右美托咪定对急性胰腺炎肺损伤大鼠的保护作用

Protective effect of dexmedetomidine against lung injury in rats with acute pancreatitis

目的观察右美托咪定（Dex）对急性胰腺炎（AP）大鼠血清炎性细胞因子水平、肺损伤、胰腺组织损伤的影响。方法32只健康成年雄性Sprague-Dawley（SD）大鼠，清洁Ⅱ级，体重190～230g，应用随机数字法分为4组，每组8只：假手术组、模型组、Dex低剂量组（2#g／kg）、Dex高剂量组（10ug／kg）。Dex均与0．9％氯化钠溶液配成10mL溶液。模型组、Dex低剂量组、Dex高剂量组采用5％牛磺胆酸钠（1mL／kg）逆行胰胆管注射法制作大鼠AP相关肺损伤模型。Dex低剂量组和Dex高剂量组在建立AP模型后即刻于大鼠尾静脉应用微量注射泵持续注射Dex10mL共15min，假手术组和模型组经微量注射泵注射0．9％氯化钠溶液10mL共15min。造模后4、12h，测定大鼠的血清TNF-α、IL-6和淀粉酶水平。造模后12h，将存活的大鼠放血致死，计算右上肺湿重与干重的比值（W／D值）；取右下肺在光学显微镜下观察肺组织病理学变化，进行肺损伤评分；取胰腺组织在光学显微镜下观察病理学变化，进行胰腺组织损伤评分。结果模型组有2只大鼠在造模后4～12h死亡。模型组、Dex低剂量组、Dex高剂量组造模后4和12h的血清TNF-α、IL-6、淀粉酶水平均显著高于假手术组同时间点（P值均〈0．05）。模型组、Dex低剂量组、Dex高剂量组造模后12h的血清IL-6水平均显著高于同组造模后4h（P值均〈O．05），模型组造模后12h的血清TNF-α水平显著高于同组造模后4h（P〈0．05）。Dex低剂量组和Dex高剂量组造模后4和12h的血清TNF-a、IL-6水平均显著低于模型组同时间点（P值均〈0．05）。Dex高剂量组造模后12h的血清TNF-α水平显著低于Dex低剂量组同时间点（P〈0．05）。模型组、Dex低剂量组、Dex高剂量组组间同时间点和组内不同时间点间血清淀粉酶水平的差异均无统计学意义（P值均〉0．05）。模型组、Dex低剂量组、Dex高剂量组的肺W／D值均显著高于假手术组（P值均〈O．01），Dex高剂量组的肺W／D值显著低于模型组（P〈0．05）。与模型组比较，Dex低剂量组和Dex高剂量组的肺组织病理学改变情况明显改善，Dex高剂量组改善更为明显。模型组、Dex低剂量组、Dex高剂量组的肺损伤评分均显著高于假手术组（P值均〈0．01），Dex高剂量组的肺损伤评分显著低于模型组（P〈0．05）。与假手术组比较，模型组、Dex低剂量组、Dex高剂量组胰腺组织存在广泛的中性粒细胞浸润、腺泡出血坏死和脂肪坏死。模型组、Dex低剂量组、Dex高剂量组的胰腺组织损伤评分均显著高于假手术组（P值均〈0．01），前3组间的差异均无统计学意义（P值均〉0．05）。结论Dex可减轻AP致急性肺损伤模型大鼠炎性细胞因子TNF-α和IL-6的释放，改善肺水肿，减轻肺组织病理损害，但不能减轻胰腺组织的损伤程度。

Objective To investigate the effects of dexmedetomidine on serum inflammatory factors and injury of lungs in acute pancreatitis(AP)rats.Methods Thirty-two healthy male Sprague-Dawley(SD)rats,weighing 190-230 g,were randomly divided into 4 groups(n=8):sham operation group(group C),model group(group M),small-dose dexmedetomidine group(group D1,2μg/kg)and large-dose dexmedetomidine group(group D2,10μg/kg).AP models were established by injecting 5% sodium taurocholate(1mL/kg)into the biliopancreatic duct in group M,D1 and D2.Dexmedetomidine(10mL)was given by micro-injection pump within15 minutes after modeling in group D1 and D2,and equal volume of normal saline was given in group C and M.Serum tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6)and amylase levels were measured at 4h and 12h after modeling.Then survival rats were sacrificed,and wet to dry weight ratio(W/D)of lung was detected and pathological changes of lung and pancreatic tissues were observed under light microscope.Results Two rats died in group M 4-12h after modeling.Serum TNF-α,IL-6 and amylase concentrations at 4h and 12 hafter modeling in group M,D1 and D2 were significantly higher than those in group C(all P<0.05).Serum IL-6 level at 12 h after modeling was significantly higher than those at 4h after modeling in group M,D1 and D2(all P<0.05).Serum TNF-α at 12 hafter modeling was significantly higher than that at 4hafter modeling in group M(P<0.05).Serum TNF-α and IL-6 levels at 4h and 12h after modeling in group D1 and D2 were significantly lower than those in group M(all P<0.05).Serum TNF-α at 12 h after modeling in group D2 was significantly lower than that in group D1(P<0.05).There were no significantly differences in serum amylase concentration between groups at any time point(all P>0.05).The W/D ratios of lung in group M,D1 and D2 were significantly higher than that in group C(all P<0.01),while the W/D of lung in group D2 was significantly lower than that in group M(P<0.05).Compared with group M,more pathologic damages of lung were found in group D1 and D2,especially in group D2.The scores of lung injury in group M,D1 and D2 were significantly higher than that in group C(all P<0.01),and the score in group D2 was significantly lower than that in group M(P<0.05).Compared with group C,move severer neutrophilic granulocyte infiltration,bleeding and necrosis of gland alveolus and fat necrosis were found in group M,D1 and D2.The scores of pathological changes in pancreatic tissues in group M,D1 and D2 were significantly higher than that in group C(all P<0.01),but no significant difference was found between group M,D1 and D2(all P >0.05).Conclusion Dexmedetomidine can attenuate lung injury in rats with acute pancreatitis,but it cannot relieve pancreatic injury.The mechanism may be related to inhibiting the release of inflammatory cytokines