36]。生理?xiàng)l件下,循環(huán)血中含有一定量的糖萼損傷標(biāo)志物,發(fā)生炎癥時(shí)其水平明顯升高[37]。
糖萼中的GAGs在免疫和炎癥過程中發(fā)揮重要作用,尤其是HA。HA參與IBD的進(jìn)展可能與下列因素有關(guān):一方面,HA可以結(jié)合凝血因子,增加血小板聚集,促進(jìn)和支持IBD期間的炎癥反應(yīng);另一方面,HA還可與胰蛋白酶α抑制劑形成復(fù)合物,與白細(xì)胞高度黏附,進(jìn)一步加劇炎癥[38]。有研究表明,HA可以參與誘導(dǎo)白細(xì)胞浸潤(rùn)腸道并激活免疫應(yīng)答,從而促進(jìn)IBD進(jìn)展[39]。
Syndecan-1在血管內(nèi)皮和循環(huán)細(xì)胞中表達(dá)上調(diào),也可在未成熟的B細(xì)胞中表達(dá),并受IL-6和LPS的調(diào)節(jié)。Syndecan-1與糖萼分解和內(nèi)皮破壞有關(guān),且syndecan-1作為包括促炎細(xì)胞因子和生長(zhǎng)因子在內(nèi)的多種細(xì)胞外配體的共受體,在炎癥過程中發(fā)揮重要作用。Syndecan-1的胞外部分在炎癥反應(yīng)和病原體感染時(shí)會(huì)從細(xì)胞表面被釋放出來,因此血液中syndecan-1可作為評(píng)估IBD進(jìn)展的潛在標(biāo)志物之一[39]。有研究以內(nèi)鏡下Mayo評(píng)分對(duì)潰瘍性結(jié)腸炎(UC)進(jìn)行分組,發(fā)現(xiàn)與非活動(dòng)性UC組(內(nèi)鏡下Mayo評(píng)分lt;2分)相比,活動(dòng)性UC組(內(nèi)鏡下Mayo評(píng)分≥2分)患者血清中syndecan-1水平顯著升高,提示syndecan-1水平與活動(dòng)性UC可能相關(guān),且克羅恩病和急性腸炎憩室等其他炎癥性腸病患者血清中syndecan-1水平亦升高;ROC曲線分析結(jié)果顯示,當(dāng)syndecan-1截?cái)嘀禐?7.1 μg/L時(shí),其診斷UC的敏感度為78%,特異度為77%,因此血清中糖萼損傷標(biāo)志物在診斷和監(jiān)測(cè)IBD中具有潛在價(jià)值[40]。
綜上所述,糖萼對(duì)維持腸道黏膜屏障完整性具有重要作用,糖萼損傷會(huì)導(dǎo)致黏膜屏障受損,進(jìn)而促進(jìn)IBD的發(fā)生。糖萼可作為IBD診斷和監(jiān)測(cè)的潛在生物標(biāo)志物,但其診斷價(jià)值尚需進(jìn)一步驗(yàn)證。
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(2023-11-14收稿 2024-02-28修回)
(本文編輯 陳麗潔)