Inhibition of early airway neutrophilia does not affect development of airway hyperresponsiveness

Christian Taube, Jerry A. Nick, Britta Siegmund, Catherine Duez, Katsuyuki Takeda, Yeong Ho Rha, Jung Won Park, Anthony Joetham, Katie Poch, Azzeddine Dakhama, Charles A. Dinarello, Erwin W. Gelfand

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Abstract

The effect of modifying early neutrophil-mediated inflammation on the development of airway hyperresponsiveness (AHR) was investigated using an interleukin (IL)-1 receptor antagonist (IL-1Ra), an anti-IL-18 antibody (anti-IL-18) or a p38 mitogen-activated protein kinase (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 min before challenge, whereas M39 was administered 4 h before the challenge. Eight hours after challenge, sensitized mice showed significantly higher numbers of neutrophils in bronchoalveolar lavage (BAL) fluid; treatment with IL-1Ra, anti-IL-18, or M39 significantly decreased the influx of neutrophils. At 48 h, 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, IL-13, interferon-γ) in BAL fluid. Anti-IL-18 or IL-1Ra had no effect on the development of AHR, whereas M39-treated mice showed a decrease in methacholine 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.

Original languageEnglish
Pages (from-to)837-843
Number of pages7
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume30
Issue number6
DOIs
Publication statusPublished - 2004 Jun

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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    Taube, C., Nick, J. A., Siegmund, B., Duez, C., Takeda, K., Rha, Y. H., Park, J. W., Joetham, A., Poch, K., Dakhama, A., Dinarello, C. A., & Gelfand, E. W. (2004). Inhibition of early airway neutrophilia does not affect development of airway hyperresponsiveness. American Journal of Respiratory Cell and Molecular Biology, 30(6), 837-843. https://doi.org/10.1165/rcmb.2003-0395OC