神經(jīng)在皮膚創(chuàng)傷再生和瘢痕愈合中的作用

張瑾，解揚(yáng)子，張選奮

神經(jīng)在皮膚創(chuàng)傷再生和瘢痕愈合中的作用

張瑾，解揚(yáng)子，張選奮

神經(jīng)是皮膚感覺和體溫調(diào)節(jié)等生理功能的基礎(chǔ)，也通過多種機(jī)制調(diào)控創(chuàng)傷再生和瘢痕愈合等病理過程。盡管失神經(jīng)支配的皮膚傷口能夠愈合，但神經(jīng)通過啟動(dòng)神經(jīng)源性炎癥反應(yīng)和神經(jīng)營(yíng)養(yǎng)作用增加傷口周圍組織的血供，促進(jìn)成纖維細(xì)胞和角質(zhì)形成細(xì)胞增殖和Ⅰ型、Ⅲ型膠原的表達(dá)，與免疫系統(tǒng)的相互作用和釋放神經(jīng)肽等機(jī)制促進(jìn)皮膚傷口愈合。如果各種參與修復(fù)細(xì)胞、細(xì)胞外基質(zhì)、神經(jīng)血管和皮膚附屬器能有機(jī)裝配則再生修復(fù)，否則瘢痕愈合。神經(jīng)自身主要在創(chuàng)傷修復(fù)早期和瘢痕塑形期通過軸突的生長(zhǎng)修復(fù)，其生長(zhǎng)速度明顯較肉芽組織形成和瘢痕化慢。而且，不同神經(jīng)纖維的軸突生長(zhǎng)也不完全相同。外源性神經(jīng)肽可促進(jìn)難愈性傷口愈合，神經(jīng)肽拮抗劑或高選擇神經(jīng)切斷等失神經(jīng)措施可減輕瘢痕增生。因此，了解神經(jīng)和各種修復(fù)成分在創(chuàng)傷再生修復(fù)與瘢痕愈合中的作用和調(diào)控機(jī)制，有助于尋找促進(jìn)皮膚和周圍神經(jīng)損傷再生修復(fù)的方法。

皮膚創(chuàng)傷；神經(jīng)；再生；瘢痕愈合；綜述

[本文著錄格式] 張瑾，解揚(yáng)子，張選奮.神經(jīng)在皮膚創(chuàng)傷再生和瘢痕愈合中的作用[J].中國(guó)康復(fù)理論與實(shí)踐,2015,21(8): 921-923.

CITED AS:Zhang J,Xie YZ,Zhang XF.Roles of nerve in regeneration and scar healing of skin wound(review)[J].Zhongguo Kangfu Lilun Yu Shijian,2015,21(8):921-923.

臨床實(shí)踐和研究發(fā)現(xiàn)，深達(dá)網(wǎng)狀層的皮膚組織丟失(如撕脫傷)或嚴(yán)重破壞(如深Ⅱ度燒傷)不能再生，愈合后瘢痕形成，而乳頭層和表皮層損傷可再生修復(fù)。這種再生修復(fù)和瘢痕愈合是由多種細(xì)胞、細(xì)胞外基質(zhì)(extracellularmatrix,ECM)、細(xì)胞因子和神經(jīng)免疫等高度精密調(diào)控的復(fù)雜過程。神經(jīng)具有營(yíng)養(yǎng)皮膚、調(diào)控其自身更新和皮膚的各種功能。皮膚創(chuàng)傷后愈合過程中伴隨的炎癥反應(yīng)刺激真皮中豐富的感覺神經(jīng)和運(yùn)動(dòng)神經(jīng)，釋放神經(jīng)肽等信號(hào)；而且，皮膚再生修復(fù)和瘢痕愈合都存在神經(jīng)自身的修復(fù)。因此，神經(jīng)對(duì)皮膚創(chuàng)面愈合具有重要作用。

近年來，對(duì)真皮組織缺損后瘢痕形成或再生的調(diào)控機(jī)制，尤其是神經(jīng)作用的研究，逐漸深入。本文綜述神經(jīng)與皮膚創(chuàng)傷再生修復(fù)和瘢痕愈合的關(guān)系，期望加深對(duì)皮膚損傷再生或瘢痕愈合機(jī)制的理解并尋找促進(jìn)創(chuàng)面愈合或提高愈合質(zhì)量的方法。

