血清高遷移率族蛋白1與急性胰腺炎嚴(yán)重程度相關(guān)性研究

蘆照青 任愛民 王紅 張淑文 文艷 杜琨 黃光偉

·論著·

血清高遷移率族蛋白1與急性胰腺炎嚴(yán)重程度相關(guān)性研究

蘆照青 任愛民 王紅 張淑文 文艷 杜琨 黃光偉

目的觀察急性胰腺炎(AP)患者血清高遷移率族蛋白1(high mobility group box chromosomal protein-1，HMGB1)的水平，探討HMGB1水平與AP嚴(yán)重程度的相關(guān)性。方法收集62例患者入院即刻及入院后24、48 h血標(biāo)本，應(yīng)用ELISA方法檢測血清HMGB1水平，并分析其與AP病情嚴(yán)重程度的相關(guān)性。以20例健康成年人作為對照組。結(jié)果62例AP患者入院即刻及入院后24、48 h血清HMGB1水平分別為(8.05±1.60)、(8.04±1.39)、(8.25±1.56)ng/ml，均顯著高于對照組的(2.20±0.57)mg/ml(P值均<0.01)。其中重癥急性胰腺炎(SAP)35例，輕癥急性胰腺炎(MAP)27例。SAP組患者血清HMGB1水平分別為(7.99±1.69)、(8.12±1.40)、(8.13±1.34)ng/ml；MAP組患者為(8.12±1.52)、(7.92±1.40)、 (8.39±1.81)ng/ml。兩組間差異無統(tǒng)計學(xué)意義。結(jié)論AP患者的血清HMGB1水平顯著高于正常人群，但其與AP的嚴(yán)重程度無平行關(guān)系。

胰腺炎； 高遷移率族蛋白質(zhì)類； 病例對照研究

材料和方法

一、臨床資料

研究對象為2008年3月至2009年2月北京友誼醫(yī)院收治的62例AP患者，其中男33例(53.2%),女29例(46.8%)，年齡(55±17)歲。均在發(fā)病后72 h內(nèi)入院，發(fā)病至入院的平均間隔時間為(34±20)h?；颊呷朐杭纯碳叭朐汉?4、48 h分別取血清樣本，于-80℃凍存待檢。

AP的診斷標(biāo)準(zhǔn)：患者存在明確的臨床癥狀、體征及影像學(xué)表現(xiàn)，血淀粉酶至少高于正常上限的3倍。根據(jù)我國2007年發(fā)布的《重癥急性胰腺炎診治指南》[2]，將AP患者分為SAP及輕癥急性胰腺炎(MAP)兩組，MAP患者27例，SAP患者35例。排除標(biāo)準(zhǔn)：住院時間不足24 h；近1周有手術(shù)史；發(fā)病前1月內(nèi)有嚴(yán)重感染；ERCP術(shù)后胰腺炎。入院后均給予抑酶、抑酸、抗感染等常規(guī)非手術(shù)治療。

另選取健康成年人20例作為對照組，其中男12例(60%)，女8例(40%)，年齡(42±17)歲。

二、血清HMGB1水平測定

血清HMGB1水平應(yīng)用ELISA方法測定，試劑盒購自美國ALD公司，按說明書操作。本法組內(nèi)差異<5%，組間差異<10%，敏感度0.01 ng/ml。

三、統(tǒng)計方法

結(jié) 果

一、一般資料

MAP與SAP患者的性別比、病因、發(fā)病至入院間隔時間、基礎(chǔ)疾病、復(fù)發(fā)病例等均無顯著性差異。但SAP組患者年齡、APACHEⅡ評分、Ranson評分、Balthazar CT分級及并發(fā)癥發(fā)生率均顯著高于MAP組(P值均<0.01，表1)。

二、AP患者血清HMGB1水平

入院即刻及入院后24、48 h時AP患者血清HMGB1水平分別為(8.05±1.60)、(8.04±1.39)、(8.25±1.56)ng/ml，均較健康對照組的(2.20±0.57)ng/ml顯著增高(P值均=0.000)。

