雌激素对失血性休克孕兔发生急性肺损伤的影响及其机制

摘要

Objective The paper is an attentative effort to evaluate the reaction and mechanism of estrogen on pregnant rabbits with acute lung injury caused by hemorrhagic shock. Methods Sixty pregnant New Zealand white rabbits were randomly divided into 6 groups, with 10 rabbits in each group, namely normal control group (NG group, with anesthesia only), estrogen group (E2G group, with additional estrogen injection at 60 min) and the other four hemorrhagic shock groups underwent hemorrhagic shock (i.e. E2SG, FSG, SBSG, E2SBSG group;mean blood pressure-40 mmHg(1 mmHg=0.133 kPa)by phlebotomy for 15 min. After maintenance of the pressure for 45 min, the rabbits were treated with E2(0.37 mg/kg), fructose injection(5%,2 ml/kg), the p38 mitogen-activated protein kinases(p38MAPK) inhibitor SB-203580 (2 mg/kg) or E2 plus SB-203580. Tumor necrosis factor alpha(TNF-α), interleukin-6(IL-6) were measured at different time points(0 min, 60 min, 80 min and 260 min), lung tissue methane dicarboxylic aldehyde(MDA) level, lung tissue myeloperoxidase(MOP), superoxide dismutase(SOD) activity, lung tissue dry weight/wet weight (DW/WW) value were measured after the experiment was finished, pulmonary pathology of the rabbits was observed. Result (1) Serum TNF-α level of NG group and E2SG group were not significantly different compared with the other four groups at the 0 min and 60 min. At 80 min and 260 min of experiment, serum TNF-αlevel of all the four shock groups were increased, E2SG group [(172.4±16.0) and (216.7±18.6) ng/L], FSG group [(171.6 ± 9.1) and (263.9 ± 7.8) ng/L], SBSG group [(172.8 ± 7.2) and (300.6 ± 4.8) ng/L], E2SBSG group [(167.9±4.8 )and (261.8±9.6) ng/L], and significantly higher than NG group and E2G group, separately (P<0.05). (2) Serum IL-6 level of NG group and E2SG group were not significantly different compared with the other four groups at the 0 min, 60 min and 80 min. At 260 min, the serum IL-6 level[(98.3 ± 0.9) and (110.4 ± 1.8) ng/L;(120.9 ± 2.3)and (109.8 ± 2.6) ng/L] of the four shock groups (E2SG, FSG, SBSG, E2SBSG group) were significantly higher than NG group and E2G group (P<0.05). (3) Lung tissue MDA level [(2.20± 0.12),(2.57±0.11),(3.17±0.08), (2.75±1.09) nmol/mg] and MPO activity [(4.45±0.25),(6.65±0.56),(9.55±0.30), (6.78 ± 0.11) U/mg] of the four shock groups (E2SG, FSG, SBSG, E2SBSG group) were higher than NG group and E2G group (P<0.05). (4) Lung tissue SOD activity [(51.8 ± 1.8),(40.2 ± 