Published ahead of print on January 23, 2004, doi:10.1165/rcmb.2003-0395OC Am. J. Respir. Cell Mol. Biol., Volume 30, Number 6, June 2004, 837-843 A more recent version of this article appeared on June 1, 2004
Submitted on November 5, 2003 INHIBITION OF EARLY AIRWAY NEUTROPHILIA DOES NOT AFFECT DEVELOPMENT OF AIRWAY HYPERRESPONSIVENESSChristian Taube1,1 Pediatrics, National Jewish Center, Denver, CO, USA, 2 Medicine, National Jewish Center, Denver, CO, USA; Medicine, University of Colorado Health Sciences Center, Denver, CO, USA, 3 Medicine, National Jewish Center, Denver, CO, USA, 4 Medicine, University of Colorado Health Sciences Center, Denver, CO, USA * To whom correspondence should be addressed. E-mail: gelfande{at}njc.org.
The effect of modifying early neutrophil-mediated inflammation on the development of airway hyperresponsiveness (AHR) was investigated using an IL-1 receptor antagonist (IL-1Ra), an anti-IL-18 antibody (anti-IL-18) or a p38 MAPK inhibitor (M39). Balb/c mice were sensitized to ovalbumin (OVA) and challenged with a single intranasal dose of OVA. Treatment with the IL-1Ra or anti-IL-18 was initiated 20 minutes before challenge, whereas M39 was administered four hours prior to the challenge. Eight hrs after challenge, sensitized mice showed significantly higher numbers of neutrophils in BAL fluid; treatment with IL-1Ra, anti-IL-18 or M39 significantly decreased the influx of neutrophils. At 48 hrs, none of the treatments affected eosinophil inflammation in BAL fluid and lung tissue, goblet cell hyperplasia or cytokine levels (IL-4, IL-5, IL-12, IFN-
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) in BAL fluid. Anti-IL-18 or IL-1Ra had no effect on the development of AHR, while M39-treated mice showed a decrease in MCh responsiveness. These results demonstrate that early neutrophil influx following allergen challenge is mediated by IL-1, IL-18 and p38 MAPK. However, neutralization of IL-1 and IL-18 did not affect the later development of AHR and eosinophilic airway inflammation. The effects of inhibiting p38 MAPK in decreasing AHR indicate activities independent of its prevention of neutrophil accumulation.
