Background: SIRT1 has been known to deacetylate several transcription factors that govern metabolism, endocrine signaling, and inflammation. Moreover, there are very recent studies in which SIRT1 is required for hypoxia inducible factor (HIF)-1a activation and stabilization. In addition to the oxygen-dependent regulation of HIF-1a activity, HIF-1a expression is regulated by a variety of cytokines and growth factors in oxygen-independent pathway and that HIF-1a plays an important role in inflammatory responses. However, to date, it is still controversial whether SIRI1 plays a pro-inflammatory role or an anti-inflammatory role in various pulmonary disorders. Methods: In this study, using LPS-instilled mice, we aimed to investigate the role of SIRT1 in the pathogenesis of LPS-induced lung inflammation focusing on the integrated signaling network, HIF-1a pathway. Results: Our results showed that SIRT1 was significantly increased in lung tissues of LPS-inhaled mice compared with control mice and that inhibition of SIRT1 attenuated typical features of lung injury, including pulmonary neutrophilia, vascular leakage, and increased phosphorylation of Akt thereby improving LPS-induced lung inflammation. Moreover, sirtinol also reduced LPS-induced HIF-1a activation and expression of VEGF. Intriguingly, increased expression of SIRT1 and HIF-1a was observed in LPS-stimulated airway epithelial cells. Lastly, our results also revealed that LPS-induced increases of nuclear translocation of NF-κB, infiltration of DCs, and TLR4 expression in the lung were significantly reduced by inhibition of SIRT1. Conclusions: These findings indicate that SIRT1 plays an important pro-inflammatory role in the pathogenesis of LPS-induced inflammation through the modulation PI3K-HIF-VEGF axis.