炎癥細(xì)胞因子在骨性關(guān)節(jié)炎疼痛中的作用機(jī)制

姚志華 裘敏蕾 樊天佑

炎癥細(xì)胞因子在骨性關(guān)節(jié)炎疼痛中的作用機(jī)制

姚志華 裘敏蕾 樊天佑

骨性關(guān)節(jié)炎( osteoarthritis，OA )是一種常見的退行性關(guān)節(jié)病，涉及到整個滑膜關(guān)節(jié)，包括軟骨、滑膜和軟骨下骨。OA 主要的臨床表現(xiàn)是關(guān)節(jié)的疼痛，這不僅會導(dǎo)致功能受限和生活質(zhì)量的降低，而且是老年人行動不利的主要原因[1]。有報(bào)道，60 歲以上的人群中，50% 在 X 線片上有骨性關(guān)節(jié)炎表現(xiàn)，80% 有骨性關(guān)節(jié)炎癥狀，并且是致殘的主要原因之一[2]。盡管目前對于 OA 疼痛的確切機(jī)制尚不明確，但普遍認(rèn)為其與膝關(guān)節(jié)局部炎癥相關(guān)，炎癥細(xì)胞因子通過直接或間接的途徑誘導(dǎo)痛覺過敏是 OA 疼痛的原因之一。

近年來，炎癥細(xì)胞因子在 OA 中所起的致痛作用越來越受到關(guān)注。現(xiàn)將近 10 年來炎癥細(xì)胞因子與 OA 疼痛機(jī)制的關(guān)系作一綜述。

一、OA 疼痛的解剖學(xué)基礎(chǔ)

大量研究顯示，傳入神經(jīng)纖維中存在著傳導(dǎo)傷害性信息的纖維成分，絕大多數(shù)是由細(xì)的有髓神經(jīng)纖維( Aδ 類 )和無髓神經(jīng)纖維( C 類 )組成。其中 C 類神經(jīng)纖維對機(jī)械、溫度以及化學(xué)刺激敏感，主要傳導(dǎo)慢性疼痛。關(guān)節(jié)軟骨中沒有神經(jīng)分布，因此軟骨損傷不會直接產(chǎn)生疼痛。而軟骨下骨、骨膜、滑膜、韌帶和關(guān)節(jié)囊均有豐富的神經(jīng)支配，這些部位的神經(jīng)末梢是 OA 傷害性刺激的根源。

C 類神經(jīng)感受器可叢狀分布于間質(zhì)和血管周圍，也可游離分布于關(guān)節(jié)囊、滑膜和關(guān)節(jié)的脂肪墊。這些感受器正常時無活性，僅在關(guān)節(jié)張力增高或暴露于化學(xué)刺激物如神經(jīng)肽、炎癥介質(zhì)等情況下才發(fā)生激活。王大勇等[3]采用Gless 神經(jīng)纖維染色將 OA 患者和單純膝關(guān)節(jié)外傷者的滑膜做比較，結(jié)果顯示：在 OA 患者的滑膜中神經(jīng)纖維分布更廣泛，從而證明了神經(jīng)纖維在 OA 疼痛中的作用。

二、OA 疼痛發(fā)生機(jī)制

OA 疼痛可分為兩類：炎性疼痛和神經(jīng)病理性疼痛。炎性疼痛主要是炎癥細(xì)胞因子誘導(dǎo)的炎癥所致。隨著疾病的進(jìn)一步發(fā)展，炎癥細(xì)胞因子長時間刺激骨關(guān)節(jié)周圍的末梢神經(jīng)可致神經(jīng)病理性疼痛。

