張瀚元，張秀英，施路一

(1.東北農(nóng)業(yè)大學(xué) 動物醫(yī)學(xué)院，哈爾濱 150030；2.黑龍江省野生動物研究所，哈爾濱 150081)

疾病的炎癥本質(zhì)及其中藥干預(yù)

張瀚元1，張秀英1，施路一2

(1.東北農(nóng)業(yè)大學(xué) 動物醫(yī)學(xué)院，哈爾濱 150030；2.黑龍江省野生動物研究所，哈爾濱 150081)

炎癥是疾病的基本病理過程，與多種疾病的進(jìn)程及轉(zhuǎn)歸相關(guān)。人類醫(yī)學(xué)領(lǐng)域的炎癥研究成果眾多，而在獸醫(yī)方面鮮有報道。因此，有必要從5方面對炎癥及其中藥干預(yù)進(jìn)行綜述：中藥通過作用于炎癥信號通路各環(huán)節(jié)，抑制或者阻斷炎癥信號傳遞，從而起到抑制炎癥的作用；中藥影響各種炎癥因子的表達(dá)水平，改變炎癥臨床表現(xiàn)；中藥通過抑制氧化產(chǎn)物生成，使炎癥機體避免過氧化損傷；中藥通過調(diào)節(jié)炎癥平衡，從而影響炎癥的發(fā)生與發(fā)展；中藥通過適當(dāng)調(diào)節(jié)炎癥因子之間的相互關(guān)系，改善SIRS的產(chǎn)生與惡化。結(jié)合疾病與炎癥的相關(guān)性以及中藥在炎癥干預(yù)方面的研究成果，綜述炎癥在各種疾病中的重要作用，為通過干預(yù)炎癥、防制炎癥相關(guān)疾病提供線索和依據(jù)。

炎癥；炎癥本質(zhì)；炎癥干預(yù)；中藥

作為重要的基本病理過程，炎癥在許多疾病中扮演著重要角色。心力衰竭與TLR4/NF-κb通路活化[1]以及下游炎癥因子TNF-α、IL-6的表達(dá)密切相關(guān)[2];血管內(nèi)皮細(xì)胞的活化和功能失調(diào)導(dǎo)致的血管炎癥，是許多慢性炎癥反應(yīng)疾病的病理基礎(chǔ)[3];手足口病患兒血清中炎癥因子 IL-10、IL-12和TNF-α表達(dá)水平異常增高，具有手足口病的療效監(jiān)控意義，可作為手足口病患兒的監(jiān)控指標(biāo)等[4];1991年，美國醫(yī)師學(xué)會(AC-CP)、危重病醫(yī)學(xué)會(SCCM)聯(lián)席會議委員會提出，將全身炎癥反應(yīng)綜合征(systemic inflammatory response syndrome,SIRS)替代原來的菌血癥、膿毒癥、膿毒性休克等概念[5]。這使炎癥病理范疇更加寬泛，隨即SIRS成為研究炎癥的熱點。其研究成果在炎癥干預(yù)方面具有代表性，進(jìn)一步確定炎癥在各種疾病中的重要意義。文章通過對炎癥過程中各種角色的綜述，對炎癥的病理過程以及中藥干預(yù)進(jìn)行小結(jié)。

1 炎癥信號通路

TLR4是TLRs受體家族中最具代表意義的一員，是一種廣泛存在于各種組織器官細(xì)胞表面的細(xì)胞膜受體蛋白。革蘭氏陰性菌的脂多糖(Lipopolysaccharide，LPS)是TLR4蛋白的經(jīng)典配體，在模擬試驗以及臨床實踐中具有代表意義，能夠激活TLR4下游MAPKs以及NF-κB信號通路[6]。LPS-TLR4復(fù)合體激活兩條經(jīng)典信號轉(zhuǎn)導(dǎo)通路：一條是MyD88依賴性信號轉(zhuǎn)導(dǎo)路徑，LPS-TLR4復(fù)合體激活轉(zhuǎn)錄因子NF-κB，后者進(jìn)入細(xì)胞核，啟動炎癥相關(guān)因子基因表達(dá)。這些炎癥因子如TNF-α、IL-1β等促炎因子是構(gòu)成炎癥反應(yīng)的重要活性分子，促炎因子以激動劑的形式反作用于NF-κB，使其活性更加增強、持續(xù)，從而增強炎癥反應(yīng)，形成促NF-κB活化的正反饋調(diào)節(jié)[7]。另一條是MyD88非依賴性信號轉(zhuǎn)導(dǎo)途徑，LPS-TLR4復(fù)合體激活轉(zhuǎn)錄因子干擾素調(diào)節(jié)因子3(IFN-regulatedfactor3，IRF3)并入核，啟動β-干擾素 (Interferonbeta，IFN-β)的轉(zhuǎn)錄，最終引起免疫反應(yīng)[8]。TLR4作為炎癥反應(yīng)始動環(huán)節(jié)，具有炎癥指示意義，成為炎癥干預(yù)的靶點。在細(xì)菌感染發(fā)生以后，TLRs受體的表達(dá)水平明顯升高[9]。在心肌炎小鼠模型中，敲除 TLR4基因的突變型小鼠經(jīng)LPS刺激不出現(xiàn)炎癥反應(yīng)[10]。Eritoran是一種TLR4選擇性抑制劑，在胃缺血再灌注損傷模型中，Eritoran能夠明顯減輕心臟缺血再灌注損傷以及炎癥反應(yīng)[11]。中藥能夠降低TLR4的表達(dá)水平，從而起到抑制炎癥的作用。

