Abstract
BackgroundThe pathophysiology of asthma involves allergic inflammation and remodelling in the airway and airway hyperresponsiveness (AHR) to cholinergic stimuli, but many details of the specific underlying cellular and molecular mechanisms remain unknown. Periostin is a matricellular protein with roles in tissue repair following injury in both the skin and heart. It has recently been shown to be up-regulated in the airway epithelium of asthmatics and to increase active TGF-β. Though one might expect periostin to play a deleterious role in asthma pathogenesis, to date its biological role in the airway is unknown.ObjectiveTo determine the effect of periostin deficiency on airway responses to inhaled allergen.MethodsIn vivo measures of airway responsiveness, inflammation, and remodelling were made in periostin deficient mice and wild-type controls following repeated intranasal challenge with Aspergillus fumigatus antigen. In vitro studies of the effects of epithelial cell-derived periostin on murine T cells were also performed.ResultsSurprisingly, compared with wild-type controls, periostin deficient mice developed increased AHR and serum IgE levels following allergen challenge without differences in two outcomes of airway remodelling (mucus metaplasia and peribronchial fibrosis). These changes were associated with decreased expression of TGF-β1 and Foxp3 in the lungs of periostin deficient mice. Airway epithelial cell-derived periostin-induced conversion of CD4+ CD25− cells into CD25+, Foxp3+ T cells in vitro in a TGF-β dependent manner.Conclusions and Clinical RelevanceAllergen-induced increases in serum IgE and bronchial hyperresponsiveness are exaggerated in periostin deficient mice challenged with inhaled aeroallergen. The mechanism of periostin's effect as a brake on allergen-induced responses may involve augmentation of TGF-β-induced T regulatory cell differentiation.
Highlights
Asthma is a common disease characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), airway inflammation, mucus hypersecretion and subepithelial fibrosis [1]
In high-density microarray studies of gene expression in the airway epithelium in asthmatic subjects and healthy controls, we recently found that periostin is among the most highly up-regulated genes in asthma and that its expression in airway epithelial cells is regulated by interleukin 13 (IL-13), a Th2 cytokine [2]
Because we have found that periostin up-regulates TGF-b, we further anticipated that upregulation of lung periostin in these mice would be associated with an increase in TGF-b
Summary
Asthma is a common disease characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), airway inflammation, mucus hypersecretion and subepithelial fibrosis [1]. Th2-type inflammation and characterized by high levels of serum IgE, systemic and lung eosinophilia, increased thickness of the reticular basement membrane and responsiveness to corticosteroids [3]. We have demonstrated that in airway epithelial cell culture models periostin increases levels of active TGF-b and that it has roles in regulating collagen synthesis and collagen gel elasticity [16]. TGF-b has multiple effects in the lung, including antiinflammatory activity attributable to its induction of T regulatory cells and pro-fibrotic activity attributable to its effects on fibroblasts [17,18,19,20,21,22,23], so that its influence on asthma outcomes, such as AHR, airway eosinophilia and airway remodelling (peribronchial fibrosis and epithelial mucins), can vary depending on the specifics of the mouse model and the mechanism of TGF-b manipulation. We included a range of outcomes in our study design, including markers of AHR, eosinophils, T regulatory cells, peribronchial fibrosis and epithelial mucins
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