1.5), (30.0 ± 1.7),(41.2 ± 2.0) U/mg] was significantly higher in the four shock groups(E2SG, FSG, SBSG, E2SBSG group) compared with NG group and E2G group (P<0.05). (5) Lung tissue DW/WW value(0.143 ± 0.008, 0.127 ± 0.008, 0.109 ± 0.006, 0.125 ± 0.008) was significantly lower in the four shock groups(E2SG, FSG, SBSG, E2SBSG group) compared with NG group and E2G group (P<0.05). (6) Lung tissue of the rabbits in NG group and E2G group is basically normal without obvious pathology changes. Lung tissue pathological damage of rabbits was observed in the four shock groups, and the pathological damage of rabbits in SBSG group was most serious. Conclusion Estrogen can reduce acute lung injury of pregnant rabbits with hemorrhagic shock, the p38MAPK pathway plays a critical role in mediating the salutary effects of E2 on shock-induced acute lung injury.%目的：探讨雌激素对失血性休克孕兔发生急性肺损伤的影响及其机制。方法60只孕兔随机分为6组，每组10只，正常对照组（无任何处理）、雌激素对照组（静脉注射苯甲酸雌二醇0.37 mg/kg），以下4组孕兔先行休克及复苏处理后再分组处理：雌激素休克组（静脉注射苯甲酸雌二醇0.37 mg/kg）、果糖休克组（静脉注射5%果糖2 ml/kg）、p38丝裂原活化蛋白激酶（p38激酶）抑制剂休克组（静脉注射p38激酶抑制剂2 mg/kg）、p38激酶抑制剂+雌激素休克组（处理同p38激酶抑制剂休克组及雌激素休克组）。各组孕兔分别于实验0、60、80及260 min时，检测血清肿瘤坏死因子α（TNF-α）及白细胞介素6（IL-6）的水平；孕兔处死后行肺组织丙二醛（MDA）含量、髓过氧化物酶（MPO）及超氧化物歧化酶（SOD）活性的检测；计算肺组织的肺干/湿质量（DW/WW）比值；对肺组织进行病理检查。结果（1）正常对照组及雌激素休克组孕兔血清TNF-α水平在实验0 min、60 min时与其他4组比较，差异均无统计学意义（P>0.05）。实验80、260 min时，各休克组孕兔血清TNF-α水平呈上升趋势，雌激素休克组[分别为（172.4±16.0）、（216.7±18.6）ng/L]、果糖休克组[分别为（171.6±9.1）、（263.9±7.8）ng/L]、p38激酶抑制剂休克组[分别为（172.8±7.2）、（300.6±4.8）ng/L]及p38激酶抑制剂+雌激素休克组[分别为（167.9±4.8）、（261.8±9.6）ng/L]，分别与正常对照组和雌激素对照组比较，差异均有统计学意义（P<0.05）。（2）正常对照组及雌激素休克组孕兔血清IL-6水平在实验0、60、80 min时分别与其他4组比较，差异均无统计学意义（P>0.05）；实验260 min时，雌激素休克组、果糖休克组、p38激酶抑制剂休克组及p38激酶抑制剂+雌激素休克组孕兔血清IL-6水平[分别为（98.3±0.9）、（110.4±1.8）、（120.9±2.3）、（109.8±2.6）ng/L]分别与正常对照组和雌激素对照组比较，差异均有统计学意义（P<0.05）。（3）与正常对照组和雌激素对照组比较，雌激素休克组、果糖休克组、p38激酶抑制剂休克组及p38激酶抑制剂+雌激素休克组孕兔肺组织MDA含量[分别为（2.20±0.12）、（2.57±0.11）、（3.17±0.08）、（2.75±1.09）nmol/mg]及MPO活性水平[分别为（4.45±0.25）、（6.65±0.56）、（9.55±0.30）、（6.78±0.11）U/mg]均明显升高，分别比较，差异均有统计学意义（P<0.05）。（4）与正常对照组和雌激素对照组比较，雌激素休克组、果糖休克组、p38激酶抑制剂休克组及p38激酶抑制剂+雌激素休克组孕兔肺组织SOD活性水平均明显降低[分别为（51.8±1.8）、（40.2±1.5）、（30.0±1.7）、（41.2±2.0）U/mg]，分别比较，差异均有统计学意义（P<0.05）。（5）与正常对照组和雌激素对照组比较，雌激素休克组、果糖休克组、p38激酶抑制剂休克组及p38激酶抑制剂+雌激素休克组孕兔肺组织DW/WW比值明显降低（分别为0.143±0.008、0.127±0.008、0.109±0.006、0.125±0.008），分别比较，差异均有统计学意义（P<0.05）。（6）正常对照组和雌激素对照组孕兔肺组织未见明显病理变化；雌激素休克组、果糖休克组、p38激酶抑制剂休克组及p38激酶抑制剂+雌激素休克组孕兔肺组织均出现损伤性病理改变，p38激酶抑制剂休克组孕兔肺组织损伤程度最为严重。结论雌激素可以在一定程度上保护失血性休克孕兔的急性肺损伤发生，其保护作用机制可能主要是通过p38激酶途径而实现。