核因子-κB(NF-κB)廣泛存在于真核細(xì)胞內(nèi)，對參與調(diào)節(jié)免疫應(yīng)答、應(yīng)激反應(yīng)、炎癥反應(yīng)和細(xì)胞凋亡等相關(guān)因子的基因表達(dá)進(jìn)行調(diào)節(jié)[12]。NF-κB轉(zhuǎn)錄因子家族共有5個成員，其中P65：P50異源二聚體以其數(shù)量最多而作為代表，NF-κB p65：p50與IκBα結(jié)合，以非活化的形式穩(wěn)定存在于細(xì)胞質(zhì)中[13]。激活后p65：p50游離出復(fù)合物，從胞質(zhì)轉(zhuǎn)入胞核，繼而與炎癥相關(guān)基因或先天免疫基因的表達(dá)啟動位點結(jié)合[14]。啟動多條信號通路并控制多個基因的表達(dá)[15]。細(xì)胞因子的生成與活化主要是通過NF-κb的激活來實現(xiàn)，NF-κb也是炎性細(xì)胞因子發(fā)揮生物活性的調(diào)控靶位[16]。在持久的炎癥過程中，促炎癥因子(TNF-α、IL-6、IL-1β等)或炎癥相關(guān)分子(iNOS、COX-2、VCAM-1D等)作用于NF-κB，導(dǎo)致NF-κB信號通路持續(xù)激活，形成持續(xù)的慢性炎癥，這些基因的異常表達(dá)往往是促進(jìn)腫瘤的發(fā)生、轉(zhuǎn)移、組織浸潤以及腫瘤細(xì)胞抗凋亡的重要因素[17]。促炎因子對組織器官具有直接的炎癥損傷作用，也能夠通過激活NF-κB通路，啟動破壞性調(diào)節(jié)，間接造成炎癥損傷。對牙周病的研究表明，TNF-α活化NF-κB信號通路，從而轉(zhuǎn)錄相關(guān)炎癥基因發(fā)揮促炎作用，同時NF-κB信號通路通過調(diào)控RANKL/RANK表達(dá)，調(diào)節(jié)成骨分化信號通路及骨基質(zhì)形成，對骨發(fā)育和骨改建過程發(fā)揮關(guān)鍵調(diào)控作用[18]。

作為經(jīng)典的炎癥信號通路，多種中藥以TLR4/NF-κb為靶點，降低TLR4、NF-κB的表達(dá)水平，阻斷TLR4/NF-κb成為干預(yù)機制的關(guān)鍵環(huán)節(jié)，同時同一種中藥的干預(yù)機制是綜合性的。在大鼠骨關(guān)節(jié)炎模型中，桂皮醛一方面抑制LPS誘導(dǎo)的大鼠滑膜細(xì)胞TLR4蛋白表達(dá)，另一方面阻斷TLR4/NF-κB通路，從而減少炎性介質(zhì)的分泌，抑制滑膜炎癥反應(yīng)，緩解骨關(guān)節(jié)炎癥狀[19]。張敏[20]在干預(yù)大鼠變應(yīng)性鼻炎研究中發(fā)現(xiàn)，雷公藤多甙能夠調(diào)節(jié)TLR及NF-κBp50的表達(dá)，影響變應(yīng)性鼻炎的發(fā)生發(fā)展。程廣東等[21]用LPS誘導(dǎo)，建立雞法氏囊炎模型，應(yīng)用連翹酯苷A進(jìn)行干預(yù)，結(jié)果表明連翹酯苷A能夠降低NF-κB的表達(dá)水平，抑制NF-κB炎癥通路，干預(yù)下游炎癥因子的生成，從而抑制LPS引起的雞法氏囊炎癥。田維毅[22]應(yīng)用黃連解毒湯抑制Mφ 信號通路TLR4/NF-κB的表達(dá)，抑制TNF-α分泌、促進(jìn)TGF-β1分泌，限制炎癥發(fā)展，減輕動脈粥樣硬化的損傷程度。張馳等[23]應(yīng)用參附注射液抑制靜脈內(nèi)皮細(xì)胞NF-κB活化，減弱TLR4/NF-κB途徑，抑制LPS介導(dǎo)的黏附分子表達(dá)，起到抑炎作用。鄒國輝[24]應(yīng)用解毒活血方抑制TLR4/NF-κB活化，降低IL-1β、TNF-α、MCP-1、ICAM-I含量，拮抗炎癥反應(yīng)，改善ISR臨床癥狀。劉碩[25]基于NF-κB-抗凋亡通路，結(jié)合中醫(yī)扶正解毒理論，通過中藥降低血清炎性細(xì)胞因子水平，減少NF-kB活化，從而阻斷“NF-kB-抗凋亡”通路，使肺癌細(xì)胞凋亡增加，提高化療療效。王雪慧[26]在急性肺損傷大鼠模型的研究中發(fā)現(xiàn)，通腑湯通過阻斷NF-κB通路，抑制NF-κB的表達(dá)，降低TNF-α、IL-6、TGF-β1的含量，防治大鼠急性肺損傷。黎玉翠[27]對廣藿香酮和廣藿香醇進(jìn)行研究，表明廣藿香酮和廣藿香醇能夠阻斷LPS激活細(xì)胞的NF-κB和MAPK信號轉(zhuǎn)導(dǎo)通路，且顯著抑制炎癥介質(zhì)相關(guān)基因的過度表達(dá)，抑制細(xì)胞炎癥。孫雪芳等[28]利用黃芪多糖抑制TLR4/NF-κB信號通路，對LPS誘導(dǎo)的乳鼠心肌細(xì)胞有保護(hù)作用，有效抑制疾病模型中心肌肥大的發(fā)生。

2 炎癥反應(yīng)中的活性物質(zhì)

TNF-α是早期促炎細(xì)胞因子，在致病菌或者其他因素刺激下，由巨噬細(xì)胞、單核細(xì)胞、網(wǎng)狀內(nèi)皮細(xì)胞等大量產(chǎn)生的TLR4/NF-κB通路下游的產(chǎn)物。TNF-α能夠激活TLR4/NF-κB通路，繼而放大炎癥級聯(lián)反應(yīng)[29]，并通過持續(xù)活化NF-κB發(fā)揮促炎效應(yīng)[30]。 TNF-α能夠啟動血管反應(yīng)，促進(jìn)白細(xì)胞在炎灶聚集與活化，引起呼吸爆發(fā)、組織損傷以及細(xì)胞因子瀑布，誘發(fā)標(biāo)的細(xì)胞凋亡[31]。TNF-α也是溝通機體固有免疫和獲得性免疫的樞紐，TNF-α是細(xì)胞因子級聯(lián)反應(yīng)的起始因子[32]，直接或間接地激活白細(xì)胞發(fā)揮其免疫功能[33]。T淋巴細(xì)胞產(chǎn)生的其他細(xì)胞因子能夠促進(jìn)TNF-α的合成[34]。TNF-α的水平能夠反映炎癥進(jìn)程[35]，進(jìn)而對敗血癥、感染性疾病等具有重要指示作用與診斷意義[36]。對敗血癥治療后的24～48 h后，TNF-α的水平持續(xù)下降，具有統(tǒng)計學(xué)意義[37]。通過TNF -α單克隆抗體特異性清除 TNF -α在SIRS的治療方面取得可喜進(jìn)展[38]。

IL-6源于單核巨噬細(xì)胞，一方面能夠激活血管內(nèi)皮細(xì)胞和炎性細(xì)胞，誘導(dǎo)急性期蛋白合成，催化放大炎性反應(yīng)[39]。另一方面也可以刺激炎癥細(xì)胞增加可溶性腫瘤壞死因子受體和人IL-1受體2的釋放，減弱TNF-α的作用，起到一定的抗炎效果。故血清IL-6表達(dá)水平和持續(xù)時間可反映炎癥程度[40]。IL-6在炎癥早期迅速上升，參與并促進(jìn)全身炎癥反應(yīng)綜合征發(fā)展的同時，激活淋巴細(xì)胞[41]。參與任何感染和炎癥刺激相關(guān)免疫系統(tǒng)的急性期反應(yīng)[42]。促進(jìn)自然殺傷細(xì)胞和細(xì)胞毒性T淋巴細(xì)胞的免疫活性，促進(jìn)T淋巴細(xì)胞和B淋巴細(xì)胞的成熟分化，激活中性粒細(xì)胞，促進(jìn)B淋巴細(xì)胞成熟并分泌抗體[43]。在感染性疾病中具有指示性意義[44]。血清中IL-6水平對急性中樞神經(jīng)系統(tǒng)感染具有診斷意義[45]。其水平的高低在新生兒感染性疾病中能夠反映疾病的嚴(yán)重程度[46]。

IL-10是強效抑制炎癥反應(yīng)的細(xì)胞因子，又被稱為細(xì)胞因子合成抑制因子(cytokine synthesis inhibitory faetor，CSIF)[47]，主要來源于單核細(xì)胞、巨噬細(xì)胞和Th2細(xì)胞等多種與炎癥免疫相關(guān)的效應(yīng)細(xì)胞[48]。IL-10一方面作為免疫調(diào)節(jié)因子，能夠促進(jìn)活化的T、B細(xì)胞分化，間接抑制T、B細(xì)胞凋亡[49]。促進(jìn)CD8+T細(xì)胞的增殖和分化[50]。增加肥大細(xì)胞數(shù)量，提高促炎因子濃度[51]。另一方面作為抑炎因子對炎癥的抑制作用是多方面的。IL-10可通過抑制APC(特別是巨噬細(xì)胞和樹突狀細(xì)胞)的抗原提呈能力，抑制DC細(xì)胞分化，誘導(dǎo)DC凋亡，同時抑制DC和巨噬細(xì)胞產(chǎn)生TNF-α、IL-1、IL-6等促炎因子[52]。 IL-10也可上調(diào)IL-1受體拮抗劑IL-1ra和可溶性TNF-α受體表達(dá)，抑制炎癥過度[53]。IL-10可通過對T細(xì)胞的抑制作用抑制炎癥水平。IL-10能夠抑制Thl細(xì)胞分泌IL-2、IFN-γ，延緩細(xì)胞介導(dǎo)炎癥反應(yīng)。能夠通過干預(yù)IL-10的表達(dá)水平調(diào)節(jié)炎癥水平。拮抗IL-10水平，IL-6 mRNA表達(dá)量增強，炎癥反應(yīng)加劇[54]。對敗血癥治療后的24～48 h 后，TNF-α的水平持續(xù)下降，但I(xiàn)L-10的水平在治療后24 h升高，48 h后下降[37]。于是可通過IL-10/TNF-α反映炎癥抗促平衡，進(jìn)而反應(yīng)炎癥水平[55]。IL-10水平與ARDS患者病死率高度相關(guān)[56]， IL-10基因啟動子區(qū)1 082位點的基因型對SIRS的發(fā)生、發(fā)展、診斷、預(yù)后以及預(yù)測具有重要意義[57]。IL-10維持細(xì)胞因子網(wǎng)絡(luò)平衡，對于SIRS具有重要意義，一方面抑制TNF-α等致炎性細(xì)胞因子的產(chǎn)生[58]，保護(hù)機體組織在炎癥因子作用下過度的病理生理改變,另一方面可造成機體的免疫功能抑制,對感染的病原微生物清除能力下降,甚至造成“免疫麻痹狀態(tài)”,從而導(dǎo)致CARS[59]，大大增加二次感染的風(fēng)險或?qū)е赂腥炯又豙60]。

