6-Hydroxy-5,7-dimethoxy-flavone suppresses the neutrophil respiratory burst via selective PDE4 inhibition to ameliorate acute lung injury

Research Highlights Life Science

A natural product opens new doors for treating chronic lung inflammation

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Asthma, Chronic Obstructive Pulmonary Disease (COPD), Acute Lung Injury (ALI), and Acute Respiratory Distress Syndrome (ARDS) are some of the main chronic diseases affecting the lung, and they all share a common denominator: severe inflammation that impairs normal lung functions, with the high risk of morbidity and even mortality.
One key immune cell population is responsible for the exacerbated inflammatory response: neutrophils.
One key enzyme is at the core of the signaling pathways involved in controlling neutrophilic response: Phosphodiesterase 4 (PDE4).
One key second messenger controls the down-regulation of neutrophil activation: cAMP.
Immune cells, enzyme, and mediator: everything is there and characterized sufficiently for screening new drugs to cure chronic lung inflammation. For decades, the quest for potent PDE4 inhibitors was indeed at the top list in pharmaceutical research. With more or less success…
And what if the answer was a “natural” and not a “chemical” drug? That is exactly what Yung-Fong Tsai and colleagues looked for. They extracted an active substance (UFM24) from the plant Uvaria flexuosa, found in Vietnam and Cambodia. The plant has been used for centuries in traditional medicine.
By using in-vitro cellular assays with LPS-stimulated neutrophils isolated from mice, they completely deciphered and characterized this natural substance’s mechanism of action on PDE4.
UFM24 is a selective PDE4 inhibitor. It down-regulates cAMP concentration and, consequently, enhances the cAMP/PKA-dependent inhibition of Akt signaling. This ultimately impairs the neutrophil oxidative stress response and reduces acute lung injury. The drug is there!
Yes, sometimes the best and most potent therapeutic compounds are right there in front of our eyes, in nature.

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.

Details

Free Radical Biology and Medicine, 2017 May;106:379-392.

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