Abstract

BackgroundFas receptor-mediated eosinophil apoptosis is currently forwarded as a mechanism resolving asthma-like inflammation. This view is based on observations in vitro and in airway lumen with unknown translatability to airway tissues in vivo. In fact, apoptotic eosinophils have not been detected in human diseased airway tissues whereas cytolytic eosinophils abound and constitute a major mode of degranulation of these cells. Also, Fas receptor stimulation may bypass the apoptotic pathway and directly evoke cytolysis of non-apoptotic cells. We thus hypothesized that effects of anti-Fas mAb in vivo may include both apoptosis and cytolysis of eosinophils and, hence, that established eosinophilic inflammation may not resolve by this treatment.MethodsWeeklong daily allergen challenges of sensitized mice were followed by airway administration of anti-Fas mAb. BAL was performed and airway-pulmonary tissues were examined using light and electron microscopy. Lung tissue analysis for CC-chemokines, apoptosis, mucus production and plasma exudation (fibrinogen) were performed.ResultsAnti-Fas mAb evoked apoptosis of 28% and cytolysis of 4% of eosinophils present in allergen-challenged airway tissues. Furthermore, a majority of the apoptotic eosinophils remained unengulfed and eventually exhibited secondary necrosis. A striking histopathology far beyond the allergic inflammation developed and included degranulated eosinophils, neutrophilia, epithelial derangement, plasma exudation, mucus-plasma plugs, and inducement of 6 CC-chemokines. In animals without eosinophilia anti-Fas evoked no inflammatory response.ConclusionAn efficient inducer of eosinophil apoptosis in airway tissues in vivo, anti-Fas mAb evoked unprecedented asthma-like inflammation in mouse allergic airways. This outcome may partly reflect the ability of anti-Fas to evoke direct cytolysis of non-apoptotic eosinophils in airway tissues. Additionally, since most apoptotic tissue eosinophils progressed into the pro-inflammatory cellular fate of secondary necrosis this may also explain the aggravated inflammation. Our data indicate that Fas receptor mediated eosinophil apoptosis in airway tissues in vivo may cause severe disease exacerbation due to direct cytolysis and secondary necrosis of eosinophils.

Highlights

  • Fas receptor-mediated eosinophil apoptosis is currently forwarded as a mechanism resolving asthma-like inflammation

  • Differing from the prior reports, that focused on airway lumen data [7,23], this study explores airway tissue effects of anti-Fas monoclonal antibody (mAb) given to mouse allergic airways with already established eosinophilic inflammation

  • Post-challenge intra-nasal administration of anti-Fas mAb to the lungs of these mice decreased the number of eosinophils in the airway lumen (BALF) at 8 and 24 hours (Figure 2A) compared to animals receiving isotype control Ab

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Summary

Introduction

Fas receptor-mediated eosinophil apoptosis is currently forwarded as a mechanism resolving asthma-like inflammation. This view is based on observations in vitro and in airway lumen with unknown translatability to airway tissues in vivo. Fas receptor stimulation may bypass the apoptotic pathway and directly evoke cytolysis of non-apoptotic cells. We hypothesized that effects of anti-Fas mAb in vivo may include both apoptosis and cytolysis of eosinophils and, that established eosinophilic inflammation may not resolve by this treatment. A specific mode of inducing death through apoptosis is stimulation of Fas antigen (Fas), a cell surface protein expressed in most cells including eosinophil granulocytes [11]. Eosinophil cytolysis causing extra-cellular spilling of eosinophil granules commonly occurs in asthmatic bronchi [13] but it is not known whether stimulation of the Fas-receptor may evoke cytolysis of eosinophils

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