Simvastatin attenuates the lipopolysaccharideinduced inflammatory response of rat pulmonary microvascular endothelial cells by downregulating toll-like receptor 4 expression

摘要

Objective: The therapeutic potential of simvastatin as an anti-inflammatory agent was explored by investigating its effect on the lipopolysaccharide (LPS)-induced inflammatory response in rat pulmonary microvascular endothelial cells (RPMVECs). Methods: RPMVECs were isolated and the mRNA and protein levels of different toll-like receptors (TLR) were assessed by qRT-PCR and western blotting. The LPS-induced expressions of TLR4, TNF-α and iNOS were analyzed in RPMVECs treated with different concentrations of simvastatin for different times. NF-?B activation was examined by immuofluroscence, luciferase reporter assay and western blotting. Results: TLR4 is abundantly expressed in RPMVECs, and its expression is induced by LPS stimulation. Simvastatin inhibited LPS-induced TLR4 expression at the mRNA and protein levels in a time-dependent manner (p<0.01), and alleviated inflammation in RPMVECs by inhibiting the release of inflammatory factors such as TNF-α and iNOS. Further study indicated that simvastatin significantly attenuated NF-?B activity by inhibiting the degradation of I?B-α. Pretreatment with pyrrolidine dithiocarbamate (PDTC) and knock-down of TLR4 expression by RNA interference down-regulated the LPS-induced inflammatory response in RPMVECs. Conclusion: Simvastatin inhibits the LPS-induced inflammatory response in RPMVECs by down-regulating TLR4 expression, suggesting its role as a potential inhibitor of LPS-induced inflammation.