BML-111对大鼠机械通气诱发肺损伤的影响

Effect of BML-111 on ventilator-induced lung injury in rats

目的评价BML-111对大鼠机械通气诱发肺损伤的影响。方法健康雄性sD大鼠48只，体重200～250g，6～8周龄，采用随机数字表法，将其分为6组（n=8）：对照组（C组）、低潮气量组（LVτ组）、高潮气量组（HVτ组）、低剂量BML-111组（BL组）、高剂量BML-111组（BH组）和BML-111＋脂氧素A4受体拮抗剂BOC-2组（BOC-2组）。C组气管插管后保留自主呼吸；其余5组行机械通气，通气频率80次／min，吸人氧浓度21％，呼气末正压0，LVτ组潮气量6ml／kg，HVτ组、BL组、BH组和BOC-2组潮气量均为20ml／kg。BL组和BH组于机械通气时分别腹腔注射BML-1110．1、1．0mg／kg；BOC-2组于机械通气前30min时腹腔注射BOC-250μg／kg，机械通气时腹腔注射BML-1111．0mg／kg。机械通气4h时采集动脉血样，测定动脉血氧分压（PaO2）。然后处死大鼠，收集左侧支气管肺泡灌洗液（BALF），进行中性粒细胞计数，计算中性粒细胞水平；取右侧肺组织，HE染色，光镜下观察病理学结果，测定湿，干重（W／D）比值、髓过氧化物酶（MPO）活性、丙二醛（MDA）、单核细胞趋化蛋白-1（MCP-1）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和IL-6的含量。结果与C组比较，HVτ组PaO2降低，BALF中性粒细胞水平、肺组织W／D比值、MPO活性、MDA、MCP-1、TNF-α、IL-1β和IL-6的含量升高（P〈0．05），LVτ组上述指标差异无统计学意义（P〉O．05）；与HVτ组比较，BV组PaO2升高，BALF中性粒细胞水平、肺组织W／D比值、MCP-1、TNF-α、IL-1β、IL-6、MPO和MDA的水平降低，BL组肺组织TNF-α、IL-β和IL-6的含量降低（P〈0．05），其它指标差异无统计学意义（P〉0．05）；与BH组比较，BOC-2组PaO2降低，BALF中性粒细胞水平、肺组织W／D比值、MCP-1、TNF-α、IL-1β、IL-6、MPO和MDA的水平升高（P〈O．05）。BH组肺组织病理学损伤轻于HV，组和BOC-2组。结论BML-111可减轻大鼠机械通气诱发肺损伤，其机制与激活脂氧素A4受体有关。

Objective To evaluate the effect of BML-111 on ventilator-induced lung injury in rats. Methods Forty-eight healthy male Sprague-Dawley rats, weighing 200-250 g, aged 6-8 weeks, were randomized into 6 groups （n = 8 each） using a random number table： control group （C group） , low tidal volume （VT） group （LVTgroup）, high VT group （HVTgroup）, low dose BML-111 group （BL group）, high dose BML-111 group （BH group） , and BML-111 plus BOC-2 （lipoxin A4 receptor antagonist） group （ BOC-2 group）. Group C kept spontaneous breathing after tracheotomy, and received no mechanical venti- lation. The rats in the other 5 groups were mechanically ventilated （respiratory rate 80 breaths/min, frac-tion of inspired oxygen 21% , positive end-expiratory pressure O）. The VT was 6 ml/kg in group LVT , or .20 ml/kg in HVT, BL, BH and BOC-2 groups. BML-111 0. 1 and 1.0 mg/kg were injected intraperitoneally during ventilation in BL and BH groups, respectively. In group BOC-2, BOC-2 50 μg/kg was injected in- traperitoneally before ventilation, and BML-111 1.0 mg/kg was injected intraperitoneally during ventilation. Arterial blood samples were collected at 4 h of ventilation, arterial oxygen partial pressure （ PaO2） was de- termined. Then animals were sacrificed by exsanguination. Bronehoalveolar lavage fluid （BALF） of the left lung was collected for determination of neutrophil count, and the level of neutrophil was calculated. The right lung tissue specimens were obtained for microscopic examination, and for determination of wet/dry lung weight ratio （W/D ratio）, myelopcroxidase （MPO） activity, and contents of malondialdehyde （ MDA）, monocyte chemoattractant protein-1 （ MCP-1）, tumor necrosis factor-alpha （ TNF-α）, interleu- kin-lbeta （IL-1β） and IL-6. Results Compared with group C, PaO2 was significantly decreased, and the level of neutrophil in BALF, W/D ratio, MPO activity, and contents of MDA, MCP-1, TNF-α, IL- 1β and IL-6 were increased in group HVT （P〈0. 05） , and no significant change was found in the variables mentioned above in group LV1, （P〉0.05）. Compared with group HVT, PaO2 was significantly increased, and the level of ncutrophil in BALF, W/D ratio, MPO activity, and contents of MDA, MCP-1, TNF-α, IL-1β and IL-6 were decreased in group BH, and the contents of TNF-α, IL-1β and IL-6 were significantly decreased （P〈O. 05） , and no significant change was found in the other variables in group BL （P〉0. 05）. Compared with group BH, PaO2 was significantly decreased, and the level of neutrophil in BALF, W/D ratio, MPO activity, and contents of MDA, MCP-1, TNF-α, IL-1β and IL-6 were increased in group BOC-2 （P〈0.05）. The pathological changes were significantly attenuated in group BL as compared with HVT and BOC-2 groups. Conclusion BML-111 ean attenuate ventilator-induced lung injury in rats, and activated lipoxin A4 receptors are involved in the mechanism.