葉雪飛，左春龍，梅虹霞，蘇穎，楊建平

（1.蘇州大學(xué)附屬第一醫(yī)院 麻醉科，江蘇 蘇州 215006；2.溫州醫(yī)科大學(xué)附屬第二醫(yī)院麻醉科，浙江 溫州 325000）

丙泊酚對(duì)小膠質(zhì)細(xì)胞炎癥因子的影響及其機(jī)制研究*

葉雪飛1，左春龍2，梅虹霞2，蘇穎2，楊建平1

（1.蘇州大學(xué)附屬第一醫(yī)院 麻醉科，江蘇 蘇州 215006；2.溫州醫(yī)科大學(xué)附屬第二醫(yī)院麻醉科，浙江 溫州 325000）

目的探討丙泊酚對(duì)小膠質(zhì)細(xì)胞炎癥因子的影響及其機(jī)制。方法將小膠質(zhì)BV-2細(xì)胞分為對(duì)照組、丙泊酚組、脂多糖（LPS）組、LPS+丙泊酚組，對(duì)照組細(xì)胞加入PBS液，丙泊酚組細(xì)胞加入丙泊酚30μmol/L，LPS組細(xì)胞加入LPS 1μg/ml，LPS+丙泊酚組細(xì)胞加入丙泊酚30μmol/L+LPS 1μg/ml。采用MTT比色實(shí)驗(yàn)測定細(xì)胞活性，采用酶聯(lián)免疫吸附法測定細(xì)胞上清液中白細(xì)胞介素1β（IL-1β）、白細(xì)胞介素6（IL-6）、腫瘤壞死因子-α（TNF-α）水平，采用逆轉(zhuǎn)錄-聚合酶鏈反應(yīng)測定細(xì)胞p38MAPK和TLR4 mRNA的表達(dá)，采用Western blot檢測細(xì)胞p38MAPK和TLR4蛋白表達(dá)量。結(jié)果LPS組和LPS+丙泊酚組小膠質(zhì)細(xì)胞活性低于對(duì)照組和丙泊酚組（P＜0.05），LPS+丙泊酚組小膠質(zhì)細(xì)胞活性高于LPS組（P＜0.05）；LPS組和LPS+丙泊酚組小膠質(zhì)細(xì)胞上清液中IL-1β、IL-6、TNF-α水平高于對(duì)照組和丙泊酚組（P＜0.05），LPS+丙泊酚組小膠質(zhì)細(xì)胞上清液中IL-1β、IL-6、TNF-α水平低于LPS組（P＜0.05）；LPS組和LPS+丙泊酚組小膠質(zhì)細(xì)胞p38MAPK、TLR4 mRNA和蛋白表達(dá)量高于對(duì)照組和丙泊酚組（P＜0.05），LPS+丙泊酚組小膠質(zhì)細(xì)胞p38MAPK、TLR4 mRNA和蛋白表達(dá)量低于LPS組（P＜0.05）；丙泊酚組和對(duì)照組小膠質(zhì)細(xì)胞各指標(biāo)比較，差異無統(tǒng)計(jì)學(xué)意義（P＞0.05）。結(jié)論丙泊酚能抑制小膠質(zhì)細(xì)胞過度活化和炎癥反應(yīng)，其機(jī)制可能與丙泊酚可下調(diào)TLR4-p38MAPK信號(hào)通路有關(guān)。

丙泊酚；小膠質(zhì)細(xì)胞；炎癥因子。

術(shù)后認(rèn)知功能障礙表現(xiàn)為術(shù)后認(rèn)知功能下降、行為障礙、語言缺失等，是老年人術(shù)后常見的并發(fā)癥之一，使患者康復(fù)延遲，醫(yī)療費(fèi)用和住院天數(shù)增加，病死率升高[1]。術(shù)后認(rèn)知功能障礙的發(fā)生與炎癥因子介導(dǎo)的神經(jīng)炎癥關(guān)系密切[2]，小膠質(zhì)細(xì)胞活化誘導(dǎo)的炎癥反應(yīng)在術(shù)后認(rèn)知功能障礙的發(fā)生中具有重要作用[3-4]。因此，防止小膠質(zhì)細(xì)胞誘導(dǎo)的炎癥反應(yīng)對(duì)預(yù)防術(shù)后認(rèn)知功能障礙具有重要意義。本文就丙泊酚對(duì)小膠質(zhì)細(xì)胞炎癥因子的影響進(jìn)行研究，并探討其可能機(jī)制，為臨床治療提供依據(jù)。

