Regular salbutamol use increases CXCL8 responses in asthma: relationship to the eosinophil response

Abstract

Regular salbutamol use can exacerbate allergen-induced airway eosinophilia in asthmatics, but its effect on airway eosinophil chemokine responses is unknown.Asthmatic subjects (n=14) were treated for 10 days with placebo or salbutamol in a double-blind, cross-over study, then given same-dose allergen challenges. Their sputa were then analysed 1 and 7 h later for a panel of eosinophil-related cytokines. Eosinophils from five test and three control subjects were tested for expression of CXCL8/interleukin (IL)-8, and its receptors and responsiveness to CCL11/eotaxin and CXCL8/IL-8.Sputum CXCL8/IL-8, but not IL-5, CCL5/regulated on activation, T-cell expressed and secreted, CCL7/monocyte chemotactic protein-3, CCL11/eotaxin, granulocytemacrophage colony-stimulating factor or tumour necrosis factor levels, were increased (42%) by the salbutamol treatments. The CXCL8/IL-8 levels correlated with the proportions of sputum eosinophils and these cells, but not other sputum cells, stained strongly for CXCL8/IL-8. The circulating eosinophils of the tested subjects (n=5) expressed CXCL8/IL-8 receptors and secreted high levels of this chemokine. Neutralisation of sputum CXCL8/IL-8 reduced eosinophil chemotactic responses to these samples by 19¡5%.These data suggest that regular use of salbutamol can augment airway CXCL8/ interleukin-8 responses to allergen challenge and that this CXCL8/interleukin-8 could contribute to the airway inflammatory response. Eur Respir J 2003; 22: 118-126 Inhaled b 2 -adrenergic receptor agonists (b 2 -agonists) comprise a primary therapy for bronchoconstriction in allergic asthma patients. However, evidence suggests that regular use of b 2 -agonists can reduce their effectiveness [1, 2] and lead to increased airway hyperresponsiveness [3][4][5] and eosinophil/ mast cell responses [4,5] to allergen challenge. Given the association of eosinophils with asthma severity and pathology [6], the cellular mechanisms that may regulate this eosinophil response were questioned.Eosinophils express receptors for many molecules that are highly pertinent to asthma pathophysiology [6]. For example, the CCR3 receptor, which binds multiple CC chemokines (e.g. CCL11/eotaxin [6]), is broadly accepted as critical to the eosinophil response. However, CXCL8/interleukin (IL)-8 is also strongly expressed within allergic lesions [7][8][9][10] and eosinophils are responsive to this CXCR1/CXCR2 ligand [11,12]. Indeed, the decreased eosinophilia after allergen immunotherapy may be related to reduced CXCL8/IL-8 responses to allergen challenge [13].In a recent study in which mildly asthmatic subjects (n=14) regularly used salbutamol (or placebo) for 10 days, an exacerbation of asthmatic responses (forced expiratory volume in one second (FEV1), serum tryptase and sputum eosinophils) to allergen challenge was observed [5]. In order to gain insight into potential mechanisms behind this eosinophilia [4,5], a panel of nine pertinent eosinophil-signalling cytokines/ chemokines in sputum, previously obtained from these subjec...

Concentration of CCL11, CXCL8 and TNF-alpha in sputum and plasma of patients undergoing asthma or chronic obstructive pulmonary disease exacerbation

“…Interestingly and in addition to CCL11, patients with asthma had elevated levels of CXCL8 and neutrophils in sputum and there was a positive correlation between these two variables. This is consistent with the results of other studies demonstrating the presence of neutrophils and CXCL8 during acute exacerbation of asthma (25)(26)(27). Nevertheless, there was no close relationship between sputum and plasma CXCL8 levels, suggesting that measurement of this chemokine in plasma is not useful to infer changes in the lung.…”

Enantiomer-Specific Effects of Albuterol on Airway Inflammation in Healthy and Asthmatic Cats

“…In this context, the observation by Baramki et al [4] that incubation of human T cells with equivalent concentrations of isomers had no effect on proliferation compared with control, but a 10-fold higher concentration of S -albuterol compared to R -albuterol led to enhanced T cell proliferation is intriguing. The results of the present study are in agreement with previous observations [32,33,34] that regular exposure to racemic albuterol for 1 week or more promotes inflammatory responses in patients with asthma, and they extend previous observations by showing that airway inflammation may be due to the detrimental effects of the S -isomer. …”

ELR-CXC Chemokine Receptor Antagonism Targets Inflammatory Responses at Multiple Levels

“…For processing, the sputum mucus plugs were dispersed by treatment with 1% DTT/HBSS, and then the cells were sedimented and the supernatants were dialyzed extensively against multiple changes of PBS, as noted previously (26 -28). The levels of CXCL8 in each sample were determined by ELISA, as noted (26). The supernatants were aliquoted and stored at Ϫ80°C.…”

“…Our ELISA protocols have been reported in detail previously (26). Culture supernatants were not diluted before the assays, whereas bronchoalveolar lavage (BAL) fluids for lactoferrin assays were diluted 1/10.…”