整合素αvβ6在大鼠呼吸机相关性肺损伤中的作用

Role of integrin αvβ6 in ventilator-induced lung injury in rats

目的探讨整合素αvβ6在大鼠呼吸机相关性肺损伤（VILI）中的作用。方法清洁级雄性SD大鼠24只，随机分为3组（n=8），对照组（C组）不行机械通气；高潮气量组（H组）行高潮气量（40ml／kg）机械通气4h，呼吸频率40次／min，氧浓度21％；高潮气量＋阻滞剂S247组（HS组）腹腔注射S247（含有αv亚单位整合素非特异性阻滞剂）100mg／kg，1次／d，持续2周，在最后一次腹腔注射S247后30min行高潮气量机械通气，参数设定同H组。C组和H组于上述相应时点腹腔注射等量生理盐水。通气结束后处死大鼠，观察肺组织病理学，计算肺湿／干重比（W／D），记录支气管肺泡灌洗液（BALF）白细胞（WBC）计数，测定总蛋白（TP）、肿瘤坏死因子-α（TNF-α）、巨噬细胞炎性蛋白-2（MIP-2）的浓度、整合素αvβ6 mRNA及其蛋白的表达水平。结果C组未见肺损伤的发生；H组肺泡结构严重破坏，肺泡内渗出物、出血和间质水肿明显；HS组中等程度炎性细胞浸润，肺泡内出血和肺泡壁增厚。与C组比较，H组和HS组肺W／D、BALF中WBC计数、TP浓度升高，整合素αvβ6 mRNA及其蛋白表达上调，H组BALF中MIP-2浓度升高（P〈0．01）；与H组比较，HS组肺W／D、BALF中WBC计数、TP、TNF-α、MIP-2浓度降低，整合素αvβ6 mRNA及其蛋白表达下调（P〈0．05或0．01）。结论整合素αvβ6参与了大鼠VILI的发生。

Objective To investigate the role of integrin αvβ6 in ventilator-induced lung injury （VILI） in rats.Methods Twenty-four specific pathogen-free male SD rats weighing 250-313 g were randomly divided into 3 groups （ n = 8 each） ： I control group （C） received no mechanical ventilation; H high tidal volume group （H） and high tidal volume ＋ S247 group （HS） . In group H and HS, the animals were anesthetized with intraperitoneal 20% urethane 1.3 g/kg, intubated and mechanically ventilated （VT = 40 ml/kg, RR = 40 bpm, FiO2 = 21% ） for 4 h. The animals in HS group （Ⅲ） received pretreatment with intraperitoneal S247 （non-specific blocker for αv subunit-containing integrin） 100 mg·kg^-1 ·d^-1× 14 days. Mechanical ventilation was started at 30 min after the last S247 injection. In group C and H normal saline was injected instead of S247. At the end of 4 h mechanical ventilation the animals were killed and the lungs were removed for microscopic examination and determination of W/D lung weight ratio; WBC count, total protein （TP）, TNF-α and macrophage-inflammatory protein 2-（MIP-2） concentrations in broncho-alveolar lavage fluid （BALF） and the expression of integrin αvβ6 mRNA and protein in the lung. Results Severe lung damage, profuse intra-alveolar exudate and hemorrhage and marked interstitial edema were observed in group H. The histo-pathologic changes were less severe in group HS than in group H. W/D ratio, WBC counts and TP concentration in BALF and expression of integrin αvβ6 mRNA and protein in the lung in group H and HS and MIP-2 concentration in group H were significantly higher than those in group C （ P 〈 0.01 ）. W/D ratio, WBC counts, TP content, TNF-α and MIP-2 concentrations in BALF and expression of integrin αvβ6 mRNA and protein in the lung were significantly lower in group HS than in group H （P 〈 0.01 or 0.05）. Conclusion Integrin αvβ6 is involved in the development of VILI in rats.