Most patients with asthma are successfully treated with inhaled corticosteroid (ICS) therapy, either alone or in combination with long-acting beta 2-agonists, with minimal or no side effects. However, a significant proportion of asthmatic patients, including present cigarette smokers and former cigarette smokers, fail to respond well to ICS, alone or in combination with other therapies.
In a randomized, placebo-controlled study, the efficacy of inhaled fluticasone propionate (FP), 1000 μg/day on peak expiratory flow (PEF) and bronchial hyper-reactivity in smokers with mild asthma was assessed compared with non-smoking asthmatics. Asthmatics who smoked showed impaired responses to ICS therapy compared with non-smoking asthmatics \[Chalmers, 2002\] and this lack of responsiveness appears to be dose-dependent. When the dose of ICS is increased, the disparity between lung function, rescue inhaler usage and asthma control seen in smokers and non-smokers decreases \[Tomlinson, 2005\].
Interestingly, smoking also affects the ability of ICS to suppress exhaled nitric oxide (eNO) levels in asthmatics \[Horváth, 2004\]. Smoking cessation improves basal lung function but requires at least a year to demonstrate any improvement in Glucocorticoid (GC) responsiveness with respect to morning peak expiratory flow, but not FEV1, after therapy with high-dose oral prednisolone \[Chaudhuri , 2006\].
Smoking asthmatics have more severe disease requiring more therapy, have more hospital admissions and are more likely to die from asthma \[Thomson, 2005\].
Cigarette smoking remains therefore one of the commonest causes of steroid resistance in asthma, however many aspects of the development and restoration of corticosteroid resistance remain unclarified in this population partly due to the paucity of studies performed.
The mechanisms underlying GC resistance in smoking asthmatics are incompletely understood but are thought to include noneosinophilic (often neutrophilic) airway inflammation \[Chalmers, 2001\], impaired corticosteroid receptor function, and/or reduced histone deacetylase activity \[Adcock, 2008\]. In support of these effects of smoking on asthma, animal models show that smoking can increase inflammation in allergic models of asthma and can affect steroid responsiveness.
Tobacco smoke exposure (4 cigarettes/day for 3weeks) had a small neutrophilic effect in mice, whereas ovalbumin exposure had no inflammatory effect in the airways, but increased allergen-specific IgE \[Moerloose, 2006\]. More recently in mouse models, cigarette smoke has been shown to enhance T-helper-(TH)2-driven airway inflammation \[Van Hove , 2008\].
Inhaled allergens are an important trigger of exacerbations in asthma \[Johnston, 2006\].
The airway inflammation induced by inhaled allergens, and the effects of drugs on this airway inflammation, can be studied using an experimental allergen challenge model. All the currently approved drugs used to treat asthma modify, in some way, allergen-induced airway responses. Following inhalation of the appropriate allergen extract, sensitive subjects, i.e. atopic-asthmatics, develop an acute bronchoconstriction which peaks at 20 to 30 minutes post-allergen and lasts for approximately two hours before recovery.
This early response (EAR) reflects mast cell activation and subsequent release of mainly spasmogenic mediators and correlates with the extent of airway inflammation and disease activity \[Grzelewska-Rsymowska, 1995\]. In approximately 50% of patients, the EAR is followed by a late-phase asthmatic response (LAR). This more prolonged airway narrowing is associated with influx of activated inflammatory cells, especially eosinophils, into the airways and represents the more chronic features of asthma, consisting of a prolonged airway narrowing through both bronchospasm and airway inflammation.
The sequelae of the LAR can last several days and up to 3 weeks. Also, the late response has been shown to be associated with an increase in airway hyperresponsiveness (AHR) to stimuli, such as methacholine for several days after allergen challenge \[Hansel, 2002\].
This clinically relevant model of allergic bronchoconstriction has been useful in humans for exploring the time-course of cellular inflammation and the associated physiological changes, particularly related to eosinophils, basophils and dendritic cells \[O'Byrne, 2009\].In non smoking asthmatics, regular treatment with inhaled corticosteroids has been shown to attenuate the early allergic response, perhaps by reducing the number of mast cells in airways \[Gauvreau, 2000\] and to improve the late-phase asthmatic response \[Kidney, 1997; Cockcroft, 1987\].
As previous allergen challenge studies with therapeutic interventions have been conducted only in the population of non-smokers, this study will be the first to examine the allergen challenge response to FP in smoking asthmatics. The primary endpoint of this study will be the degree of attenuation of the late-phase asthmatic response.