中藥通過降低炎癥因子水平表現(xiàn)出抗炎干預(yù)作用。濃度在20 μmol/L以上的薏苡仁酯液能夠有效降低血管內(nèi)皮細(xì)胞炎癥反應(yīng)模型中促炎因子TNF-α、IL-1水平，降低抗炎因子IL-10與TGF-β水平，提示薏苡仁酯液通過炎癥干預(yù)途徑具有防制心血管疾病的作用[61]。補腎活血解郁方能夠顯著降低類風(fēng)濕關(guān)節(jié)炎伴發(fā)抑郁癥大鼠血清IL-1β、IL-6、TNF-α水平，對疾病有積極作用[62]。小鼠干燥綜合征模型中，增液湯干預(yù)前后血清中TNF-α和IL-1β的含量與發(fā)病情況正相關(guān)[63]。內(nèi)異止痛湯降低EMs大鼠血清TNF-α表達(dá)。抑制NF-κBp65蛋白表達(dá)，從而減輕炎癥反應(yīng)，抑制異位組織生長[64]。甘露消毒丹提高抑炎因子IL-10表達(dá)水平，降低促炎因子TNF-α的分泌，從而減輕炎癥反應(yīng)[65]。婦炎寧湯通過作用于細(xì)胞因子IL-10、IFN-γ、TNF-α的表達(dá)，對慢性盆腔炎及陽虛型慢性盆腔炎大鼠模型具有較好的療效[66]。魚腥草素鈉抑制LPS誘導(dǎo)奶牛子宮內(nèi)膜上皮細(xì)胞和炎性細(xì)胞的TNF-α、IL-1β、IL-6和IL-8的蛋白分泌水平，抑制IκBα的降解和NF-κBp65的磷酸化，壓制ERK、JNK、p38磷酸化水平，顯著減弱模型組小鼠子宮內(nèi)膜的炎性反應(yīng)，對試驗性子宮內(nèi)膜炎模型小鼠有很好的治療效果[67]。加味黃芩湯下調(diào)大鼠IL-6 mRNA的表達(dá)，降低血清IL-6含量及血清sIL-6Rα含量，減輕sIL-6Rα與IL-6形成復(fù)合物而引起的炎癥反應(yīng)[68]。

脂質(zhì)炎癥介質(zhì)在炎癥反應(yīng)中扮演重要角色，其主要來源于細(xì)胞膜磷脂，其中的花生四烯酸是重要的脂質(zhì)介質(zhì)來源。ω-3PUFAs能夠通過改變細(xì)胞膜磷脂構(gòu)成，減少花生四烯酸的含量[69]。ω-3 多不飽和脂肪酸(EPA、DHA)一方面通過置換細(xì)胞膜磷脂中的花生四烯酸，競爭環(huán)氧酶和脂氧合酶，從而減少源于花生四烯酸分解后的炎性產(chǎn)物產(chǎn)生，減輕炎癥反應(yīng)[70]。另一方面ω-3PUFAs改變細(xì)胞膜磷脂脂肪酸構(gòu)成，影響細(xì)胞膜上的相關(guān)信號分子、酶以及受體功能，從而改變信號轉(zhuǎn)導(dǎo)過程，干預(yù)炎癥因子的轉(zhuǎn)錄表達(dá)以及其他損傷性調(diào)節(jié)[71]。繼而影響細(xì)胞分子功能[72]。內(nèi)異止痛湯降低子宮內(nèi)膜異位癥模型大鼠的血清環(huán)氧酶COX-2 表達(dá)，從而減輕炎癥反應(yīng)，抑制異位組織生長[73]。前列腺素E2受體具有4個亞型，前列腺素E2通過與不同亞型受體結(jié)合的方式調(diào)節(jié)促炎反應(yīng)和抗炎反應(yīng)，在炎癥的發(fā)展過程中具有重要的調(diào)節(jié)意義[74]。PGE2通過EP2在由LPS引起的神經(jīng)元氧化損傷中發(fā)揮作用，其促進(jìn)神經(jīng)元周圍的炎癥反應(yīng)[75]。但在腫瘤環(huán)境中，PGE2又通過EP2抑制樹突狀細(xì)胞的免疫遞呈作用并導(dǎo)致免疫缺陷的發(fā)生[76]。在風(fēng)濕性關(guān)節(jié)炎小鼠模型中，PGE2能通過EP4促進(jìn)淋巴細(xì)胞尤其是Th1淋巴細(xì)胞的遷移和增殖[77]。