其中SAP組患者血清HMGB1水平分別為(7.99±1.69)、(8.12±1.40)、(8.13±1.34)ng/ml；MAP組分別為(8.12±1.52)、(7.92±1.40)、(8.39±1.81)ng/ml。兩組間差異無統(tǒng)計學(xué)意義(P=0.77、0.62、0.53)。

表1 兩組AP患者的一般臨床資料比較

注：與MAP組比較，aP<0.01

討 論

HMGB1是一種存在于細(xì)胞核內(nèi)的非組蛋白的核蛋白，具有晚期炎癥因子作用[3]。在膿毒癥及其他炎性疾病中血清HMGB1水平亦顯著升高[4-9]。動物實驗結(jié)果表明，急性壞死性胰腺炎(ANP)大鼠血清HMGB1水平在建模后12 h開始明顯升高，至建模后48 h仍維持在高水平，且與大鼠胰腺組織HMGB1 mRNA表達(dá)水平呈平行關(guān)系[10-11]。應(yīng)用HMGB1聯(lián)合?；悄懰徕c逆行注射大鼠胰管可明顯增加胰腺壞死[12]，但臨床數(shù)據(jù)與動物實驗結(jié)果并不一致。Sundén-Cullberg等[13]報道，膿毒癥患者血清HMGB1水平與感染的嚴(yán)重程度并無相關(guān)性，病死組患者血清HMGB1甚至顯著性降低。van Zoelen等[10]結(jié)果與其一致。Angus等[11]報道，社區(qū)獲得性肺炎患者血清HMGB1水平與有無膿毒癥無相關(guān)性。Yasuda等[14]報道，SAP患者血清HMGB1水平較正常人明顯增高，但其與APACHEⅡ評分、Ranson評分并無相關(guān)性，且發(fā)生臟器衰竭、感染或病死患者血清HMGB1水平較其他SAP患者并無顯著增高，提示其與疾病的嚴(yán)重程度并不呈明顯平行關(guān)系。沈美琴等[15]報道，SAP患者血清HMGB1水平明顯高于MAP者，MAP者又明顯高于健康對照組，提示HMGB1水平與AP嚴(yán)重程度相關(guān)。本研究顯示，AP患者血清HMGB1水平較正常人顯著增高，但SAP組與MAP組患者血清HMGB1水平無顯著性差異，提示HMGB1水平與AP的嚴(yán)重程度并無平行關(guān)系。因此，HMGB1在AP中的作用究竟如何，是否具有臨床意義，尚需更大規(guī)模的臨床研究數(shù)據(jù)加以論證。

[1] Goodwin GH,Sanders C,Johns EW.A new group of chromatin-associated proteins with a high content of acidic and basic amino acids.Eur J Biochem,1973,38:14-19.

[2] 中華醫(yī)學(xué)會外科學(xué)分會胰腺外科學(xué)組. 重癥急性胰腺炎診治指南.中華外科雜志,2007,45:727-729.

[3] Wang H,Bloom O,Zhang M,et al.HMG-1 as a late mediator of endotoxin lethality in mice.Science,1999,285:248-251.

[4] Lutz W,Stetkiewicz J.High mobility group box 1 protein as a late-acting mediator of acute lung inflammation.Int J Occup Med Environ Health,2004,17:245-254.

[5] Abraham E,Arcaroli J,Carmody A,et al.HMG-1 as a mediator of acute lung inflammation.J Immunol,2000,165:2950-2954.

[6] Ueno H,Matsuda T,Hashimoto S,et al.Contributions of high mobility group box protein in experimental and clinical acute lung injury.Am J Respir Crit Care Med,2004,170:1310-1316.

[7] Taniguchi N,Kawahara K,Yone K,et al.High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine.Arthritis Rheum,2003,48:971-981.

[8] Kokkola R,Sundberg E,Ulfgren AK,et al.High mobility group box chromosomal protein 1:a novel proinflammatory mediator in synovitis.Arthritis Rheum,2002,46:2598-2603.