滑膜炎是導(dǎo)致 OA 疼痛最值得注意的起因。滑膜炎是OA 的一個重要特征?；ぱ自?OA 疼痛中可能起重要作用，即所謂的“炎性痛”?；そM織中增多的神經(jīng)肽、細(xì)胞因子和炎癥介質(zhì)等進(jìn)入關(guān)節(jié)液，作用于軟骨下骨髓腔內(nèi)的感覺神經(jīng)，產(chǎn)生“骨痛”[4]；同時關(guān)節(jié)液中的上述物質(zhì)也可“逆行”刺激滑膜中的痛覺神經(jīng)末梢；關(guān)節(jié)軟骨剝脫后，軟骨下骨髓腔內(nèi)的感覺神經(jīng)纖維也可能被關(guān)節(jié)液中的神經(jīng)肽、細(xì)胞因子等激活加重疼痛。關(guān)節(jié)軟骨和滑膜損傷引起的神經(jīng)病理性變化與 OA 組織之間的動態(tài)交互作用常影響外周傳入神經(jīng)和背根神經(jīng)節(jié)( DRG )的神經(jīng)元，從而誘導(dǎo)痛覺過敏[5]，降低疼痛閾而引起 OA 病理性疼痛，即便正常刺激亦可出現(xiàn)疼痛感[6]。

三、炎癥細(xì)胞因子在 OA 疼痛中的作用

炎癥是 OA 疼痛刺激閾降低的潛在原因。在 OA 進(jìn)展中，炎癥反應(yīng)和疼痛相互作用，炎癥會引起疼痛，而疼痛又會反過來刺激炎癥反應(yīng)。OA 疼痛過程涉及到大量神經(jīng)細(xì)胞的異常，其中炎癥細(xì)胞因子水平的異常增高可能是導(dǎo)致 OA 疼痛的關(guān)鍵，包括白介素( IL-1、IL-6 )、腫瘤壞死因子( TNF-α )、趨化因子( MCP-1 )[5,7-8]。

1. 白介素與 OA 疼痛：白介素是指由各種白細(xì)胞產(chǎn)生，介導(dǎo)細(xì)胞之間相互作用的細(xì)胞因子。其中 IL-1 是典型的炎癥細(xì)胞因子，其在激活疼痛途徑方面起著顯著的作用。Bowles 等[9]通過碘化乙酸乙酯( MIA )誘導(dǎo)大鼠 OA模型發(fā)現(xiàn)，IL-1β 與 OA 大鼠的疼痛明顯相關(guān)，推論 IL-1β在 OA 模型的疼痛進(jìn)展中起直接作用。Attur 等[10]觀察發(fā)現(xiàn)，OA 患者的 IL-1β 水平較高，且通過 qPCR 測定顯示IL-1β 的基因表達(dá)與疼痛指數(shù)成正相關(guān)。IL-1β 致痛途徑有兩種，一種是通過復(fù)雜的信號級聯(lián)放大效應(yīng)誘導(dǎo)其它傷害性分子釋放，并與其協(xié)同作用來誘導(dǎo)炎癥反應(yīng)，直接或間接通過細(xì)胞內(nèi)激酶激活誘導(dǎo)疼痛過敏。生物學(xué)上，IL-1β 被認(rèn)為在 mRNA 和蛋白水平上增加了 Cox-2 的表達(dá)和前列腺素 E 合酶 -1[11]。Li 等[12]研究了 PGE2 在成人關(guān)節(jié)軟骨中的動態(tài)平衡和可能的疼痛途徑，發(fā)現(xiàn)當(dāng)與 IL-1相結(jié)合時，PGE2 協(xié)同上調(diào)體外 IL-6 的水平，促進(jìn)了炎癥反應(yīng)。另一種是 IL-1β 直接作用于傷害感受器產(chǎn)生疼痛。Sahbaie 等[13]在 OA 大鼠后爪皮內(nèi)注射 IL-1β 能導(dǎo)致很強(qiáng)的機(jī)械痛覺過敏。Binshtok 等[14]證明了 IL-1β 能夠直接作用于痛覺感受器產(chǎn)生痛敏。Liang 等[15]發(fā)現(xiàn) IL-1β 能迅速直接作用于周圍痛覺感受器，使傳入神經(jīng)元產(chǎn)生動作電位并介導(dǎo)痛覺過敏，而阻斷 IL-1β 的產(chǎn)生能夠起到抗炎和鎮(zhèn)痛的效果。所以，IL-1β 既能通過誘導(dǎo)周圍其它炎性介質(zhì)的上調(diào)從而加重炎性疼痛，也能通過刺激關(guān)節(jié)周圍神經(jīng)末梢傷害感受器，調(diào)節(jié)神經(jīng)元的興奮性，降低疼痛閾而導(dǎo)致疼痛。