1 材料與方法

1.1 實(shí)驗(yàn)材料

小膠質(zhì)BV-2細(xì)胞（中國科學(xué)院基礎(chǔ)醫(yī)學(xué)細(xì)胞中心），丙泊酚、脂多糖（Lipopolysaccharide，LPS）購自美國Sigma公司，MTT試劑盒、PCR試劑盒、小牛血清、DMEM培養(yǎng)基購自美國Gibco公司，兔抗鼠p38MAPK抗體、兔抗鼠TLR4抗體等購自美國Santa Cruz公司。

1.2 方法

1.2.1 小膠質(zhì)BV-2細(xì)胞培養(yǎng)將小膠質(zhì)BV-2細(xì)胞接種到DMEM高糖培養(yǎng)基（含100μ/ml鏈霉素、100μ/ml青霉素和10%新生牛血清）中培養(yǎng)，換液1次/48 h，2～3d傳代1次，傳代2次取生長良好的細(xì)胞用于實(shí)驗(yàn)研究。

1.2.2 小膠質(zhì)BV-2細(xì)胞分組將小膠質(zhì)BV-2細(xì)胞分為對(duì)照組、丙泊酚組、LPS組、LPS+丙泊酚組。對(duì)照組細(xì)胞加入PBS液，丙泊酚組細(xì)胞加入丙泊酚30μmol/L，LPS組細(xì)胞加入LPS 1μg/ml，LPS+丙泊酚組細(xì)胞加入丙泊酚30μmol/L+LPS 1μg/ml，每組取8個(gè)樣本，培養(yǎng)24 h。

1.2.3 細(xì)胞活性測定將對(duì)數(shù)生長的細(xì)胞制成單細(xì)胞懸液，接種到96孔板（5×103個(gè)細(xì)胞/孔）中培養(yǎng)，細(xì)胞貼壁后用無血清培養(yǎng)基培養(yǎng)24 h，采用MTT比色實(shí)驗(yàn)測定24 h時(shí)各組小膠質(zhì)BV-2細(xì)胞的活性，小膠質(zhì)BV-2細(xì)胞活性（%）=干預(yù)組OD值/對(duì)照組OD值×100%。各組細(xì)胞干預(yù)后24 h取上清液，采用酶聯(lián)免疫吸附法測定上清液中白細(xì)胞介素1β（Interleukin-1β，IL-1β）、白細(xì)胞介素6（Interleukin-6，IL-6）、腫瘤壞死因子-α（tumor necrosis factor-α，TNF-α）水平。

1.2.4 p38MAPK和TLR4 mRNA表達(dá)量測定各組細(xì)胞干預(yù)24 h后，提取細(xì)胞總RNA，以GADPH作為內(nèi)參照，采用逆轉(zhuǎn)錄-聚合酶鏈反應(yīng)（reverse transcription-polymerase chain reaction，RT-PCR） 測定各組小膠質(zhì)細(xì)胞p38MAPK和TLR4 mRNA的表達(dá)，PCR反應(yīng)條件：95℃預(yù)變性4 min，95℃變性30 s，55℃退火60 s，72℃延伸60 s，共42個(gè)循環(huán)，72℃繼續(xù)延伸5 min。每個(gè)樣本設(shè)8個(gè)復(fù)孔，RT-PCR結(jié)果以CT代表，以2-ΔΔCT作為目的基因的相對(duì)表達(dá)量，2-ΔΔCT=各組小膠質(zhì)BV2細(xì)胞目的基因表達(dá)量/對(duì)照組細(xì)胞目的基因表達(dá)量。

1.2.5 p38MAPK和TLR4蛋白表達(dá)量測定各組細(xì)胞干預(yù)24 h后，采用Western blot檢測各組細(xì)胞p38MAPK和TLR4 蛋白表達(dá)量，用Bradford測定各組細(xì)胞總蛋白濃度，取10μl蛋白樣品進(jìn)行電泳，用脫脂奶粉封閉，分別加入p38MAPK和TLR4一抗孵育過夜，加入二抗孵育2 h，加入ECL顯色，X線下曝光，采用Quantity One圖像分析系統(tǒng)測定各組細(xì)胞p38MAPK和TLR4蛋白的灰度值。

