Increased Levels of Airway Neutrophils Reduces the Inhibitory Effects of Inhaled Glucocorticosteroids on Allergen‐Induced Airway Eosinophils

Abstract

BACKGROUND: Treatment with inhaled glucocorticosteroids attenuates allergen-induced airway inflammation but is less effective in people with asthma who have noneosinophilic airway inflammation. OBJECTIVE: Studies in which glucocorticosteroid treatment was used before allergen challenges were re-examined to determine whether the efficacy of steroid treatment could be predicted by baseline levels of sputum inflammatory cells. PATIENTS AND METHODS: Twenty-eight nonsmoking subjects with atopic asthma controlled by beta 2 -agonists participated in only one of three studies, each carried out with a double-blind, placebo controlled, randomized, crossover design. Subjects were treated with glucocorticosteroids or placebo for six to eight days and then underwent allergen inhalation challenge. Spirometry was measured for 7 h after allergen challenge, and then sputum inflammatory cells were measured. Sputum inflammatory cells were also measured before and after treatment, and 24 h after allergen challenge. The per cent inhibition of the allergeninduced airway responses by glucocorticosteroids was calculated. RESULTS: Inhaled gluticocorticosteroids significantly attenuated the early and late asthmatic responses, and the number of allergeninduced sputum eosinophils (P<0.05). There was a significant negative relationship between the number of sputum neutrophils at baseline, and the per cent inhibition of allergen-induced sputum eosinophils measured at 7 h (r=-0.61, P<0.001) and 24 h (r=-0.73, P<0.0001) after challenge, suggesting that glucocorticosteroids are less effective in attenuating allergen-induced airway inflammation in subjects with high levels of neutrophils. There was no correlation between the number of sputum eosinophils at baseline and the per cent inhibition of allergen-induced responses. CONCLUSIONS: Baseline airway neutrophils, not eosinophils, can be used to predict the efficacy of inhaled steroids on allergeninduced sputum eosinophils. Key Words: Airway inflammation; Allergen inhalation; Eosinophils; Glucocorticosteroids; Neutrophils; Sputum induction Résumé à la page suivanteA sthma is well recognized as an inflammatory disorder of the airways characterized by increased levels of eosinophils (1,2). Eosinophils have been shown to be sensitive to the effects of gluticorticoids, because treatment with glucocorticoids has been shown to reduce the level of eosinophils in the peripheral blood (3,4) and airways of individuals with asthma (5), and to inhibit the allergeninduced increased levels of eosinophils in the peripheral blood and airways (6-8). The level of sputum eosinophils has been shown to predict the clinical benefit of steroid treatment for people with asthma (9,10).Although eosinophils are considered to be the hallmark of asthmatic airway inflammation, there is increasing evidence that neutrophils may also play a prominent role. Elevated levels of neutrophils have been measured in the airways of subjects with stable asthma (11), during exacerbations of asthma (12) and in fatal asthma of sudden onset ...

Allergen inhalation challenge in smoking compared with non-smoking asthmatic subjects

“…The smoking subjects had a significantly higher number of sputum neutrophils at baseline than did the non‐smokers. An allergen‐induced change in sputum neutrophils is often seen in non‐smoking mild asthmatics [21], but the lack of change in the smoking asthmatics was an unexpected finding.…”

Downmodulation of CXCL8/IL-8 receptors on neutrophils after recruitment in the airways

“…Moreover, the evaluation of neutrophil inflammation and the state of activation of these cells in asthmatic patients could be noteworthy for therapy and follow-up, considering that glucocorticoids are less effective in attenuating allergen-induced airway inflammation in subjects with high amounts of neutrophils. 27 Neutrophil recruitment is driven not only by CXCL8/IL-8 but also by other chemotactic factors, such as GCP-2, epithelial cellderived neutrophil attractan 78, and growth-related oncogene a-b-g, and thus the inhibition of a multiligandspecific receptor such as CXCR2 appears to be a more suitable therapeutic target than the inhibition of the activity of each single neutrophil chemotactic molecule. Recently, different antagonists of CXCR2 have been developed to prevent neutrophil accumulation; in particular, a selective nonpeptide antagonist of CXCR2 has been shown to exhibit significant anti-inflammatory effects in acute and chronic models of arthritis in rabbits.…”

Allergen-induced airway responses

“…The most prominent increase is in airway eosinophils [58,61] but also airway basophils [12] and, less consistently, neutrophils [62].…”