特异性血栓素合成酶抑制剂对急性坏死性胰腺炎犬胰腺及肺损伤的影响

Effect of specific thromboxane synthase inhibitor on pancreas and lung injury in dogs with acute necrotizing pancreatitis

目的观察特异性血栓素合成酶抑制剂对急性坏死性胰腺炎（ANP）犬胰腺及肺损伤的影响，探讨其作用机制。方法20只健康雄性杂种犬按数字表法随机分为对照组（4只）、ANP组（8只）及特异性血栓素合成酶抑制剂（商品名：丹奥）治疗组（治疗组，8只）。采用胰管内逆行注射5％牛黄胆酸钠及胰蛋白酶混合液的方法制备ANP模型，治疗组于制模成功后2h起静脉输注2mg／kg体质量的丹奥，每天2次，连用7d。术后动态监测各组血清钙、超敏C反应蛋白（HCRP）、血栓素A2（TXA2）、前列环素（PGI2）水平。7d后处死动物，取胰腺及肺组织行病理学检查，并评分。结果对照组胰腺及肺组织无明显病理改变；ANP组胰腺及肺损伤严重；治疗组胰腺及肺组织损伤较ANP组减轻。对照组、ANP组、治疗组的胰腺病理评分分别为（1．25±0．96）、（7．00±2．39）、（4．63±1．19）分；肺组织病理评分分别为（0．75±0．50）、（7．13±1．55）、（4．88±0．83）分，ANP组、治疗组的胰腺、肺组织病理评分均显著高于对照组，而治疗组的评分又较ANP组显著降低（P值均〈0．05）。对照组术后1d的血清钙、HCRP、TXB2、keto—PGFla水平及TXB2／keto—PGFla比值分别为（2．45±0．07）mmol／L、（30．36±4．29）mg／L、（345．8±46．8）pg／ml、（187．8±18．6）pg／ml、1．85±0．16；ANP组为（2．21±0．08）mmol／L、（72．04±10．22）mg／L、（1227．3±118．2）pg／ml、（368．8±64．4）pg／ml、3．33±0．19；治疗组为（2．32±0．08）mmol／L、（66．51±4，28）mg／L、（1179．5±116．3）pg／ml、（371．8±65．2）pg／ml、3．17±0．18。ANP组与治疗组术后血清钙水平较对照组显著下降，而其他指标显著升高，差异均具有统计学意义（P值均〈0．01）。治疗组血清钙水平显著高于ANP组，血HCRP水平显著低于ANP组，差异有统计学意义（P〈0．05或〈0．01）。结论应用特异性血栓素合成酶抑制剂治疗后ANP犬的胰腺及肺脏损伤程度减轻，其机制与阻断TXA2合成，纠正TXA2／PGI2的比例失衡，改善胰腺及肺组织微循环有关。

Objective To study the role of specific thromboxane synthase inhibitor in dogs with acute necrotizing pancreatitis （ANP） associated lung injury and investigate the possible mechanism. Methods Twenty healthy male mongrel dogs were randomly divided into simple operation group （ control group, n = 4 ） , ANP model group （ ANP group, n = 8 ） and ANP model with specific thromboxane synthase inhibitor （Ozagrel） treatment group （treatment group, n =8）. The ANP model was induced by retrograde injection with 5% sodium taurocholate and trypsin into the pancreatic duct. The treatment group was given intravenous infusion of Ozagrel （2 mg/kg, twice a day for 7 days ） 2 h after the induction of ANP model. The serum calcium, hypersensitive C-reactive protein （HCRP）, thromboxane A2（TXA2）, prostacyclin （PGI2） levels weremonitored dynamically. Seven days later, the dogs were sacrificed, pancreas and lung tissues were harvested for pathological examinations and scored. Results No obvious pathological changes were seen in pancreas and lung tissues in control group, but significant pathological changes were observed in ANP group, and the pathological changes in treatment group were attenuated. The pathological scores of pancreas in control group, ANP group and treatment group were （ 1.25 ± 0.96 ）, （ 7.00 ± 2.39）, （4.63 ± 1.19 ）, and the pathological scores of lung were （0.75±0.50）, （7.13± 1.55）, （4.88±0.83）, and the values in ANP group and treatment group were significantly higher than that in control group, in addition, the value in treatment group was significantly lower than that in ANP group （ P 〈 0.05 ）. The serum levels of calcium, HCRP, TXB2, keto PGFla and TXB2/keto PGFla ratio were （ 2.45 ± 0.07 ） mmol/L, （ 30.36 ± 4.29 ） mg/L, （ 345.8 ± 46.8 ） pg/ ml, （187.8 ± 18.6）pg/ml, 1.85 ± 0. 16 in control group 1 d later; the corresponding values in ANP group were （2.21 ± 0.08 ） mmol/L, （ 72.04 ± 10.22 ） mg/L, （ 1227.3 ± 118.2 ） pg/ml, （ 368.8 ± 64.4 ） pg/ml, 3.33 ± 0.19 ; and the corresponding values in treatment group were （2.32 ± 0.08 ） mmol/L, （66.51 ± 4.28 ） mg/L, （1179.5 ± 116.3 ）pg/ml, （371.8 ± 65.2）pg/ml, 3.17 ± 0.18. The serum levels of calcium in ANP group and treatment group were significantly lower than that in control group, but other parameters were significantly increased, and the difference among the 3 groups was statistically significant （ P 〈 0.01 ）. The serum level of calcium in treatment group was significantly higher than that in ANP group, while the serum level of HCRP was significantly lower than that in ANP group, and the difference between the two groups was statistically significant （ P 〈 0.01 ）. Conclusions The pancreas and lung injury in dogs with acute necrotizing pancreatitis is attenuated with specific thromboxane synthase inhibitor treatment, and its mechanism may be blockade of TXA2 synthesis, correction of TXA2/PGI2 imbalance and improved pancreas and lung microcirculation.