1.3 統(tǒng)計(jì)學(xué)方法

數(shù)據(jù)分析采用SPSS 20.0統(tǒng)計(jì)軟件，計(jì)量資料以均數(shù)±標(biāo)準(zhǔn)差（±s）表示，用方差分析，兩兩比較用LSD-t檢驗(yàn)，P＜0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 各組小膠質(zhì)細(xì)胞活性比較

對(duì)照組、丙泊酚組、LPS組和LPS+丙泊酚組小膠質(zhì)細(xì)胞活性分別為（100.00±0.01）%、（103.24±1.57）%、（38.69±11.05）% 和（64.37± 14.26）%，經(jīng)方差分析，差異有統(tǒng)計(jì)學(xué)意義（F=109.426，P=0.000）。進(jìn)一步兩兩比較經(jīng)LSD-t檢驗(yàn)，LPS組和LPS+丙泊酚組小膠質(zhì)細(xì)胞活性均低于對(duì)照組和丙泊酚組（P＜0.05），LPS+丙泊酚組小膠質(zhì)細(xì)胞活性高于LPS組（P＜0.05）。

2.2 各組小膠質(zhì)細(xì)胞上清液中IL-1β、IL-6、TNF-α含量比較

對(duì)照組、丙泊酚組、LPS組和LPS+丙泊酚組的IL-1β、IL-6、TNF-α水平比較，經(jīng)方差分析，差異有統(tǒng)計(jì)學(xué)意義（P＜0.05）。進(jìn)一步兩兩比較經(jīng)LSD-t檢驗(yàn)，LPS組和LPS+丙泊酚組小膠質(zhì)細(xì)胞上清液中IL-1β、IL-6、TNF-α水平均高于對(duì)照組和丙泊酚組（P＜0.05），LPS+丙泊酚組小膠質(zhì)細(xì)胞上清液中IL-1β、IL-6、TNF-α水平低于LPS組（P＜0.05）。見表1。

2.3 各組小膠質(zhì)細(xì)胞p38MAPK和TLR4 mRNA表達(dá)量比較

對(duì)照組、丙泊酚組、LPS組和LPS+丙泊酚組小膠質(zhì)細(xì)胞p38MAPK和TLR4 mRNA表達(dá)量比較，經(jīng)方差分析，差異有統(tǒng)計(jì)學(xué)意義（P＜0.05）。進(jìn)一步兩兩比較經(jīng)LSD-t檢驗(yàn)，LPS組和LPS+丙泊酚組小膠質(zhì)細(xì)胞p38MAPK和TLR4 mRNA表達(dá)量均高于對(duì)照組和丙泊酚組（P＜0.05），LPS+丙泊酚組小膠質(zhì)細(xì)胞p38MAPK和TLR4 mRNA表達(dá)量低于LPS組（P＜0.05）。見表2。

2.4 各組小膠質(zhì)細(xì)胞p38MAPK和TLR4蛋白表達(dá)量比較

對(duì)照組、丙泊酚組、LPS組和LPS+丙泊酚組小膠質(zhì)細(xì)胞p38MAPK和TLR4 蛋白表達(dá)量比較，經(jīng)方差分析，差異有統(tǒng)計(jì)學(xué)意義（P＜0.05）。進(jìn)一步兩兩比較經(jīng)LSD-t檢驗(yàn)，LPS組和LPS+丙泊酚組小膠質(zhì)細(xì)胞p38MAPK和TLR4 蛋白表達(dá)量均高于對(duì)照組和丙泊酚組（P＜0.05），LPS+丙泊酚組小膠質(zhì)細(xì)胞p38MAPK和TLR4 蛋白表達(dá)量低于LPS組（P＜0.05）。見表3。

表1 各組小膠質(zhì)細(xì)胞上清液中IL-1β、IL-6、TNF-α含量比較 （pg/ml，±s）

表1 各組小膠質(zhì)細(xì)胞上清液中IL-1β、IL-6、TNF-α含量比較 （pg/ml，±s）

注：1）與對(duì)照組比較，P ＜0.05；2）與丙泊酚組比較，P ＜0.05；3）與LPS組比較，P ＜0.05

組別 IL-1β IL-6 TNF-α對(duì)照組 43.26±4.73 158.35±8.79 182.32±5.47丙泊酚組 44.18±5.02 163.24±9.01 179.35±5.38 LPS組 176.48±7.621）2） 412.53±15.471）2） 532.14±16.581）2）LPS+丙泊酚組 121.43±6.371）2）3）297.58±12.431）2）3）378.43±13.241）2）3）F值 218.647 995.463 1 170.324 P值 0.000 0.000 0.000