IL-6 是另外一種涉及到軟骨退變的炎癥細(xì)胞因子[16]，其與關(guān)節(jié)組織中的痛覺過敏及感覺敏感相關(guān)。Stannus 等[17]通過對 149 例觀察發(fā)現(xiàn)，當(dāng)站立時 IL-6 與疼痛的變化密切相關(guān)。有研究發(fā)現(xiàn)，初級傳入神經(jīng)對 IL-6有應(yīng)答反應(yīng)，IL-6 在關(guān)節(jié)炎的疼痛傳遞中起著重要作用，主要影響周圍和中樞疼痛進(jìn)展[18-19]。在大鼠周圍和中樞神經(jīng)應(yīng)用 IL-6 可引起熱痛過敏、機(jī)械性痛覺過敏和異常疼痛[20-22]。在人體中，IL-6 與類風(fēng)濕關(guān)節(jié)炎、慢性疼痛及術(shù)后疼痛程度相關(guān)[23-25]。IL-6 可能刺激了傷害感受器，從而進(jìn)一步引起毒性作用而導(dǎo)致疼痛強(qiáng)度的增加。Lee等[26]通過對 OA 患者和正常人進(jìn)行痛覺測試，評估其對熱、冷及機(jī)械性刺激后的痛覺敏感程度，發(fā)現(xiàn) OA 患者對疼痛更敏感，在急性疼痛刺激后 IL-6 增加，其與冷痛的忍耐度呈負(fù)相關(guān)，而與熱痛的頻率呈正相關(guān)。

2. 腫瘤壞死因子與 OA 疼痛：腫瘤壞死因子來源于巨噬細(xì)胞、纖維母細(xì)胞、軟骨細(xì)胞等，是軟骨基質(zhì)降解的重要介質(zhì)，在 OA 的疼痛機(jī)制中起重要作用。Orita 等[27]實(shí)驗(yàn)發(fā)現(xiàn)，腫瘤壞死因子在膝關(guān)節(jié) OA 的滑膜病變中起重要作用，其中 TNF-α 與疼痛相關(guān)。

TNF-α 能通過部分神經(jīng)或炎癥環(huán)境致痛。有研究發(fā)現(xiàn)，軟骨或滑膜細(xì)胞中的 TNF-α 能誘導(dǎo)脊髓和 DRG 內(nèi)IL-6 的上調(diào)和神經(jīng)病理性疼痛[28]。另有研究發(fā)現(xiàn)，IL-6增加了 TNF-α 受體的表達(dá)[29]，這表明炎癥細(xì)胞因子的交互作用能進(jìn)一步誘導(dǎo)炎癥反應(yīng)。在炎癥反應(yīng)中，TNF-α 可以調(diào)節(jié)白細(xì)胞的活化、成熟、細(xì)胞因子和趨化因子的釋放及活性氧、一氧化氮中間產(chǎn)物的形成。神經(jīng)損傷或炎癥的早期，外周和中樞的膠質(zhì)細(xì)胞活化后釋放 TNF-α，可激活內(nèi)皮細(xì)胞，這些細(xì)胞一方面促進(jìn)炎癥細(xì)胞因子的大量合成和釋放，另一方面增加細(xì)胞表面黏附分子的表達(dá)，將循環(huán)中的炎癥細(xì)胞招募到神經(jīng)損傷部位，聚集的炎癥細(xì)胞活化后進(jìn)一步釋放炎性介質(zhì)，從而形成瀑布式的炎癥反應(yīng)，最終活化痛覺傳導(dǎo)通路神經(jīng)元。