NO由一氧化氮合酶NOS催化L-精氨酸產(chǎn)生，NO作用于自身細(xì)胞或者鄰近細(xì)胞，與轉(zhuǎn)錄因子或蛋白激酶等結(jié)合，從而發(fā)揮不同的調(diào)節(jié)作用。內(nèi)源性NO能夠作用于NF-κB，使NF-κB P p50亞基的半胱氨酸殘基硝基化，降低NF-κB的DNA結(jié)合活性，從而減弱炎癥級聯(lián)反應(yīng)信號強度，對炎癥反應(yīng)予以負(fù)調(diào)節(jié)[78]。NO抑制NF-κB，減少炎癥因子介質(zhì)的釋放，減少TNF-α、IL-1等釋放[79]。而另一方面，誘導(dǎo)型NO在較高濃度下激活NF-κB，誘導(dǎo)促炎細(xì)胞因子TNF-α、IL-1β等產(chǎn)生，后者的產(chǎn)生又能激活誘導(dǎo)型NO合酶，促進(jìn)機體產(chǎn)生更多NO，從而形成正反饋環(huán)。抑制NO合成可改善典型的炎癥癥狀[80]。

TNF-α和IL-1是炎癥早期釋放的炎癥因子，所以針對這些炎癥因子的拮抗治療難以奏效[81]。這提示一方面要進(jìn)行預(yù)防性干預(yù)炎癥的發(fā)生程度與發(fā)展速度；另一方面，選擇可控性強的炎癥因子予以拮抗治療。作為重要的晚期炎癥介質(zhì)，高遷移率族蛋白 B1 (high mobility group protein Bl, HMGB1)能夠增強LPS活性，協(xié)同刺激炎癥因子的釋放[82]。HMGB1也參與膿毒癥、出血性休克、急性肺損傷、風(fēng)濕性關(guān)節(jié)炎和彌散性血管內(nèi)凝血的病理生理過程[83]。與TNF-α、IL-1等速發(fā)型炎性介質(zhì)相比,具有更大的臨床意義[84]。

降鈣素原(PCT)是感染的相關(guān)性標(biāo)志物。是SIRS的臨床輔助診斷標(biāo)準(zhǔn)之一，其水平的高低可反映病情的危重狀態(tài)[85]，并為臨床病情轉(zhuǎn)歸提供客觀依據(jù)[86]。當(dāng)機體處于嚴(yán)重感染時，即使患者處于免疫抑制狀態(tài)或尚無明顯的臨床表現(xiàn)，血漿中PCT濃度也明顯升高，其升高程度與感染的嚴(yán)重度呈正相關(guān)[87]，PCT具有早期、特異、敏感的特性，優(yōu)于傳統(tǒng)的炎性標(biāo)志物，而且它對病情的早期評估、預(yù)后評價及療效觀察具有一定的意義[88]。

3 炎癥損傷

組織過氧化是炎癥損傷的重要機制之一。SOD中重要的抗氧化酶能夠清除自由基，減輕自由基引起的組織損傷。動物體的抗氧化能力與SOD活力有密切聯(lián)系。MDA是一種自由基，能夠直接反映脂質(zhì)過氧化的程度與速率，組織氧化程度與血清中MDA含量相關(guān)。于小婷等[89]應(yīng)用大腸埃希菌感染仔兔，結(jié)果發(fā)現(xiàn)大腸埃希菌感染后，仔兔腸道內(nèi)MDA含量增加，SOD活性下降，從而造成對腸道組織的氧化損傷。谷胱甘肽(GSH)能夠清除機體氧化物，其含量具有指示機體抗氧化效果的意義。連翹酯苷A能夠降低動物機體內(nèi)的過氧化物水平，增加抗氧化水平，從而保護(hù)組織不受炎癥損傷?；钚匝鮎OS的增加或者抗氧化劑的減少能夠?qū)е略S多類型細(xì)胞凋亡，包括內(nèi)皮細(xì)胞，尤其脂多糖能夠誘導(dǎo)內(nèi)皮細(xì)胞產(chǎn)生大量ROS，這也是細(xì)菌感染造成炎性血管中心反應(yīng)的重要機制，而這種凋亡的誘發(fā)與核因子的活化存在相關(guān)性[90]。相反，抑制血管內(nèi)皮細(xì)胞產(chǎn)生活性氧可以減輕細(xì)胞的誘凋亡損傷[91]。

避免過氧化損傷是減少炎癥損傷的重要手段。吳金梅[92]在治療奶牛乳房炎的研究中發(fā)現(xiàn)，甘草總黃酮能夠抑制金黃色葡萄球菌毒力因子的表達(dá)，抑制過氧化損傷，從而對奶牛乳房炎的治療具有積極意義。仲偉婷[93]研究發(fā)現(xiàn)商陸皂苷甲作用于Nrf2，增強內(nèi)生性抗氧化劑的表達(dá)，進(jìn)而抑制ROS等氧化劑的產(chǎn)生，減弱氧化損傷和炎癥反應(yīng)，以及輔助地塞米松發(fā)揮抗炎作用。徐宵龍[94]研究發(fā)現(xiàn)，安石榴苷可以降低巨噬細(xì)胞內(nèi)氧自由基的生成，調(diào)節(jié)超氧化物歧化酶1(Superoxidedismutase1，SOD1)活性，從而緩解LPS誘導(dǎo)的巨噬細(xì)胞炎癥反應(yīng)。史亞凝[95]研究發(fā)現(xiàn)，雞蛋膜蛋白酶解物具有較好的化學(xué)抗氧化性能，能夠促進(jìn)腸道細(xì)胞內(nèi)抗氧化酶的活力，促進(jìn)抗氧化物GSH的生成，從而抑制細(xì)胞內(nèi)脂質(zhì)與蛋白質(zhì)的氧化。

