Fas deficiency delays the resolution of airway hyperresponsiveness after allergen sensitization and challenge

Background: In asthma, persistent inflammation might be the result of (1) a n impaired ability to clear inflammatory cells from the airways and/or (2) impaired apoptotic responses. Objective: In a mouse model, we investigated the regulatory role of Fas (CD 95)-induced apoptosis in the development and resolution of airway inflammat ion and airway hyperresponsiveness (AHR). Methods: Mice that were either Fas-sufficient (wild-type; WT) or Fas-defici ent (lpr) were sensitized by intraperitoneal injections of ovalbumin (OVA) and challenged once intranasally with OVA (IP-IN mice). Control (IN) mice w ere challenged only. Results: IP-IN WT mice developed AHR at 48 hours; changes in airway resista nce resolved by 96 hours. Airway responsiveness at 48 hours in IP-IN lpr mi ce was sin-Alar to that in IP-IN WT mice. However, in contrast to WT mice, IP-IN lpr mice sustained significant AHR at 96 hours in comparison with IN lpr mice; the AHR resolved by 6 days. Bronchoalveolar lavage fluid cell com position was similar in all of the different groups at 48 hours and 96 hour s. Both IP-IN WT mice and lpr mice exhibited similar tissue eosinophilia, w hereas IP-IN lpr mice had significantly lower numbers of TdT-mediated dUTP nick end labeling (TUNEL)-positive cells in comparison with IP-IN WT mice a t 48 hours. Anti-IL-5 antibody given to IP-IN lpr mice 48 hours and 72 hour s after the challenge significantly decreased AHR and eosinophilic inflamma tion and increased TUNEL-positive cell numbers at 96 hours. Conclusion: These results suggest that Fas expression can regulate the onse t and resolution of AHR through an increase in eosinophil apoptosis.