1 神經(jīng)可促進(jìn)皮膚創(chuàng)傷愈合，但對(duì)瘢痕形成和再生的影響存在爭(zhēng)議

臨床實(shí)踐中，顱腦或脊髓等中樞神經(jīng)損傷(如截癱患者)的皮膚傷口能愈合，但糖尿病患者皮膚的慢性潰瘍較難愈合，同時(shí)伴有末梢神經(jīng)病變，而麻風(fēng)病引起的神經(jīng)炎卻從未出現(xiàn)增生性瘢痕。該結(jié)果提示神經(jīng)調(diào)節(jié)在皮膚傷口愈合過程中發(fā)揮重要作用。

先前實(shí)驗(yàn)研究發(fā)現(xiàn)，切斷單側(cè)坐骨神經(jīng)或辣椒素誘導(dǎo)感覺神經(jīng)(C-纖維)神經(jīng)肽耗盡法失神經(jīng)支配小鼠的皮膚與正常皮膚在愈合速度和組織學(xué)上沒有差異[1]。但是多數(shù)研究認(rèn)為，神經(jīng)可促進(jìn)皮膚傷口再生和瘢痕愈合[2-5]：①在損傷局部啟動(dòng)神經(jīng)源性炎癥反應(yīng)和激活炎癥介質(zhì)刺激的炎癥反應(yīng)[6]；②通過擴(kuò)張傷口局部血管增加傷口及其周圍組織的血供，促進(jìn)內(nèi)皮細(xì)胞、血管平滑肌細(xì)胞和角質(zhì)形成細(xì)胞、成纖維細(xì)胞(fibroblast,FB)合成DNA并增殖[7]；③促進(jìn)新生血管形成；④通過與神經(jīng)-免疫反應(yīng)系統(tǒng)的相互作用調(diào)節(jié)創(chuàng)傷愈合；⑤通過神經(jīng)營(yíng)養(yǎng)作用，加速傷口愈合[6,8]；⑥促進(jìn)成纖維細(xì)胞轉(zhuǎn)化為肌成纖維細(xì)胞[7,9]；⑦增加Ⅰ型和Ⅲ型膠原的表達(dá)且促進(jìn)膠原收縮[7,9]。相反，手術(shù)切斷神經(jīng)或破壞脊髓核團(tuán)或辣椒素等失或減少神經(jīng)支配的皮膚傷口成纖維細(xì)胞減少，細(xì)胞增殖低下，血管增生受到抑制，導(dǎo)致愈合時(shí)間延長(zhǎng)[10-13]；而且增加傷口愈合過程中Ⅲ型膠原的表達(dá)，導(dǎo)致Ⅰ/Ⅲ膠原比例降低，瘢痕形成相對(duì)減少。提示在創(chuàng)傷上皮化后采用暫時(shí)失神經(jīng)措施可能有助于減輕瘢痕增生和瘢痕的癥狀[2]，但是失神經(jīng)處理措施減輕癥狀的程度以及具體采取失神經(jīng)措施的操作時(shí)機(jī)需要深入研究證實(shí)。然而，失神經(jīng)支配可阻礙MRL(Murphy Roths Large)/MpJ鼠耳2mm環(huán)形切除傷口胚基形成和軟骨發(fā)生，導(dǎo)致皮膚再生受阻[14]。

另有研究表明，交感神經(jīng)遞質(zhì)多巴胺通過強(qiáng)烈的抗血管增生作用抑制皮膚創(chuàng)傷愈合，且感覺神經(jīng)對(duì)創(chuàng)面愈合的影響較運(yùn)動(dòng)神經(jīng)纖維顯著[3,15-16]。這意味著支配皮膚的交感神經(jīng)、感覺神經(jīng)和運(yùn)動(dòng)神經(jīng)對(duì)傷口愈合可能存在不同的作用。

2 神經(jīng)肽促進(jìn)創(chuàng)傷愈合

皮膚軟組織損傷后，周圍神經(jīng)持續(xù)分泌降鈣素基因相關(guān)肽(calcitonin gene-related peptide,CGRP)、P物質(zhì)(Substance P)和血管活性腸肽等多種神經(jīng)肽，作為疼痛遞質(zhì)在向大腦傳遞痛覺信號(hào)的同時(shí)，還通過多種機(jī)制加速傷口愈合，如增加成纖維細(xì)胞和角質(zhì)形成細(xì)胞的增殖以及Ⅰ型、Ⅲ型膠原的表達(dá)，促進(jìn)成纖維細(xì)胞轉(zhuǎn)化為肌成纖維細(xì)胞[8]。在皮膚創(chuàng)面愈合過程中，P物質(zhì)增加一直維持到愈合后的瘢痕期[5]，但CGRP的表達(dá)仍存爭(zhēng)議[3-5]。增生性瘢痕組織中P物質(zhì)和CGRP神經(jīng)肽含量均增加，而成熟瘢痕則沒有變化[10]；同時(shí)胚胎無瘢痕愈合的傷口局部釋放較少的神經(jīng)肽[8]。該結(jié)果提示神經(jīng)肽可能有助于難愈性傷口愈合，已有聯(lián)合應(yīng)用外源性P物質(zhì)和表皮干細(xì)胞促進(jìn)糖尿病創(chuàng)面愈合、胎兔皮膚瘢痕愈合與神經(jīng)再生的研究報(bào)道[15,17]。另一方面，P物質(zhì)等神經(jīng)肽的拮抗劑可能有助于減輕瘢痕增生甚至實(shí)現(xiàn)再生修復(fù)[18]。