TNF-α 引起的局部炎癥反應(yīng)還可能進(jìn)一步引起神經(jīng)損傷，從而誘發(fā)神經(jīng)病理性疼痛。Orita 等[30]研究發(fā)現(xiàn)，大鼠注射 MIA 后的早期，TNF-α 和 IL-6 均增高，降鈣素基因相關(guān)肽( CGRP )在右側(cè) DRG 神經(jīng)元顯著增加，右膝觸痛覺異常和細(xì)胞因子濃度增高相關(guān)，右側(cè)脊髓后角小膠質(zhì)細(xì)胞逐漸增加。神經(jīng)生長因子( NGF )產(chǎn)生于關(guān)節(jié)中，與慢性炎癥或神經(jīng)病理性疼痛相關(guān)[31]。CGRP 的增加一直被認(rèn)為是炎性疼痛的原因之一，而 CGRP-ir DRG 與 NGF 密切相關(guān)，并在炎癥所誘導(dǎo)的痛覺過敏反應(yīng)中起著關(guān)鍵作用。另有報(bào)道，小膠質(zhì)細(xì)胞的增加常提示神經(jīng)損傷，其與神經(jīng)病理性疼痛相關(guān)[32-33]。從而推論：在 MIA 誘導(dǎo)的大鼠 OA 模型中，炎癥細(xì)胞因子( TNF-α、IL-6 等 )所引起的局部炎癥造成疼痛，這種炎性疼痛逐漸引起神經(jīng)損傷，進(jìn)而可能誘導(dǎo)神經(jīng)病理性疼痛。任建華等[34]將切除大鼠右膝內(nèi)側(cè)半月板及內(nèi)側(cè)副韌帶后發(fā)現(xiàn)：大鼠后肢的機(jī)械刺激疼痛閾顯著下降并維持在較低水平；術(shù)后髕軟骨中VEDF 和 NGF 的表達(dá)隨時間顯著增強(qiáng)；TNF-α 和 P 物質(zhì)的表達(dá)顯著增強(qiáng)，且主要分布于增生的血管壁周圍基質(zhì)和軟骨細(xì)胞中；術(shù)后第 2、4 周，手術(shù)組重塑的軟骨下骨、增生的血管周圍細(xì)胞和基質(zhì)中檢測到大量 TNF-α。有報(bào)道認(rèn)為，大量 TNF-α 和 NGF 可改變軟骨局部內(nèi)環(huán)境，敏化增生的感覺神經(jīng)末梢，造成患肢痛閾的顯著下降[35]。所以，OA 軟骨下骨中增生的血管及其周圍上調(diào)的 TNF-α 和 NGF可能是膝關(guān)節(jié)痛閾下降的重要原因。

3. 趨化因子與 OA 疼痛：趨化因子可根據(jù)結(jié)構(gòu)分為CC、CXC 以及 CX3C。其中 CC 主要作用于單核細(xì)胞和淋巴細(xì)胞。MCP-1( CCL2 )是 CC 的一種，由軟骨細(xì)胞和滑膜細(xì)胞產(chǎn)生，并通過單核細(xì)胞募集方式在 OA 中起重要作用，誘導(dǎo)傷害形成[36]。

Dawes 等[37]應(yīng)用 MIA 誘導(dǎo) OA 疼痛模型在第 3、14 天發(fā)現(xiàn)炎癥介質(zhì)顯著增高，第 3 天軟骨和脂肪墊中觀察到巨噬細(xì)胞、中性粒細(xì)胞顯著性浸潤，CCL2 蛋白表達(dá)整體上調(diào)，從而推論：在 OA 疼痛模型中，CCL2 可作為進(jìn)一步研究 OA 的標(biāo)志物。Ogura 等[38]用 IL-1β 刺激顳頜關(guān)節(jié)炎( TMD )患者的滑膜組織后發(fā)現(xiàn)：患者滑膜細(xì)胞中的 CCL2 mRNA 升高顯著，并在刺激后 4 h 達(dá)到峰值；預(yù)先用 NF-kB 和 MAPK 抑制劑處理滑膜細(xì)胞后能夠抑制IL-1β 誘導(dǎo) MCP-1 的產(chǎn)生；伴有疼痛的 TMD 患者的滑液中 MCP-1 濃度的中位數(shù)是無疼痛的 2.3 倍。推論：伴有疼痛表現(xiàn)的 TMD 患者的滑液中 MCP-1 更高，是由 IL-1β 通過 NF-kB 和 MAPK 兩種途徑刺激滑膜細(xì)胞產(chǎn)生的。

