Effects of long-term use of simvastatin on ventilator-induced lung injury / 中华危重病急救医学

ABSTRACT

Objective To study the effects of long-term use of simvastatin on mechanical ventilation induced lung injury.Methods Forty SPF adult male Sprague-Dawley (SD) rats weighing 300-350 g were randomly divided into four groups (n =10,each)normal saline (NS) control group (group A),mechanical ventilation group (group B),simvastatin control group (group C),and simvastatin + mechanical ventilation group (group D).The rats in groups C and D were treated with simvastatin dissolved in 1 mL NS by gavage with a dose of 10 mg/kg,and the rats in groups A and B were treated with the same volume of NS by gavage for 28 days.Half an hour after the last garage,the rats in groups B and D underwent tracheostomy and intubation for 4 hours,and then received a tidal volume of 30 mL/kg with the respiratory frequency of 40 times/min,inspiratoryexpiratory ratio of 13,and the rats in groups A and C received tracheostomy and intubation,spontaneous breathing for 4 hours.Four hours later rats were sacrificed by abdominal aorta bloodletting,and the lung tissue was harvested for hematoxylin and eosin (HE) staining to observe pathological changes under light microscope.The activity of malondialdehyde (MDA),superoxide dismutase (SOD),and myeloperoxidase (MPO) was determined.The lung wet/dry weight ratio (W/D) and white blood cell (WBC) count in bronchoalveolar lavage fluid (BALF) were determined.The levels of interleukins-6 (IL-6) and tumor necrosis factor-α (TNF-α) in BALF were determined by enzyme linked immunosorbent assay (ELISA).Results Under light microscope,the structure of lung tissue was integrity in groups A and C without obvious edema and inflammatory cells aggregation;the pathological changes in lung tissue in group B was obvious;and the alveolar structure was clear in group D,pulmonary edema and inflammatory cells aggregation were significantly reduced as compared with those of group B.Compared with group A,SOD activity in group B was significantly decreased (U/g17.97±2.27 vs.28.51 ±4.58,P ＜ 0.01),while MDA,MPO,lung W/D ratio and WBC,IL-6,TNF-α in BALF were significantly increased [MDA (μmol/g)5.40 ± 0.71 vs.3.56 ± 0.55,MPO (U/g)1.26±0.29 vs.0.68±0.12,lung W/D ratio6.60±0.99 vs.4.84±0.26,WBC (× 109/L)6.59±0.82 vs.2.35±1.31,IL-6 (ng/L)207.11± 18.67 vs.123.17±20.15,TNF-o (ng/L)421.38±36.27 vs.207.15±44.39,all P ＜ 0.01].Compared with group B,SOD activity in group D was significantly increased (U/g22.05±2.45 vs.17.97±2.27,P ＜ 0.05),MDA,MPO,lung W/D ratio,and WBC,IL-6,TNF-α in BALF were significantly decreased [MDA (μmol/g)3.77±0.55 vs.5.40±0.71,MPO (U/g)0.96±0.14 vs.1.26±0.29,lung W/D ratio5.16±0.42 vs.6.60±0.99,WBC (× 109/L)3.18± 1.24 vs.6.59±0.82,IL-6 (ng/L)147.90±21.70 vs.207.11 ± 18.67,TNF-α (ng/L)237.16±50.83vs.421.38 ± 36.27,all P ＜ 0.01].There were no significant difference in all parameters between group C and group A.Conclusion The long-term simvastatin treatment could significantly reduce lung injury induced by mechanical ventilation in rats,and its mechanism was related with simvastatin reduced oxidation-antioxidant imbalance and the inflammatory cytokines activity changes.