血管生成素2在EV71感染性肺水肿中的作用研究

The exploration of the role of angiopoietin-2 in pulmonary edema induced by EV71 infection

目的观察肠道病毒71型（EV71）感染性肺水肿患儿的临床特点及血管生成素2（Ang-2）的变化，探讨Ang-2与肺水肿发生的关系。方法前瞻性序贯收集2011年5月至2013年9月滨州医学院附属医院重症监护病房（ICU）的EV71感染性肺水肿患儿（肺水肿组）和EV71感染无肺水肿患儿（非肺水肿组）各20例，以同期年龄、性别匹配的20例择期腹股沟疝手术婴幼儿作为对照组。收集患儿入ICU时的生命体征、血常规、生化、胸片、脑脊液检查等资料；取严重肺水肿患儿的肺水和血清，检测总蛋白、白蛋白、Ang-2水平[酶联免疫吸附试验（ELISA）]及其肺水／血清比值。结果肺水肿组死亡9例，非肺水肿组均存活。EV71感染患儿体温、心率、血压、白细胞计数（WBC）、血糖、肌酸激酶同工酶（CK-MB）均较对照组不同程度升高，白蛋白、氧合指数均不同程度降低。与非肺水肿组比较，肺水肿组心率、血糖、WBC升高更为显著[心率（次／rain）：181±31比146±19，t=3．397，P=0．003；血糖（mmol／L）：14．9±9．8比6．3±1．5，t=2．793，P=O．012；WBC（×109／L）：22．1±9．8比10．2±3．6，f=3．579，P=0．002]，白蛋白及氧合指数（PaOJFiO：）下降更为显著[白蛋白（叽）：33．6±5．9比42．7±2．9，f=3．258，P：0．004；Pa02／Fi02（mmHg，1mmHg=0．133kPa）：142±76比396±39，f=3．927，P=O．000]。非肺水肿组和肺水肿组脑脊液压力均明显升高，有核细胞数正常或轻中度升高，以单核细胞为主，蛋白含量正常。肺水肿组血清Ang-2水平[236．17（167．63，366．65）n#L3较对照组[19．67（8．72，33．68）ng／L3及非肺水肿组[23．46（13．28，46．77）ng／L]明显升高（均T=210，均P=0．000）。采集了8例严重肺水肿患儿的肺水，其中总蛋白、白蛋白、乳酸脱氢酶（LDH）、Ang-2均升高，肺水／血清总蛋白比值分别为0．67、1．33、1．12、0．72、0．84、0．73、1．09、1．24，肺水／血清白蛋白比值分别为0．72、1．64、0．84、0．87、1．06、0．92、1．12、1．48，肺水／血清LDH比值分别为2．33、4．45、2．89、3．61、3．40、3．72、3．37、4．13，肺水／血清Ang-2比值分别为0．98、1．10、1．17、1．05、1．20、0．92、1．03、1．17。结论EV71感染性肺水肿患儿肺水中富含蛋白，且血清及肺水中均高表达Ang-2，Ang-2可能参与肺部血管渗漏、肺水肿的发病过程。

Objective To observe the clinic character of pulmonary edema （PE） induced by enterovirns 71 （ EV71 ） and the change in angiopoietin-2 （ Ang-2 ）, and to explore the correlation between Ang-2 and PE. Methods Twenty consecutive infants with PE induced by EV71 admitted to intensive care unit （ICU） of Binzhou Medical College Affiliated Hospital from May 2011 to September 2013 were prospectively enrolled in PE group; 20 infants with similar age infected by EV71 without PE and hospitalized in ICU were enrolled as non-PE group; and 20 similar age infants suffering from selective inguinal hernia operation were served as control group. Data of infants with or without PE were collected including vital signs, complete blood count, blood biochemistry tests, chest X-ray and cerebrospinal fluid at ICU admission. Pulmonary edema liquid and serum were collected from infants suffered from severe PE by tracheal intubation. Total protein, albumin and Ang-2 [enzyme linked immunosorbent assay （ELISA） ] were determined and those of pulmonary edema liquid/serum （P/S） ratio were calculated. Results Nine infants with PE died, and all of infants without PE survived. Body temperature, heart rate, blood pressure, white blood cell count （WBC）, blood sugar and MB isoenzyme of creatine kinase （CK-MB） in EV71 infection infants were higher than those in controls, and albumin and oxygenation index （PaO2/FiO2） were lowered. Heart rate, blood sugar and WBC of infants with PE were significantly higher than those of infants without PE [ heart rate （bmp） ： 181 ± 31 vs. 146 ± 19, t= 3.397, P=0.003; blood sugar （mmol/L） ： 14.9 ± 9.8 vs. 6.3 ± 1.5, t=2.793, P=O.O12; WBC （ x 109/L） ： 22.1 ± 9.8 vs. 10.2 ± 3.6, t= 3.579, P=O.002], and serum albumin and PaO2/FiO2 of infants with PE were significantly lower ~albumin （g/L）： 33.6 ± 5.9 vs. 42.7 ± 2.9, t=3.258, P=0.004; PaO2/FiO2 （mmHg, 1 mmHg=0.133 kPa）： 142 ± 76 vs. 396 ± 39, t =3.927, P=O.O00）. Cerebrospinal fluid pressure was significantly elevated in both non-PE and PE groups, the number of nucleated cells were normal or mildly to moderately elevated, most were mononuclear cells, and proteincontent were normal. Ang-2 levels of infants with PE [ 236.17 （ 167.63, 366.65 ） ng/L 3 was higher than that of control infants [ 19.67 （8.72, 33.68） ng/Ll and infants without PE [23.46 （ 13.28, 46.77） ng/L, both T=210, both P= 0.000]. Pulmonary edema liquid was collected from 8 infants with severe PE. Total protein, albumin, lactate dehydrogenase （LDH） and Ang-2 in severe PE infants were elevated. Total protein of P/S ratio was 0.67, 1.33, 1.12, 0.72, 0.84, 0.73, 1.09, 1.24, albumin of P/S ratio was 0.72, 1.64, 0.84, 0.87, 1.06, 0.92, 1.12, 1.48, LDH of P/S ratio was 2.33, 4.45, 2.89, 3.61, 3.40, 3.72, 3.37, 4.13, and Ang-2 of P/S ratio was 0.98, 1.10, 1.17, 1.05, 1.20, 0.92, 1.03, 1.17, respectively. Conclusions Pulmonary edema liquid of infants with PE induced by EV71 infection is rich of protein, and Ang-2 level rises in serum and puhnonary edema liquid. Ang-2 may involve in pulmonary vascular leak and development of PE.