4 炎癥平衡學(xué)說

T細(xì)胞按其功能可分為CD4+T細(xì)胞和CD8+T細(xì)胞等亞群。CD4+T細(xì)胞多為Th細(xì)胞(輔助性T細(xì)胞)。根據(jù)產(chǎn)生細(xì)胞因子和生物功能的不同，傳統(tǒng)上將CD4+T細(xì)胞分為Th1和Th2兩類細(xì)胞亞群，它們在免疫過程中相互調(diào)節(jié)并相互制約。Th1細(xì)胞分泌γ-干擾素(interferon-γ，IFN-γ)和腫瘤壞死因子-α(tumor necrosis factor-α，TNF-α)，Th2細(xì)胞分泌白細(xì)胞介素10(interleukin-10，IL-10)。IFN-γ和TNF-α為活化巨噬細(xì)胞，是啟動細(xì)胞外免疫活動的主要活性分子，但過量的IFN-γ和TNF-α可能導(dǎo)致免疫應(yīng)答過度，加重組織的炎癥反應(yīng)甚至導(dǎo)致組織壞死等。IL-10又稱為細(xì)胞因子生成抑制因子(CSIF)，是IL-10家族的首要成員。IL-10能夠下調(diào)IFN-γ和TNF-α，從而在保護(hù)性免疫和免疫病理的平衡中起著重要作用。

CD4+CD25+調(diào)節(jié)性T細(xì)胞(regulatory T cells，Treg，表達(dá)轉(zhuǎn)錄因子FoxP3)是近年來發(fā)現(xiàn)的一類不同于Th1和Th2細(xì)胞的CD4+T細(xì)胞，作為一種調(diào)節(jié)性T細(xì)胞下調(diào)自身免疫和炎癥反應(yīng)[96]。其發(fā)揮效應(yīng)的一條重要途徑為分泌TGF-β和IL-10。Th17是另一類新發(fā)現(xiàn)的不同于Thl和Th2細(xì)胞的CD4+T細(xì)胞亞群，以分泌IL-17為主，Th17細(xì)胞在促進(jìn)炎癥反應(yīng)和自身免疫病發(fā)病中發(fā)揮重要作用[97]。Th17/Treg免疫失衡所致炎癥紊亂，即免疫-炎癥軸失衡參與靶器官炎癥反應(yīng)和損傷[98]。

在許多疾病的發(fā)生發(fā)展過程中均能見到炎癥平衡的影子，其變化與疾病進(jìn)程密切相關(guān)。急性弓形蟲眼部感染時，房水與血清中IFN-γ和TNF-α的水平明顯升高，IL-10的水平明顯降低。脾臟中Treg/Th17的比值明顯降低。外源性IL-10可通過降低體內(nèi)IFN-γ和TNF-α的濃度以及改變體內(nèi)Treg/Th17的平衡狀態(tài)減輕弓形蟲感染小鼠的眼部炎癥反應(yīng)[99]。炎癥性腸病(inflammatory bowel disease，IBD)部分起因是致病因素活化免疫系統(tǒng)，由腸道上皮細(xì)胞、巨噬細(xì)胞和淋巴細(xì)胞分泌多種細(xì)胞因子，進(jìn)而形成病原、細(xì)胞和因子之間的級聯(lián)反應(yīng)。細(xì)胞與因子間的綜合作用造成腸道局部炎癥。炎癥因子和抗炎因子比例的消長決定炎癥的轉(zhuǎn)歸和預(yù)后[100]。同時輔助性T細(xì)胞、調(diào)節(jié)性T細(xì)胞、細(xì)胞因子和自身抗體等免疫因素在炎癥性腸病的發(fā)病和持續(xù)發(fā)展中起重要作用[101]。支原體肺炎患兒細(xì)胞因子IL-10水平升高，提示抗炎性細(xì)胞因子和促炎性細(xì)胞因子平衡失調(diào)，可能導(dǎo)致Treg/Th17平衡失調(diào)，機體發(fā)生細(xì)胞免疫紊亂，引起患兒肺部出現(xiàn)免疫炎癥反應(yīng)、免疫損傷及纖維化，而出現(xiàn)一系列臨床表現(xiàn)[102]。