表2 各組小膠質(zhì)細(xì)胞p38MAPK和TLR4 mRNA表達(dá)量比較 （±s）

表2 各組小膠質(zhì)細(xì)胞p38MAPK和TLR4 mRNA表達(dá)量比較 （±s）

注：1）與對(duì)照組比較，P ＜0.05；2）與丙泊酚組比較，P ＜0.05；3）與LPS組比較，P ＜0.05

組別 p38MAPK mRNA TLR4 mRNA對(duì)照組 1.00±0.02 1.00±0.01丙泊酚組 0.98±0.03 1.01±0.02 LPS組 6.45±0.761）2） 6.87±0.821）2）LPS+丙泊酚組 3.24±0.471）2）3） 3.54±0.631）2）3）F值 231.523 241.264 P值 0.000 0.000

表3 各組小膠質(zhì)細(xì)胞p38MAPK和TLR4 蛋白表達(dá)量比較 （±s）

表3 各組小膠質(zhì)細(xì)胞p38MAPK和TLR4 蛋白表達(dá)量比較 （±s）

注：1）與對(duì)照組比較，P ＜0.05；2）與丙泊酚組比較，P ＜0.05；3）與LPS組比較，P ＜0.05

組別 p38MAPK 蛋白 TLR4 蛋白對(duì)照組 0.26±0.03 0.37±0.04丙泊酚組 0.24±0.04 0.41±0.02 LPS組 0.97±0.121）2） 1.32±0.171）2）LPS+丙泊酚組 0.62±0.081）2）3） 0.82±0.151）2）3）F值 192.325 213.276 P值 0.000 0.000

3 討論

小膠質(zhì)細(xì)胞占10%～20%中樞神經(jīng)系統(tǒng)細(xì)胞，是中樞神經(jīng)系統(tǒng)內(nèi)主要的免疫效應(yīng)細(xì)胞，在炎癥反應(yīng)中發(fā)揮主導(dǎo)作用，小膠質(zhì)細(xì)胞為大腦的第一道防線，具有保護(hù)大腦免受病原體入侵和損傷的作用[5-6]，并可清除細(xì)胞碎片，維持腦內(nèi)穩(wěn)態(tài)，但過度、持續(xù)活化的小膠質(zhì)細(xì)胞分泌IL-1β、IL-6、TNF-α等促炎因子，對(duì)神經(jīng)元有損傷作用[7]，在中樞神經(jīng)系統(tǒng)炎癥損傷性疾病中具有重要作用。ZHOU等[8]研究發(fā)現(xiàn)，大腦中動(dòng)脈缺血再灌注可引起大腦區(qū)域梗死，小膠質(zhì)細(xì)胞活化可釋放大量炎癥因子，在大腦中動(dòng)脈缺血再灌注前給予丙泊酚可減少大腦梗死面積，降低小膠質(zhì)細(xì)胞釋放的炎癥因子水平。PEI等[9]研究發(fā)現(xiàn)，LPS可誘導(dǎo)外周血單核細(xì)胞產(chǎn)生IL-1β、IL-6、TNF-α、NO等炎癥因子的釋放，丙泊酚可抑制外周血單核細(xì)胞釋放炎癥因子，具有抗炎作用。本研究結(jié)果發(fā)現(xiàn)，LPS可降低小膠質(zhì)細(xì)胞的活性，增加小膠質(zhì)細(xì)胞IL-1β、IL-6、TNF-α水平，丙泊酚可增加LPS干預(yù)小膠質(zhì)細(xì)胞活性，降低小膠質(zhì)細(xì)胞IL-1β、IL-6、TNF-α水平，可見丙泊酚能降低小膠質(zhì)細(xì)胞活性，降低活化小膠質(zhì)細(xì)胞炎癥因子水平，通過抗炎作用發(fā)揮對(duì)神經(jīng)的保護(hù)作用。

