Reactive free oxygen radicals are known to play an important role in the pathogenesis of various lung diseases such as idiopathic pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS) or cystic fibrosis (CF). They can originate from endogenous processes or can be part of exogenous exposures (e.g. ozone, cigarette smoke, asbestos fibres). Consequently, therapeutic enhancement of anti-oxidant defence mechanisms in these lung disorders seems a rational approach. In this regard, N-acetyl-L-cysteine (NAC) and ambroxol have both been frequently investigated. Because of its SH group, NAC scavenges H2O2 (hydrogen peroxide), .OH (hydroxol radical), and HOCl (hypochlorous acid). Furthermore, NAC can easily be deacetylated to cysteine, an important precursor of cellular glutathione synthesis, and thus stimulate the cellular glutathione system. This is most evident in pulmonary diseases characterized by low glutathione levels and high oxidant production by inflammatory cells (e.g. in IPF and ARDS). NAC is an effective drug in the treatment of paracetamol intoxication and may even be protective against side-effects of mutagenic agents. In addition NAC reduces cellular production of pro-inflammatory mediators (e.g. TNF-alpha, IL-1). Also, ambroxol [trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexane hydrochloride] scavenges oxidants (e.g. .OH, HOCl). Moreover, ambroxol reduces bronchial hyperreactivity, and it is known to stimulate cellular surfactant production. In addition, ambroxol has anti-inflammatory properties owing to its inhibitory effect on the production of cellular cytokines and arachidonic acid metabolites. For both substances effective anti-oxidant and anti-inflammatory function has been validated when used in micromolar concentrations. These levels are attainable in vivo in humans. This paper gives an up-to-date overview about the current knowledge of the hypothesis that oxidant-induced cellular damage underlies the pathogenesis of many human pulmonary diseases, and it discusses the feasibility of anti-oxidant augmentation therapy to the lung by using NAC or ambroxol.

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IntroductionMyrtol standardized is established in the treatment of acute and chronic bronchitis and sinusitis. It increases mucociliar clearance and has muco-secretolytic effects. Additional anti-inflammatory and antioxidative properties have been confirmed for Myrtol standardized, eucalyptus oil, and orange oil in several in vitro studies.ObjectiveThe aim of this study was to prove the ability of essential oils to reduce cytokines release and reactive oxygen species (ROS) production derived from ex vivo cultured alveolar macrophages.Material and methodsAlveolar macrophages from patients with chronic obstructive pulmonary disease (COPD, n = 26, GOLD III-IV) were pre-cultured with essential oils (10-3-10-8%) for 1 h and then stimulated with LPS (1 μg/ml). After 4 h and 20 h respectively a) cellular reactive oxygen species (ROS) using 2',7'-dichlorofluorescein (DCF), and b) TNF-α, IL-8, and GM-CSF secretion were quantified.ResultsIn comparison with negative controls, pre-cultured Myrtol, eucalyptus oil and orange oil (10-4%) reduced in the LPS-activated alveolar macrophages ROS release significantly after 1+20 h as follows: Myrtol - 17.7% (P = 0.05), eucalyptus oil -21.8% (P < 0.01) and orange oil -23.6% (P < 0.01). Anti-oxidative efficacy was comparable to NAC (1 mmol/l). Essential oils also induced a TNF-α reduction: Myrtol (-37.3%, P < 0.001), eucalyptus oil (-26.8%, P < 0.01) and orange oil (-26.6%, P < 0.01). TNF-α reduction at 1+4 h and 1+20 h did not vary (Myrtol: -31.9% and -37.3% respectively, P = 0.372) indicating that this effect occurs early and cannot be further stimulated. Myrtol reduced the release of GMCSF by -35.7% and that of IL-8 only inconsiderably.ConclusionsAll essential oils tested have effective antioxidative properties in ex vivo cultured and LPS-stimulated alveolar macrophages. Additionally, Myrtol inhibited TNF-α and GM-CSF release best indicating additional potent anti-inflammator y activity.

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