Experimental Study of the Protective Effect of Simvastatin on Lung Injury in Rats with Sepsis
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ORIGINAL ARTICLE
Experimental Study of the Protective Effect of Simvastatin on Lung Injury in Rats with Sepsis Yu Wang ,1,2 Wenping Yang,1 Xin Zhao,1 and Rong Zhang1
Simvastatin, which is primarily prescribed to lower cholesterol, may also mitigate lung injury caused by sepsis, although the mechanisms remain elusive. This study aimed to evaluate the protective effect of simvastatin on acute lung injury in rats with sepsis and to investigate possible mechanisms. Male Wistar rats were pretreated with simvastatin (0.2 μg/g) for 1 week before cecal ligation and puncture. Treatment with simvastatin demonstrated significant decreases in the concentration of protein, TNF-α, IL-1β, IL-6, and lipocalin 2, and the number of polymorphonuclear neutrophils in bronchoalveolar lavage fluid in septic rats. In addition, simvastatin also reduced levels of Evans blue, malondialdehyde, 8hydroxy-2′-deoxyguanosine, and wet/dry lung weight ratios, and increased the activity of superoxide dismutase in lung tissue. Furthermore, expression levels of TLR4, NF-κB p65, and active caspase-3 proteins and Bax mRNA were also decreased by simvastatin. H&E staining showed that severe lung injury occurred in the sepsis group and that lung injury was reduced by treatment with simvastatin. In conclusion, simvastatin improved endothelial permeability and mitigated the inflammatory response of lung tissue, the oxidative stress response, and cell apoptosis by inhibiting the TLR4/NF-κB signaling pathway, thereby alleviating sepsis-induced acute lung injury in rats. Abstract—
KEY WORDS: simvastatin; sepsis; acute lung injury; TLR4/NF-κB.
INTRODUCTION Sepsis, which is an out of control host response to infection, results in life-threatening organ dysfunction and is a major cause of death in intensive care units. The lung is the most vulnerable target organ in sepsis, and acute lung injury (ALI) occurs at the earliest time points and has the highest incidence [1]. ALI involves multiple inflammatory signaling pathways that are gradually amplified. The 1
Emergency Department, Shengjing Hospital of China Medical University, No. 36 Sanhao street, Heping district, Shenyang, Liaoning Province 110004, China 2 To whom correspondence should be addressed at Emergency Department, Shengjing Hospital of China Medical University, No. 36 Sanhao street, Heping district, Shenyang, Liaoning Province 110004, China. Email: [email protected]
resulting cascade of cytokines and inflammatory mediators causes direct or indirect damage to pulmonary capillary endothelial cells, leading to endothelial dysfunction and an increase in permeability of pulmonary capillaries. This, in turn, results in vascular leakage, inflammatory exudation, and, eventually, acute respiratory distress syndrome [2]. Toll-like receptor 4 (TLR4) is an important mediator of innate immunity and the inflammatory response. TLR4 plays an important role in the development of sepsisinduced lung injury and knockout or targeted inhibition of the TLR4 gene significantly reduces the severity of ALI [3–5]. TLR4
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