炎癥失衡是造成SIRS的重要原因之一，中藥能夠從多方面重建炎癥平衡，從而起到防制作用。孫俊穎[103]使用魚腥草對雞毒支原體感染進(jìn)行治療發(fā)現(xiàn)，魚腥草揮發(fā)油能夠增強IFN-γ、L-12表達(dá)，抑制IL-4表達(dá)，重建Thl/Th2反應(yīng)的平衡，實現(xiàn)對免疫功能的調(diào)節(jié)。周興華[104]通過對急性肝損傷進(jìn)行研究發(fā)現(xiàn)，加味茵陳蒿湯通過調(diào)節(jié)Th1、Th2類細(xì)胞因子，糾正Th1/Th2的免疫失衡狀態(tài)，顯著減輕肝細(xì)胞損傷，調(diào)節(jié)機體的免疫反應(yīng)而起到保肝作用。王建國[105]通過對血虛風(fēng)燥證慢性濕疹的臨床觀察發(fā)現(xiàn)，中藥方劑養(yǎng)血消風(fēng)飲能有效調(diào)節(jié)Th1/Th2細(xì)胞因子的平衡狀態(tài)，減少炎性反應(yīng)介質(zhì)釋放，從而減輕血虛風(fēng)燥證慢性濕疹臨床癥狀。董秀蘭[106]應(yīng)用中藥方劑加味五虎湯治療痰熱閉肺型小兒支原體肺炎取得較好效果，其主要機制在于中藥加味五虎湯調(diào)節(jié)IL-10、IL-17、TGF-β1水平及Treg/Th17平衡，減輕肺部免疫炎癥反應(yīng)及肺部纖維化，而提高臨床療效。在大鼠變應(yīng)性鼻炎模型中，張敏[20]使用雷公藤多甙糾正Th1/Th2細(xì)胞因子的比例，降低IgE的表達(dá)，影響變應(yīng)性鼻炎的發(fā)生發(fā)展。

5 全身炎癥反應(yīng)綜合征

全身炎癥反應(yīng)綜合征(SIRS) 是機體在各種致病因素作用下，機體免疫系統(tǒng)發(fā)生活化免疫細(xì)胞、表達(dá)炎癥相關(guān)受體、釋放大量致炎細(xì)胞因子和抗炎細(xì)胞因子等免疫防御表現(xiàn)，上述活動中各種過量釋放或失控的炎癥介質(zhì)相互作用形成網(wǎng)絡(luò)式級聯(lián)放大效應(yīng)，繼而造成促炎/抗炎平衡的破壞，損害血管內(nèi)皮及微環(huán)境，造成機體相應(yīng)器官或全身的損害，最后導(dǎo)致DIC，進(jìn)一步將導(dǎo)致多器官功能衰竭綜合征(multiple organ dysfunction syndrome，MODS)[107]。

在SIRS干預(yù)方面，大劑量的抗生素應(yīng)用以及炎性因子拮抗劑不能有效降低嚴(yán)重創(chuàng)傷的并發(fā)癥和死亡率，雖然較廣譜的細(xì)胞因子阻滯劑研究正方興未艾, 但其最終應(yīng)用于臨床及治療的效果有待進(jìn)一步確定[108]?，F(xiàn)有研究成果表明血清TNF-α、sTNFR-Ⅰ及sTNFR-Ⅰ/TNF-α比值變化可較好地反映SIRS改變，對預(yù)測其病情變化有重要意義[109]。下調(diào)TNF-α水平，上調(diào)IL-10水平可以減輕組織器官炎癥反應(yīng)的病理損害而起保護(hù)作用，避免SIRS進(jìn)一步向MODS發(fā)展[110]。因此，早期預(yù)測和有效干預(yù)SIRS可能是防治MODS的關(guān)鍵。在臨床上，由于眾多炎癥介質(zhì)和細(xì)胞因子的多向協(xié)同或拮抗效應(yīng)，造成對其認(rèn)識過程和手段的復(fù)雜化，至今尚無能夠阻斷這種炎癥級聯(lián)反應(yīng)的有效措施[111]。

在不同疾病中，相應(yīng)的炎癥因子體系之間的級聯(lián)反應(yīng)各異，級聯(lián)關(guān)系復(fù)雜，且炎癥因子種類及其相應(yīng)水平各異，尤其在動物疾病領(lǐng)域幾乎沒有炎癥指標(biāo)體系，同時無法確定在特定疾病SIRS病理過程中關(guān)鍵的炎性因子樞紐與靶點，所以藥物干預(yù)是寬泛的。這提示從炎癥發(fā)生角度看待動物疾病將是動物疾病研究的新領(lǐng)域，能夠作為動物群體性疾病預(yù)防的一個新啟示，從動物機體自身的穩(wěn)定調(diào)解入手解決動物疾病問題，彌補不足。盡管現(xiàn)有關(guān)于中藥干預(yù)以炎癥為基礎(chǔ)病理的各類疾病的效果是積極的，但是尚有盲目性和不全面性，但是就目前研究資料來看，結(jié)合中醫(yī)中藥理論作指導(dǎo)，以炎癥理論為研究基礎(chǔ)，對從炎癥角度闡述疾病本質(zhì)、防治各類疾病具有積極意義，同時在畜牧養(yǎng)殖實踐中，黃芩、黃芪等清熱解毒、補中益氣中藥是常用的中藥預(yù)混劑，但所起作用往往被認(rèn)為是通過提高機體免疫力產(chǎn)生的，忽視動物機體本身對致病因素的反應(yīng)性。因此，在生產(chǎn)實踐中使用中藥提高機體應(yīng)激時的穩(wěn)態(tài)保持能力，是具備一定實際價值的。

6 展 望

通常認(rèn)為炎癥是疾病的基本病理過程，是臨床表現(xiàn)的重要病因之一。炎癥水平與許多疾病發(fā)生發(fā)展程度相關(guān)，炎癥相關(guān)因子具有極其重要的推動作用及指示意義。血管反應(yīng)是炎癥的核心過程，多種細(xì)胞以及活性分子參與其中，機體通過血管反應(yīng)激活并釋放活性細(xì)胞及分子，對靶器官產(chǎn)生生物活性，積極維持生命穩(wěn)態(tài)。炎癥以有限度地綜合性協(xié)調(diào)方式表現(xiàn)出防御作用，當(dāng)炎癥反應(yīng)持續(xù)或者超限便產(chǎn)生疾病。所以，干預(yù)炎癥的發(fā)生，以及控制炎癥的發(fā)展程度對于疾病的預(yù)防以及控制具有積極意義，盲目抗炎可能不利于疾病的治療。

炎癥是綜合的病理過程。巨噬細(xì)胞對炎癥的啟動具有十分重要的作用，是經(jīng)典的炎癥細(xì)胞，也是重要抗原提呈細(xì)胞。炎癥的發(fā)展方向與Th等免疫細(xì)胞功能與數(shù)量緊密相關(guān)，炎癥產(chǎn)物往往也成為發(fā)動免疫反應(yīng)的抗原提呈物，免疫反應(yīng)甚至是炎癥反應(yīng)的后續(xù)結(jié)果及外延，二者相互關(guān)聯(lián)。炎癥表現(xiàn)是眾多復(fù)雜的相關(guān)細(xì)胞與分子結(jié)成網(wǎng)絡(luò)，并相互作用的結(jié)果。炎癥反應(yīng)中各種因素的生物活性不同，與疾病種類、致病因子、內(nèi)環(huán)境等因素密切相關(guān)。NF-κb、TNF-α等經(jīng)典炎癥因子的表達(dá)水平被認(rèn)為是能夠指示炎癥發(fā)生發(fā)展程度的重要指標(biāo)，但許多研究將二者進(jìn)行統(tǒng)計學(xué)關(guān)聯(lián)，前者對后者的指示作用僅具有統(tǒng)計學(xué)意義，沒有詳細(xì)闡述炎癥相關(guān)分子間協(xié)調(diào)關(guān)系，以及標(biāo)準(zhǔn)量化。因此，以炎癥因子網(wǎng)絡(luò)、功能調(diào)節(jié)方向為對象，展開炎癥分子水平干預(yù)，炎癥指標(biāo)體系建立等系統(tǒng)性研究更具有實踐指導(dǎo)意義。

中國傳統(tǒng)醫(yī)學(xué)對于疾病有獨特的見解，學(xué)術(shù)界雖以其缺乏客觀可見性而尚存異議，但許多現(xiàn)代研究表明，中藥通過協(xié)調(diào)炎癥因子水平與功能能夠治療與緩解疾病。這提示以中藥為紐帶，借鑒中醫(yī)“扶正祛邪、辨證施治”的治療思想對炎癥，以及炎癥相關(guān)疾病的研究或許具有一定的指導(dǎo)意義。綜上，關(guān)于炎癥的研究不能夠孤立地進(jìn)行，對于疾病本質(zhì)的研究要具有整體觀。

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(責(zé)任編輯：郭柏壽 Responsible editor:GUO Baishou)

Inflammatory Nature of Disease and Intervention by the Traditional Chinese Medicine

ZHANG Hanyuan1, ZHANG Xiuying1and SHI Luyi2

(1. College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; 2. Wildlife Research Institute of Heilongjiang Province, Harbin 150081, China)

The inflammation is a primary pathological process involved in the progression and prognosis of various diseases. There are numerous studies on inflammation in the human medical field, but it is rarely reported in the field of veterinary. This article summarized recently reports about inflammation and the intervention of the traditional Chinese medicine (TCM) in five aspects:TCM inhibits the inflammation by suppressing or even blocking the transmission of inflammatory signals in each step of the signaling pathway.TCM influences the progression of inflammation by regulating the expression of various inflammatory cytokines.TCM protects cells from damage of peroxidation in the development of inflammation via inhibiting the formation of oxidation products.TCM influences the occurrence and development of inflammation by adjusting the inflammatory homeostasis.TCM prevents the occurrence and progression of SIRS by adjusting the interactions between inflammatory cytokines. Based on the correlation between diseases and inflammation, and the reports about the effect of TCM on inflammation, this article reviewed the significant role of inflammation in various diseases, and provided clue and evidence for the inflammatory intervention method by which to prevent and cure the diseases associated with inflammation.

Inflammation; Inflammatory nature; Inflammatory intervention; Traditional Chinese medicine

ZHANG Hanyuan, male，doctoral student. Research area:veterinary pharmacology and toxicology.E-mail:mjoiner@163.com

ZHANG Xiuying, female, professor,doctoral supervisor. Research area:veterinary pharmacology and toxicology.E-mail:zhangxiuying@neau.edu.cn

2016-04-15

2016-06-07

黑龍江重點基金(ZD201405)。

張瀚元，男，博士研究生，研究方向為獸醫(yī)藥理毒理學(xué)。E-mail:mjoiner@163.com

張秀英，女，教授，博士生導(dǎo)師，研究方向為獸醫(yī)藥理毒理學(xué)。E-mail:zhangxiuying@neau.edu.cn

日期：2016-12-20

S859.7

A

1004-1389(2017)01-0001-13

網(wǎng)絡(luò)出版地址：http://www.cnki.net/kcms/detail/61.1220.S.20161220.1640.002.html

Received 2016-04-15 Returned 2016-06-07

Foundation item Provincial Key Fund Project of Heilongjiang(No.ZD201405).