Asthma is a chronic
lung disease characterized by local
inflammation that can result in structural alterations termed
airway remodeling. One component of
airway remodeling involves fibroblast accumulation and activation, resulting in deposition of
collagen I around small bronchi.
Prostaglandin E(2) (
PGE(2)) is the main
eicosanoid lipid mediator produced by lung fibroblasts, and it exerts diverse anti-fibrotic actions. Dysregulation of the
PGE(2) synthesis/response axis has been identified in human pulmonary fibrotic diseases and implicated in the pathogenesis of animal models of lung parenchymal
fibrosis. Here we investigated the relationship between the fibroblast
PGE(2) axis and airway
fibrosis in an animal model of chronic allergic
asthma. Airway
fibrosis increased progressively as the number of airway challenges with
antigen increased from 3 to 7 to 12. Compared with cells from control lungs, fibroblasts grown from the lungs of asthmatic animals, regardless of challenge number, exhibited no defect in the ability of
PGE(2) or its analogs to inhibit cellular proliferation and
collagen I expression. This correlated with intact expression of the EP(2) receptor, which is pivotal for
PGE(2) responsiveness. However,
cytokine-induced upregulation of
PGE(2) biosynthesis as well as expression of
cyclooxygenase-2 (COX-2) and microsomal
PGE synthase-1 declined with increasing numbers of
antigen challenges. In addition, treatment with the COX-2-selective inhibitor
nimesulide potentiated the degree of airway
fibrosis following repeated
allergen challenge. Because endogenous COX-2-derived
PGE(2) acts as a brake on airway
fibrosis, the inability of fibroblasts to upregulate
PGE(2) generation in the inflammatory milieu presented by repeated
allergen exposure could contribute to the
airway remodeling and
fibrosis observed in chronic
asthma.