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Geraniol (GOH), a special type of acyclic monoterpene alcohol, has been widely used to treat many diseases associated with inflammation and apoptosis. Acute lung injury (ALI) is a common clinical disease in humans characterized by pulmonary inflammation and apoptosis. In the present study, we investigated the protective effects of GOH in a mouse model of ALI induced by the intranasal administration of lipopolysaccharide (LPS) and elucidated the underlying molecular mechanisms in RAW 264.7 cells. In vivo, GOH treatment markedly ameliorated pathological injury and pulmonary cell apoptosis and reduced the wet/dry (W/D) weight ratio of lungs, myeloperoxidase (MPO) activity and the production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). In vitro, the levels of pro-inflammatory cytokines, iNOS and COX-2 were significantly increased in LPS-stimulated RAW 264.7 cells, an effect that was decreased by GOH treatment. Moreover, GOH treatment dramatically reduced the expression of Toll-like receptor 4 (TLR4) and then prevented the nuclear factor-κB (NF-κB) activation. GOH treatment also promoted anti-apoptotic Bcl-2 expression and inhibited pro-apoptotic Bax and Caspase-3 expression. Furthermore, knockdown of TLR4 expression exerted a similar effect and inhibited the phosphorylation of p65, as well as the Bax and Caspase-3 expression. Taken together, these results suggest that GOH treatment alleviates LPS-induced ALI via inhibiting pulmonary inflammation and apoptosis, a finding that might be associated with the inhibition of TLR4-mediated NF-κB and Bcl-2/Bax signalling pathways.

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Inhibiting hypoxia-inducible factor (HIF)-1α activity has been proposed as a novel therapeutic target in LPS-induced sepsis syndrome. We have reported that tanshinone IIA (TIIA) can reduce LPS-induced lethality and lung injury in mice, but the precise mechanisms have not been fully described. Therefore, the present study investigated whether the protective effect of TIIA was related to the inhibition of LPS-induced HIF-1α expression and what mechanisms accounted for it. This study showed that TIIA pretreatment improved LPS-induced biochemical and cellular changes and reduced the production of inflammatory cytokines. Pretreatment with TIIA decreased LPS-induced HIF-1α expression in vivo and in vitro. TIIA did not affect the LPS-induced HIF-1α mRNA level but inhibited HIF-1α protein translation by the inhibition of the PI3K/AKT and MAPK pathways and related protein translational regulators, such as p70S6K1, S6 ribosomal protein, 4E-BP1, and eIF4E, and promoted HIF-1α protein degradation via the proteasomal pathway in LPS-stimulated macrophages. These observations partially explain the antiinflammatory effects of TIIA, which provides scientific basis for its application for the treatment of acute lung injury/acute respiratory distress syndrome or sepsis.

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