雾化吸入和静脉注射米力农对大鼠急性肺损伤疗效的比较

Therapeutic effect of inhaled aerosolized versus intravenous milrinone on oleic acid-induced acute lung injury in rats

目的比较雾化吸入和静脉注射米力农对大鼠急性肺损伤（ALI）的疗效。方法SD大鼠40只，体重300—350g，随机分为4组（n=10）：对照组（Ⅰ组）、ALI组（Ⅱ组）、米力农雾化吸入组（Ⅲ组）和米力农静脉注射组（Ⅳ组）。Ⅰ组经右颈外静脉插管注入0．1％BSA溶液2ml／kg；Ⅱ组经20min注入油酸混悬液2ml／kg；Ⅲ组注入油酸后30min雾化吸入1mg／ml米力农10min，每60分钟重复一次，共4次；Ⅳ组注入油酸后30min经右颈外静脉注射米力农10μg／kg，然后静脉输注米力农1μg·kg^-1·min^-1 10min，每60分钟重复一次，共4次。各组于第4次治疗结束后放血处死大鼠。于治疗开始即刻、第1次治疗时、第2次治疗时、第3次治疗时和第4次治疗时，记录平均动脉压（MAP）和肺动脉压（PAP），测定动脉血气和混合静脉血气，计算氧合指数（PaO2／FiO2）和肺内分流率（Qs／Qt）。回收支气管肺泡灌洗液（BALF），进行中性粒细胞计数，采用Bradford法测定蛋白浓度；测定肺组织湿／干重比（W/D）和髓过氧化物酶（MPO）活性；观察肺组织超微结构。结果与Ⅲ组比较，Ⅳ组第3次治疗和第4次治疗时MAP和PaO2/FiO2降低，第4次治疗时PAP和Qs／Qt升高，BALF蛋白浓度、中性粒细胞计数和肺组织W／D、MPO活性均升高（P〈0．05）。结论雾化吸入米力农减轻大鼠ALI的作用优于静脉注射米力农，对血液动力学影响小。

Objective To compare the therapeutic effect of inhaled aerosolized and intravenous milrinone, a phosphodiesterase-3 inhibitor in rats with oleic acid-induced acute lung injury （ALI）. Methods Forty male SD rats weighing 300-350 g were randomly divided into 4 groups （ n = 10 each） ： group Ⅰ normal control： group Ⅱ ALI; pup Ⅲ milrinone inhalation and group Ⅳ intravenous milrinone. The animals were anesthetized with intraperitoneal 2% pentobarbital 40 mg/kg, tracheostomized and mechanically ventilated （FiO2 30%, VT 10 ml/ kg, RR 80 bpm, I ： E = 1 ： 2）. The chest was opened and the heart was exposed. Pulmonary artery was catheterized via right ventricle. MAP, CVP, airway pressure and pulmonary artery pressure （PAP） were monitored. ALI was induced with 10% oleic acid 2 ml/kg administered through right external jugular vein in group Ⅱ, Ⅲ and Ⅳ. In control group 0.1% BSA solution 2 ml/kg was administered iv instead of oleic acid. In group Ⅲ at 30 min after oleic acid administration aerosolized milrinone 1 mg/ml was inhaled 4 times at 60 min interval. Each time milrinone was inhaled for 10 min. In group Ⅳ at 30 min after oleic acid administration a bolus of 10 μg/ kg milrinone was given iv followed by 10 min milrinone infusion at 1 μg· kg^- 1 . min^- 1. The same procedure was repeated 4 times at 60 min interval. MAP and PAP were recorded and blood samples were taken from carotid artery and pulmonary artery for blood gas analysis at the 1st, 2nd, 3rd and 4th treatment. PaO2/FiO2 and Qs/Qt were calculated. The animals were sacrificed by exsanguination after the 4th treatment. The lungs were removed. The left lung was lavaged. Neutrophil count and protein content in broncho-alveolar lavage fluid （BALF） were determined. W/D lung weight ratio and lung myeloperoxidase （MPO） activity were measured. The ultrastructure of the lung was examined with electron microscope. Results The MAP was significantly lower after oleic acid administration in group Ⅳ than in other 3 groups. PaO2/FiO2 was significantly decreased and Qs/Qt increased by iv oleic acid in group Ⅱ ,Ⅲ and Ⅳ. PAP was significantly increased after iv oleic acid in group Ⅱ , Ⅲ and Ⅳ but was significantly lower in group Ⅲ and Ⅳ than in group Ⅱ . The neutrophil count and total protein content in BALF, W/D ratio and lung MPO activity were significantly increased in group Ⅱ , Ⅲ and Ⅳ as compared with control group （ Ⅰ ） and were significantly higher in group Ⅳ than in group m . The lung damage induced by oleic acid was less serious in group m and Ⅳ than in group Ⅱ. Conclusion Inhaled aerosolized milrinone has better therapeutic effect than intravenous milrinone in rats with oleic acid-induced ALI and is safer.