TLR4可介導(dǎo)小膠質(zhì)細(xì)胞的活化，引起大量促炎因子的釋放，從而損傷神經(jīng)系統(tǒng)[10-11]。TLR4激活后通過2種下游途徑傳遞信號(hào)：髓樣分化因子88依賴性通道和含TIR結(jié)構(gòu)域受體介導(dǎo)的干擾素β通道。LU等[12]研究發(fā)現(xiàn)，小鼠脛骨骨折后出現(xiàn)認(rèn)知功能下降，并伴有TLR4/MyD88升高。WANG等[13]研究發(fā)現(xiàn)，大鼠脾切除術(shù)后早期出現(xiàn)認(rèn)知功能下降，并伴有TLR4水平升高，表達(dá)TLR4的小膠質(zhì)細(xì)胞及炎癥因子水平增加，表明小膠質(zhì)細(xì)胞上TLR4信號(hào)激活可能是術(shù)后認(rèn)知功能障礙的潛在機(jī)制。P38MAPK是調(diào)節(jié)小膠質(zhì)細(xì)胞釋放促炎因子TLR4誘導(dǎo)的下游信號(hào)通路[14-15]。ZHOU等[16]研究證實(shí)，丙泊酚可通過TLR4/p38MAPK信號(hào)通路，發(fā)揮對(duì)脊髓星形膠質(zhì)細(xì)胞釋放炎癥因子的抑制作用。

綜上所述，小膠質(zhì)細(xì)胞受LPS干預(yù)后，p38MAPK、TLR4 mRNA和蛋白表達(dá)量升高，丙泊酚可降低LPS干預(yù)后小膠質(zhì)細(xì)胞p38MAPK、TLR4 mRNA和蛋白表達(dá)量。由此可見，丙泊酚對(duì)小膠質(zhì)細(xì)胞炎癥反應(yīng)的抑制作用可能與丙泊酚下調(diào)TLR4/ p38MAPK信號(hào)通路有關(guān)。

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Effect of Propofol on in flammatory cytokines in microglia and its mechanism*

Xue-fei Ye1, Chun-long Zuo2, Hong-xia Mei2, Ying Su2, Jian-ping Yang1
(1.department of Anesthesiology, the First Aff i liated Hospital of Suzhou University, Suzhou, Jiangsu 215006, China; 2.department of Anesthesiology, the Second Aff i liated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China)

ObjectiveTo investigate the effect of Propofol on inflammatory cytokines in microglia and its mechanism.MethodsMicroglial BV-2 cells weredivided into control group, Propofol group, lipopolysaccharide (LPS) group, and LPS+Propofol group. The cells of the control group were added with PBS. The cells of the Propofol group were added with 30 μmol/L Propofol. The cells of the LPS group were treated with 1 μg/ml LPS. The cells of the LPS+Propofol group were added with 30 μmol/L Propofol and 1 μg/ml LPS. The cell viability wasdetermined by MTT colorimetric assay. The levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in supernatant were measured by ELISA. The expressions of p38MAPK and TLR4 mRNAs weredetected by RT-PCR. The expressions of p38MAPK and TLR4 proteins weredetected by Western blot.ResultsThe activity of microglia in the LPS group and the LPS+Propofol group were lower than that in the control group and the Propofol group (P＜ 0.05). The activity of microglia in the LPS+Propofol group was higher than that in the LPS group (P＜ 0.05). The levels of IL-1β, IL-6 and TNF-α in the supernatant of the LPS group and the LPS+Propofol group were higher than those in the control group and the Propofol group (P＜ 0.05). The levels of IL-1β, IL-6 and TNF-α in the supernatant of the LPS+Propofol group were lower than those in the LPS group (P＜ 0.05). The mRNA and protein expressions of p38MAPK and TLR4 in the LPS group and the LPS+Propofol group were higher than those in the control group and the Propofol group (P＜ 0.05). The mRNA and protein expressions of p38MAPK and TLR4 in the LPS+Propofol group were lower than those in the LPS group (P＜ 0.05). There were no significant differences in the above indices between the Propofol group and the control group (P＞ 0.05).ConclusionsPropofol has the effect of inhibiting the hyperactivity and in flammatory response of microglia, and its mechanism may be related to thedownregulation of TLR4-p38MAPK signaling pathway.

Propofol; microglia; in flammatory factor

10.3969/j.issn.1005-8982.2018.02.006

1005-8982（2018）02-0033-04

R614

A

2016-07-31

浙江省醫(yī)藥衛(wèi)生科技計(jì)劃項(xiàng)目（No：2016KYA140）

（童穎丹 編輯）