近年來， MCP-1 在神經(jīng)系統(tǒng)病理生理學(xué)方面作為調(diào)節(jié)機(jī)制備受關(guān)注。DRG 慢性損傷時其神經(jīng)元中 MCP-1 水平的增高會引起神經(jīng)的過度興奮及慢性炎癥[39]。已證實(shí)細(xì)胞因子可直接興奮 DRG 傷害神經(jīng)元而產(chǎn)生疼痛，這一途徑與神經(jīng)元內(nèi)鈉離子的濃度上調(diào)相關(guān)。體外研究顯示[40-41]：MCP-1 能夠增加 DRG 神經(jīng)元的鈉離子通道亞基Nav1.8 的活性，抑制 Nav1.8 后能減少 MIA 模型的疼痛表現(xiàn)。因此，關(guān)節(jié)中產(chǎn)生的 MCP-1 可能通過直接刺激感覺神經(jīng)纖維誘導(dǎo)痛覺過敏。

炎癥細(xì)胞因子與 OA 疼痛密不可分。關(guān)節(jié)內(nèi)結(jié)構(gòu)的不穩(wěn)、軟骨的機(jī)械性磨損等往往導(dǎo)致炎癥細(xì)胞因子的產(chǎn)生，形成關(guān)節(jié)內(nèi)的炎性環(huán)境，引起炎性疼痛。之后隨著炎癥侵及到滑膜、軟骨下骨及韌帶等富含神經(jīng)末梢的組織，長久地刺激神經(jīng)纖維進(jìn)而引起患膝周圍末梢神經(jīng)的損傷。受損的神經(jīng)既可分泌 P 物質(zhì)、NGF 等神經(jīng)損害因子，致使出現(xiàn)神經(jīng)病理性疼痛的相關(guān)癥狀，又可通過激活神經(jīng)膠質(zhì)細(xì)胞進(jìn)一步合成和分泌炎癥細(xì)胞因子，加劇炎癥反應(yīng)，形成惡性循環(huán)，最終表現(xiàn)為長期的 OA 疼痛[42]。

目前，關(guān)于炎癥細(xì)胞因子在 OA 疼痛方面的諸多問題仍有待進(jìn)一步解決：許多炎癥細(xì)胞因子在 OA 疼痛的作用機(jī)制尚不明確；缺少簡便有效的檢測方法；炎癥細(xì)胞因子抑制劑僅在實(shí)驗(yàn)中應(yīng)用，臨床應(yīng)用尚有待進(jìn)一步研究。因此，解決這些問題將為臨床治療 OA 提供新的思路與方法。

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( 本文編輯：代琴 )

Mechanism of infammatory cytokines in osteoarthritis pain

YAO Zhi-hua, QIU Min-lei, FAN Tian-you. Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, 200071, PRC

In order to provide theoretical basis for the clinical treatment of osteoarthritis, the mechanism of inflammatory cytokines in osteoarthritis pain was investigated. A computer-based search of PubMed and China National Knowledge Infrastructure( CNKI )database was performed for the related articles with the keywords of“inflammatory cytokines, interleukin, tumor necrosis factor, chemokines, osteoarthritis pain, neuropathic pain and biochemical mechanisms” in English or in Chinese. The literatures related to the mechanism of infammatory cytokines in osteoarthritis pain were selected. A total of 84 literatures were primarily selected and 42 articles were reviewed according to the inclusion criteria. Osteoarthritis pain is one of the main factors affecting the life quality of the patients, and a variety of abnormal cells of the peripheral and central nervous systems were involved. Infammatory cytokines played an important role in the pathogenesis of osteoarthritis. The relationship between osteoarthritis pain and common infammatory cytokines were reviewed in the review, so as to explore the important role of infammatory cytokines in osteoarthritis pain and provide theoretical basis for the clinical treatment of osteoarthritis.

Osteoarthritis; Pain; Cytokines; Interleukins; Tumor necrosis factors; Chemokines

10.3969/j.issn.2095-252X.2014.05.012

R684.3

200071 上海中醫(yī)藥大學(xué)附屬市中醫(yī)醫(yī)院

樊天佑，Email: fantianyou365@hotmail.com

2014-02-04 )