3 創(chuàng)傷后神經(jīng)的修復(fù)過程

皮膚傷口愈合過程中神經(jīng)纖維的修復(fù)主要出現(xiàn)于愈合后的瘢痕塑形期。在瘢痕愈合的皮膚傷口中，神經(jīng)密度在傷后48 h即回到傷前皮膚水平[19]；在接下來的新血管形成和上皮化過程，神經(jīng)生長(zhǎng)相對(duì)較為緩慢[20]；上皮化后的瘢痕增生期逐漸增加[21-23]；隨著瘢痕進(jìn)入改建塑形期逐漸減少[22,24]，導(dǎo)致瘢痕組織中神經(jīng)密度高于成熟瘢痕。然而，瘢痕組織中增加的神經(jīng)為形態(tài)異常的無髓鞘C神經(jīng)纖維，缺乏Aβ纖維[24]，有髓神經(jīng)纖維Aδ是否增加存在爭(zhēng)議[14,25]。這不僅解釋了多數(shù)增生性瘢痕存在瘙癢和神經(jīng)敏感性疼痛等感覺異常的原因，而且意味著神經(jīng)軸突增生晚于其他組織。因此，受瘢痕組織的影響，增生的神經(jīng)軸突無法形成正常的神經(jīng)纖維，常形成神經(jīng)瘤，抑制傷口瘢痕形成，有利于神經(jīng)軸突的正常再生[26-27]。

創(chuàng)傷后皮膚神經(jīng)軸突生長(zhǎng)的方式不完全相同。胎兒無瘢痕愈合傷口神經(jīng)生長(zhǎng)有兩種方式：傷口基底完整神經(jīng)的側(cè)枝發(fā)芽和傷口周圍神經(jīng)斷端的增生。成體切開模型中，僅有切口邊神經(jīng)軸突斷端增生，在表皮下水平方向擴(kuò)展，傷后13 d時(shí)，真皮深層神經(jīng)軸突橫斷面開始向真皮淺層垂直生長(zhǎng)，逐漸取代水平側(cè)枝發(fā)芽增生的軸突；傷后30～75 d時(shí)，真皮中軸突密度達(dá)到正常水平。在成體切除模型中，隨傷口收縮切口邊緣的神經(jīng)軸突末梢受到牽拉向傷口中心靠攏，同時(shí)切口邊緣的神經(jīng)軸突斷端發(fā)芽增生，逐漸緩慢長(zhǎng)入傷口中心，但直到傷后23個(gè)月，神經(jīng)尚未完全再生[28]。

神經(jīng)軸突生長(zhǎng)受其周圍環(huán)境的影響[29]。MRL/MpJ鼠耳傷口在10～12 h內(nèi)再生修復(fù)，同時(shí)伴有高密度的神經(jīng)再生，其胚基樣基質(zhì)如聚集蛋白聚糖(aggrecan)給神經(jīng)再生提供方向[30]。另有研究表明，人椎間盤聚集蛋白聚糖抑制神經(jīng)突觸伸展，并阻止感覺神經(jīng)小體形成[31]，但人椎間盤細(xì)胞通過合成神經(jīng)營(yíng)養(yǎng)因子促進(jìn)神經(jīng)軸突生長(zhǎng)，可部分對(duì)抗聚集蛋白聚糖的抑制作用[32]。然而，在成體真皮乳頭層損傷必然有神經(jīng)末梢和感覺小體損傷，傷口以再生的方式修復(fù)，但這些神經(jīng)組織的修復(fù)與傷口再生間的關(guān)系尚不清楚。

