LAUSR

Abstract Over‐activated neutrophils produce enormous oxidative stress and play a key role in the development of acute and chronic inflammatory diseases. 6‐Hydroxy‐5,7‐dimethoxy‐flavone (UFM24), a flavone isolated from the Annonaceae Uvaria flexuosa, showed inhibitory effects on human neutrophil activation and salutary effects on lipopolysaccharide (LPS)‐induced acute lung injury (ALI) in mice. UFM24 potently inhibited superoxide anion (O2•−) generation, reactive oxidants, and CD11b expression, but not elastase release, in N‐formyl‐l‐methionyl‐l‐leucyl‐l‐phenylalanine (fMLF)‐activated human neutrophils. However, UFM24 failed to scavenge O2•− and inhibit the activity of subcellular NADPH oxidase. fMLF‐induced phosphorylation of protein kinase B (Akt) was inhibited by UFM24. Noticeably, UFM24 increased cyclic adenosine monophosphate (cAMP) concentration and protein kinase (PK) A activity in activated human neutrophils. PKA inhibitors significantly reversed the inhibitory effects of UFM24, suggesting that the effects of UFM24 were through cAMP/PKA‐dependent inhibition of Akt activation. Additionally, activity of cAMP‐related phosphodiesterase (PDE)4, but not PDE3 or PDE7, was significantly reduced by UFM24. Furthermore, UFM24 attenuated neutrophil infiltration, myeloperoxidase activity, and pulmonary edema in LPS‐induced ALI in mice. In conclusion, our data demonstrated that UFM24 inhibits oxidative burst in human neutrophils through inhibition of PDE4 activity. UFM24 also exhibited significant protection against endotoxin‐induced ALI in mice. UFM24 has potential as an anti‐inflammatory agent for treating neutrophilic lung damage. Graphical abstract Figure. No Caption available. HighlightsUFM24 inhibits respiratory burst in activated neutrophils with an IC50 at 0.22 &mgr;M.UFM24 attenuates LPS‐resulted acute lung injury in mice.UFM24 enhances cAMP/PKA‐dependent inhibition of Akt activation.UFM24 is a natural PDE4 inhibitor.