Regulation of monocyte redox balance by 1,8-cineole (eucalyptol) controls oxidative stress and pro-inflammatory responses in vitro: A new option to increase the antioxidant effects of combined respiratory therapy with budesonide and formoterol?

Abstract

Background

Airway mucus hypersecretion is the typical feature of COPD and asthma. Hypersecretion is caused by reactive oxygen species (ROS) and links the COPD-bronchitis phenotype to frequent exacerbations. Since the monoterpene 1,8-cineole is known for its secretolytic activity, we studied the antioxidant activity of 1,8-cineole.

Methods

Using a culture model of fetal calf serum (FCS)-stimulated human monocytes, we determined the effects of 1,8-cineole, at therapeutic concentrations (10⁻¹⁰–10⁻⁵ M) on superoxide anions (O₂⁻), superoxide dismutase (SOD), hydrogen peroxide (H₂O₂) and of LPS-stimulated 8-isoprostanes (8-IsoP) and TNF-α. The effect of formoterol (F), budesonide (BUD), BUD + F without and with 1,8-cineole were determined on O₂⁻-release.

Results

1,8-cineole (10⁻⁵ M) strongly inhibited O₂⁻ (−53%, p < 0.001), partially inhibited SOD (−28%, p = 0.0039) and inhibited H₂O₂ in an undulating manner at 10⁻¹⁰ M (−48%, p = 0.0274), while total cellular antioxidant activity as determined by inhibition of 8-IsoP increased dose-dependently from 10⁻⁶ M (−42%, p = 0.0288) to 10⁻⁵ M (−84%, p < 0.0001) comparable to TNF-α. Only weak antioxidant and, at higher concentrations, even pro-oxidant effects were detectable for F and BUD, respectively, but no pro- or antioxidant effects of F + BUD. The antioxidant effects of 1,8-cineole were not substantially influenced during co-incubation with F + BUD.

Conclusions

We report an inhibition of superoxide anions, balancing partial dismutation of superoxide anions and independent inhibition of H₂O₂ by 1,8-cineole. These results suggest a non-specific combined, antioxidant and anti-inflammatory mode of action of 1,8-cineole as bifunctional drug for further clinical evaluation in mild to severe COPD and as adjunctive therapy to control disease progression.