4 展望

皮膚創(chuàng)傷瘢痕愈合或難愈合一直是臨床面臨的難題之一。糖尿病、慢性皮膚潰瘍和皮膚創(chuàng)傷，由于受傷的皮膚和傷口邊緣處的皮膚神經(jīng)纖維的數(shù)量減少，往往伴有神經(jīng)營(yíng)養(yǎng)障礙，常致傷口愈合困難，甚至不愈，愈合后形成的瘢痕有瘙癢和疼痛等癥狀，這意味著皮膚創(chuàng)傷愈合及瘢痕形成的演變過程受神經(jīng)等因素的調(diào)控，但具體調(diào)控機(jī)制尚不清楚。皮膚創(chuàng)傷后神經(jīng)肽的促增殖作用和神經(jīng)營(yíng)養(yǎng)作用有利于促進(jìn)創(chuàng)面愈合，單獨(dú)或聯(lián)合使用干細(xì)胞等外源性應(yīng)用神經(jīng)肽有助于促進(jìn)難愈性傷口的愈合和神經(jīng)的再生[33-34]。采取神經(jīng)肽的拮抗劑或高選擇神經(jīng)切斷等失神經(jīng)措施是否有助于減輕瘢痕增生甚至實(shí)現(xiàn)再生修復(fù)，尚需研究證實(shí)。

在神經(jīng)的調(diào)控下，真皮成纖維細(xì)胞和膠原纖維等細(xì)胞外基質(zhì)構(gòu)成復(fù)雜而有機(jī)結(jié)合的真皮組織的同時(shí)，神經(jīng)自身也通過軸突的生長(zhǎng)修復(fù)。神經(jīng)軸突的生長(zhǎng)必然也受肉芽組織和瘢痕組織中細(xì)胞、細(xì)胞外基質(zhì)和各種調(diào)控因子的影響，神經(jīng)和各種調(diào)控愈合因子形成相互作用的復(fù)雜網(wǎng)絡(luò)。因此，了解神經(jīng)和各修復(fù)成分在創(chuàng)傷再生修復(fù)與瘢痕愈合中的變化和作用以及調(diào)控機(jī)制，將深入闡明皮膚創(chuàng)面愈合的機(jī)制；尋找通過調(diào)控神經(jīng)和神經(jīng)肽促進(jìn)皮膚再生的方法，研究皮膚傷口愈合過程中神經(jīng)增生及其調(diào)控機(jī)制，為探索周圍神經(jīng)損傷的再生修復(fù)提供參考。

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Rolesof Nerve in Regeneration and Scar Healing of SkinWound(review)

ZHANG Jin,XIEYang-zi,ZHANG Xuan-fen
Departmentof Plastic Surgery,the Second Hospitalof Lanzhou University,Lanzhou,Gansu 730030,China

Nerve is the foundation of the physiological function such as the skin feeling and thermoregulation,and also regulates the regeneration and scar healing of skin wound bymultiplemechanisms.Though the denervated skin wound can heal spontaneously,the nerve might accelerate wound healing by activating the neurogenic inflammation and nerve trophism,increasing the blood supply around the wound,promoting the proliferation of fibroblastsand keratinocytes,stimulating theexpression of collagen Iand III,and interactingwith immune system and releasing neuropeptides.If all kindsof repair cells,extracellularmatrix,nerve,blood vesseland cutaneousappendagesassemble organically,the skinwound regenerates,and otherw ise the scar heals.The nerve axon growth occursmainly in the early stage of the wound healing and the scar rebuilding process,and thenerve grow th rate isobviously slower than the granulation tissue formation and cicatrization.Furthermore,the axon grow th of differentnerve fibers are notentirely the same.The exogenous neuropeptidesmight promote the wound repairand the nerve regeneration.The antagonistof the neuropeptidesorhigh selective nerveabscissionmight reduce the scar hyperplasia.Therefore,it contribute to findmethods to promote the regeneration of skin wound and peripheral nerve injury by understanding the effectsand regulatorymechanism of both nerveand various repairelements in regeneration orscarhealing of skinwound.

skinwound;nerve;regeneration;scarhealing;review

10.3969/j.issn.1006-9771.2015.08.010

R641

A

1006-9771(2015)08-0921-03

2015-05-14

2015-06-02)

1.甘肅省自然科學(xué)基金項(xiàng)目(No.1107RJZA207)；2.甘肅省衛(wèi)生行業(yè)計(jì)劃項(xiàng)目(No.GSWT09-07)。

蘭州大學(xué)第二醫(yī)院整形外科，甘肅蘭州市730030。作者簡(jiǎn)介：張瑾(1975-)，女，漢族，甘肅天水市人，主治醫(yī)師，主要研究方向：皮膚創(chuàng)傷再生與瘢痕愈合。通訊作者：張選奮，男，醫(yī)學(xué)博士，教授，博士研究生導(dǎo)師，主要研究方向：皮膚創(chuàng)傷再生與瘢痕愈合。E-mail：zhxf9304@126.com。