[9] Ombrellino M,Wang H,Ajemian MS,et al.Increased serum concentrations of high-mobility-group protein 1 in haemorrhagic shock.Lancet,1999,354:1446-1447.

[10] van Zoelen MA,Laterre PF,van Veen SQ,et al.Systemic and local high mobility group box 1 concentrations during severe infection.Crit Care Med,2007,35:2799-804.

[11] Angus DC,Yang L,Kong L,et al.Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis.Crit Care Med,2007,35:1061-1067.

[12] 楊智勇,王春友,熊炯炘，等.重癥急性胰腺炎大鼠血清高遷移率族蛋白-1水平的時相變化及意義.華中科技大學(xué)學(xué)報(醫(yī)學(xué)版),2004,33:466-468.

[13] Sundén-Cullberg J,Norrby-Teglund A,Rouhiainen A,et al.Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock.Crit Care Med,2005,33:564-573.

[14] Yasuda T,Ueda T,Takeyama Y,et al.Significant increase of serum high-mobility group box chromosomal protein 1 levels in patients with severe acute pancreatitis.Pancreas,2006,33:359-363.

[15] 沈美琴，夏敏.急性胰腺炎患者血清高遷移率族蛋白B1水平的變化及意義.中華胰腺病雜志，2010,10:312-314.

2010-08-24)

(本文編輯：屠振興)

Therelationshipbetweenserumhighmobilitygroupboxchromosomalprotein-1levelsandtheseverityofacutepqncreatitis

LUZhao-qing,RENAi-min,WANGHong,ZHANGShu-wen,WENYan,DUKun,HUANGGuang-wei.

DepartmentofEmergencyMedicine,BeijingFriednessHospital,CapitalMedicalUnivesity,Beijing100050,China

RENAi-min,Email:julie444@126.com

ObjectiveTo investigate the high mobility group box chromosomal protein-1 (HMGB1) levels in patients with acute pancreatitis (AP); and to study the relationship between the serum level of HMGB1 and the severity of AP.MethodsThe patients′ serum HMGB1 concentrations were determined right after admission, 24, 48 hour after admission. The levels of HMGB1 were measured by ELASA kit and its relationship with the severity of AP was analyzed. 20 healthy adults were treated as the control group.ResultsAt the time of admission, and 24, 48 hours after admission, the serum HMGB1 levels in AP patients were (8.05±1.60), (8.04±1.39), (8.25±1.56)ng/ml, respectively, which were significantly higher than that in the healthy control [(2.20±0.57)ng/ml,P<0.01]. There were 35 patients with severe acute pancreatitis (SAP) and 27 patients with mild acute pancreatitis (MAP). The HMBG1 levels in patients with SAP were (7.99±1.69),(8.12±1.40), (8.13±1.34)ng/ml, and they were (8.12±1.52), (7.92±1.40), (8.39±1.81)ng/ml in patients with MAP, and the difference between the two groups was not statistically significant.ConclusionsThe serum HMGB1 level in AP patients was significantly higher than that in healthy controls, but it was not related with the severity of AP.

Pancreatitis; High mobility group proteins; CaseK-control studies

目前認(rèn)為，重癥急性胰腺炎(SAP)的發(fā)病有多種炎癥因子的參與。高遷移率族蛋白1(high mobility group box chromosomal protein-1，HMGB1)是在30年前發(fā)現(xiàn)的非組蛋白的核蛋白[1]。1999年首次發(fā)現(xiàn)其在膿毒癥中具有晚期炎癥介質(zhì)作用。進(jìn)一步動物實驗顯示，HMGB1在SAP的發(fā)生、發(fā)展中發(fā)揮重要作用。本研究觀察AP患者血清HMGB1水平，探討其與疾病嚴(yán)重程度是否存在相關(guān)性。

10.3760/cma.j.issn.1674-1935.2011.04.002

北京市中醫(yī)局5151工程項目

100050 北京，首都醫(yī)科大學(xué)附屬北京友誼醫(yī)院感染暨急救醫(yī)學(xué)科

任愛民，Email: julie444@126.com