长期服用辛伐他汀对机械通气肺损伤大鼠肺组织血红素加氧酶-1表达的影响

The effects of long -term use of simvastatin on pulmonary heme oxygenase-1 expression in rats of ventilator-induced lung injury

目的研究长期服用辛伐他汀对机械通气肺损伤大鼠肺组织血红素加氧酶-1（HO-1）的影响。方法成年雄性清洁SD大鼠32只，体质量300～350 g，随机分4组（n＝8）：正常对照组（A组）；机械通气组（B组）；辛伐他汀组（C组）；辛伐他汀＋机械通气组（D组）。 A、B组以生理盐水1 mL/d灌胃， C、D组将辛伐他汀按10 mg/kg体质量溶于1 mL生理盐水灌胃，共灌28 d。第28天，灌胃后0．5 h，A、C组做气管切开和气管插管，自主呼吸4 h，B、D组行气管切开、插管，机械通气4 h，潮气量30 mL/kg，4 h后腹主动脉放血处死大鼠，取肺组织，分别行肺病理切片HE染色光镜下观察病理学改变，测肺湿干重比（W/D），Western blot 法检测HO-1表达， RT-PCR法检测HO-1 mRNA的表达水平。结果与A组比较， B组病理切片苏木精-伊红（HE）染色光镜下观察病理损伤改变明显加重、肺组织W/D升高（P＜0．01），HO-1和HO-1 mRNA表达水平明显升高（P＜0．01，P＜0．05），C组肺组织病理切片HE染色、肺组织W/D无明显改变， HO-1和HO-1 mRNA表达水平明显升高（ P＜0．01）；与B组比较，C组肺组织病理切片HE染色无病理改变、肺组织W/D明显降低（P＜0．01），HO-1和HO-1 mRNA表达水平比较差异无统计学意义，D组肺组织病理切片HE染色病理改变明显减轻、肺组织W/D明显降低（ P＜0.01），HO-1和HO-1 mRNA表达水平明显增高（P＜0．05，P＜0．01）；与C组比较，D组病理切片HE染色、肺组织W/D差异无统计学意义，肺组织HO-1和HO-1 mRNA表达水平明显升高（ P＜0.01）。结论长期辛伐他汀处理可以明显减弱机械通气导致的大鼠肺损伤，其机制与辛伐他汀增加肺组织HO-1和HO-1 mRNA表达水平相关。

Objective To study the effects of long-term use of simvastatin on pulmonary heme oxygenase-1（HO-1） expression in rats of ventilator -induced lung injury.Methods Thirty-two SPF adult male SD rats, weighing 300~350 g were randomly divided into 4 groups （ n=8, each）：control group （ group A ）; mechanical ventilation group （ group B ）; simvastatin group （ group C ）;simvastatin＋mechanical ventilation group （ group D ） .Group A and B were treated with 1 mL/d of saline by gavage for 28 days;group C and D were treated with simvastatin dissolved in 1 mL saline by gavage with a dose 10 mg/kg for 28 days.Half hour after gavage on the 28th day, group A and C received tracheostomy and intubation , spontaneous breathing for 4 h; group B and D underwent tracheostomy and intubation and then received tidal volume of 30 mL/kg with mechanical ventilation for 4 h;4 h later rats were sacrificed and the lung tissue were collected and stored with correct methods .The lung tissue were performed HE staining and pathological changes were observed under light microscope . Lung wet/dry weight ratio （W/D）, the expression of HO -1 mRNA and protein was detected using RT-PCR and Western blot .Results Compared with group A , group B showed significantly increased pathological damages, significantly increased W/D （P〈0.01）, significantly increased expression level of HO-1 protein and mRNA （P〈0.01 and P〈0.05, respectively）.Compared with group A, group C showed no significant pathological change and W /D, but significantly increased expression level of HO-1 protein and mRNA （P 〈0.01）.Compared with group B, group C did not show significant changes in lung pathological damage and HO -1 expression level , but the W/D was significantly reduced （ P 〈0.01 ） .Compared with group B , group D showed significantly decreased pathological damages, significantly reduced W/D （P 〈0.01）, and significantly increased expression of HO -1 protein and mRNA （P 〈0.05 and P 〈0.01, respectively）.Compared with group C, pathological damages and W/D in group D were not significantly difference , but the expression of HO -1 protein and mRNA were significantly increased （P〈0.01）.Conclusion The long -term simvastatin treatment significantly reduces lung injury caused by mechanical ventilation in rats and its mechanism is related to that simvastatin increases the expression of HO -1 protein and mRNA .