How allergens increase lung fibrosis in asthma

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In asthma, repeated exposure to allergens lowers PGE2 expression in the lung fibroblasts, among other things. This increases lung remodeling through fibrosis. Samter's patients have an increased version of this process going on, since Samter's in itself is a condition where PGE2 is under-produced. Hence, those of us with asthma have greater lung fibrosis, and therefore worse asthma, than other asthma patients. (But note that other pathways may also contribute to the increased severity of asthma in Samter's).--------------Am J Physiol Lung Cell Mol Physiol. 2011 Aug 26. [Epub ahead of print]AIRWAY REMODELING IN MURINE ASTHMA CORRELATES WITH A DEFECT IN PGE2 SYNTHESIS BY LUNG FIBROBLASTS.Stumm CL, Wettlaufer SH, Jancar S, s-Golden M.Source1University of São o.AbstractAsthma is a chronic lung disease characterized by local inflammation which 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. When compared to 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 (mPGEs-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. Since 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.PMID: 21873451 [PubMed - as supplied by publisher]