Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge

Arihiko Kanehiro, Toshihide Ikemura, Mika J. Mäkelä, Michael Lahn, Anthony Joetham, Azzeddine Dakhama, Erwin W. Gelfand

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

We compared for the first time the therapeutic potential of a specific phosphodiesterase 4 (PDE4) inhibitor, rolipram, with anti-VLA-4 and anti-IL-5 in a model of secondary allergen exposure of previously sensitized and challenged mice. To address these issues, mice were sensitized and challenged with ovalbumin (OVA) (primary challenge). Six weeks later, sensitized/challenged mice were reexposed to OVA (secondary challenge) and airway response (resistance [RL] and dynamic compliance [Cdyn]) to inhaled methacholine was monitored. After secondary OVA challenge, RL significantly increased as did the number of lung inflammatory cells and IL-4 and IL-5 production in bronchoalveolar lavage fluid (BALF). Administration of rolipram, in a dose-dependent manner, significantly prevented both changes in RL and Cdyn, as well as eosinophil, lymphocyte, and neutrophil accumulation in the BALF; IL-4 and IL-5 levels in BALF were also significantly reduced. In contrast, treatment with anti-VLA-4 and anti-IL-5 only prevented changes in RL and eosinophil numbers and IL-5 production in BALI. Further, goblet cell hyperplasia was suppressed only by treatment with rolipram. None of the treatments affected OVA-specific antibody levels. These studies confirm that IL-5 dependent eosinophilic inflammation plays an essential role in the development of certain aspects of airway function after rechallenge of sensitized mice and that lymphocytes and neutrophils are also important in the development of altered airway function. The use of agents that inhibit PDE4 may have an important role in the treatment of asthma in previously sensitized mice.

Original languageEnglish
Pages (from-to)173-184
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume163
Issue number1
Publication statusPublished - 2001
Externally publishedYes

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Type 4 Cyclic Nucleotide Phosphodiesterase
Interleukin-5
Allergens
Ovalbumin
Rolipram
Inflammation
Bronchoalveolar Lavage Fluid
Integrin alpha4beta1
Eosinophils
Interleukin-4
Neutrophils
Phosphodiesterase 4 Inhibitors
Lymphocytes
Therapeutics
Airway Resistance
Goblet Cells
Methacholine Chloride
Compliance
Hyperplasia
Asthma

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge. / Kanehiro, Arihiko; Ikemura, Toshihide; Mäkelä, Mika J.; Lahn, Michael; Joetham, Anthony; Dakhama, Azzeddine; Gelfand, Erwin W.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 163, No. 1, 2001, p. 173-184.

Research output: Contribution to journalArticle

Kanehiro, Arihiko ; Ikemura, Toshihide ; Mäkelä, Mika J. ; Lahn, Michael ; Joetham, Anthony ; Dakhama, Azzeddine ; Gelfand, Erwin W. / Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge. In: American Journal of Respiratory and Critical Care Medicine. 2001 ; Vol. 163, No. 1. pp. 173-184.
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