Simvastatin suppresses lung inflammatory response in a rat cardiopulmonary bypass model.
BACKGROUND
Inflammatory response in the lungs is a well-known complication after cardiopulmonary bypass (CPB). The main aims of our study were to explore whether pretreatment with simvastatin would inhibit toll-like receptor 4 expression and suppress lung inflammatory response in a rat CPB model.


METHODS
Male Sprague-Dawley rats were divided into four groups (n = 6 each): sham group; CPB (control group); CPB plus low-dose simvastatin (5 mg/kg daily [L-Sim group]); and CPB plus high-dose simvastatin (10 mg/kg daily [H-Sim group]). Blood samples were collected at the beginning and at the termination of CPB, and at 1, 2, 4, and 24 hours after operation. The bronchoalveolar lavage fluid and lungs were harvested 24 hours postoperatively.


RESULTS
The simvastatin-treated groups had significantly higher ratios of PaO(2)/FiO(2) and lower values of respiratory index than the control group. We observed that simvastatin reduced CPB-induced toll-like receptor 4 and nuclear factor-kappaB expressions in CPB groups (p < 0.01, versus control group). The levels of interleukin-6, tumor necrosis factor-alpha, and monocyte chemotactic protein-1 in serum, bronchoalveolar lavage fluid, and lung tissues increased in CPB groups, whereas pretreatment with simvastatins reduced these inflammatory marks in a dose-dependent manner (p < 0.01, versus control group). Furthermore, pretreatment with simvastatin had a lower lung injury score (p < 0.05, versus control group).


CONCLUSIONS
These findings suggest that simvastatin inhibited CPB-induced toll-like receptor 4 upregulation and nuclear factor-kappaB activation, efficaciously reduing the pulmonary inflammatory response after CPB.
Department of Cardiothoracic Surgery, Jinling Hospital, Clinical Medicine School of Nanjing University, Nanjing, China.
Hongtao
H
Shao
Yi
Y
Shen
Hao
H
Liu
Guohua
G
Dong
Jianjun
J
Qiang
Hua
H
Jing
D000818:Animals; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D018932:Chemokine CCL2 / Q000032:analysis / Q000097:blood; D004305:Dose-Response Relationship, Drug; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000517:prevention & control*; D015850:Interleukin-6 / Q000032:analysis / Q000097:blood; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D016328:NF-kappa B; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin