Importance of concomitant local and systemic eosinophilia in uncontrolled asthma
- 1Dept Clinical Pharmacology, Laboratory Medicine, Lund University Hospital, Lund, Sweden
- 2Dept Experimental Medical Science, Unit of Respiratory Immunopharmacology, Lund University, Lund, Sweden
- Carl Persson, Dept Clinical Pharmacology, Laboratory Medicine, Lund University Hospital, S-22185 Lund, Sweden. E-mail: Carl.persson{at}med.lu.se
To the Editor:
We read with interest the comprehensive, combined retrospective and prospective study on eosinophilia in asthma by Schleich et al. [1]. As compellingly demonstrated by Schleich et al. [1] concomitant elevation of sputum and blood eosinophil numbers is an important factor in poorly controlled asthma. These data agree with the view that both local airway “inflammation” and blood eosinophilia contribute as risk factors in asthma [2]. However, there are additional eosinophil features, other than just counts, that characterise asthma. Here we draw attention to the potential roles of primary lysis/necrosis of eosinophils as blood biomarkers and bronchial-pathogenic mechanisms, especially in uncontrolled asthma.
Schleich et al. [1] briefly discuss previous findings on eosinophil numbers reported by Volbeda et al. [3]. However, a principal message of the latter study concerned association between poor asthma control and “activated eosinophils” and loss of “epithelial intactness”, respectively, in bronchial biopsies. It emerged that the eosinophils had been activated by primary lysis that results in the spilling of toxic protein-releasing free eosinophil granules (FEGs) in the bronchial tissue [3, 4].
Furthermore, contrasting the significant associations with FEGs, poor asthma control was not associated with the number of eosinophils in sputum or bronchial tissue [3, 4].
The observations by Volbeda et al. [3] support pathogenic roles of primary eosinophil lysis-produced, release-competent FEGs. Intriguing is the potential of this mechanism to derange the epithelial lining and evoke inflammation and remodelling as a consequence of exaggerated epithelial repair [5]. Inflammation should probably be equalled to inflammatory activity rather than the number of eosinophils.
Muniz-Junqueira et al. [6] demonstrate that blood eosinophils undergo lysis (plus spilling of FEGs) more readily the more severe the asthma is. Unprecedentedly, the pro-lysis propensity distinctly separates three levels of severity amongst children with acute asthma exacerbations [6]. Hence, proclivity of blood eosinophils for primary lysis may biomark severe asthma.
Inferentially, eosinophils would be primed for cytolysis before arriving in severely diseased bronchi. Priming may be produced by interleukin (IL)-5, which switches pro-apoptosis responses into primary lysis, as reviewed in Persson and Uller [7]. We think such switching is important as: 1) it may explain the enigmatic absence of apoptotic eosinophils in diseased airways; and 2) anti-IL5 drugs may owe part of their anti-asthma effects to the inhibition of pro-lysis priming.
Furthermore, bronchial wall FEGs and clinical asthma were not reduced in anti-IL5-treated asthmatics despite the inhibition of sputum and blood eosinophils [8]. Hence, additional priming factors are likely to be involved in eosinophil lysis in asthma.
Hargreave's research group reported that FEGs in sputum distinguish severe exacerbations of asthma from stable asthma, and demonstrated the inhibition of FEGs at clinical improvement by systemic corticosteroids [9].
However, there are limitations with the sputum approach. Potentially underestimating the frequency of eosinophilic asthma, occurrence of intact and lytic eosinophils/FEGs in sputum does not always reflect bronchial wall events. For example, obesity-asthma exhibits bronchial tissue FEGs; in these patients, who lack sputum eosinophilia, lysis would have prevented tissue eosinophils from migrating into the bronchial lumen.
Hence, lysis of tissue-dwelling eosinophils may partly explain the lack of sputum eosinophilia in patients who nevertheless suffer from eosinophilic asthma [7].
Primary eosinophil lysis involves chromatolysis, cell membrane rupture, release of FEGs (in turn releasing toxic proteins and cytokines) and nuclear and cytosolic danger molecules [7]. Asthma-relevant stimuli, including allergens and microbial factors, produce prompt eosinophil lysis. Abundance of FEGs in lethal asthma, severe aspirin-sensitive asthma, severe late-onset asthma and asthma exacerbations, reflect extensive eosinophil lysis in these patients and the lack of inhibition of eosinophil lysis by standard corticosteroid treatment (as reviewed in Persson and Uller [7]).
Genomics may now be combined with other omics and systems-biology approaches in attempts to find molecular signatures of asthma [10]. However, progress in understanding asthma still relies on developments using classical research as evidenced by Schleich et al. [1]. We propose that propensity for, and execution of, primary lysis of eosinophils in blood and bronchi, respectively, needs attention in studies of severe asthma.
Footnotes
Conflict of interest: None declared.
- Received June 2, 2014.
- Accepted June 2, 2014.
- ©ERS 2014