Anti-Fas mAb-induced apoptosis and cytolysis of airway tissue eosinophils aggravates rather than resolves established inflammation

• Main Authors: Persson Carl GA, Rydell-Törmänen Kristina, Uller Lena, Erjefält Jonas S
• Format: Article
• Language: English
• Published: BMC 2005-08-01
• Series: Respiratory Research
• Subjects: asthma; allergy; eosinophils; apoptosis; chemokines
• Online Access: http://respiratory-research.com/content/6/1/90

<p>Abstract</p> <p>Background</p> <p>Fas receptor-mediated eosinophil apoptosis is currently forwarded as a mechanism resolving asthma-like inflammation. This view is based on observations <it>in vitro </it>and in airway lumen with unknown translatability to airway tissues <it>in vivo</it>. 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 <it>in vivo </it>may include both apoptosis and cytolysis of eosinophils and, hence, that established eosinophilic inflammation may not resolve by this treatment.</p> <p>Methods</p> <p>Weeklong 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.</p> <p>Results</p> <p>Anti-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.</p> <p>Conclusion</p> <p>An efficient inducer of eosinophil apoptosis in airway tissues <it>in vivo</it>, 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 <it>in vivo </it>may cause severe disease exacerbation due to direct cytolysis and secondary necrosis of eosinophils.</p>