Dysregulated Airway Epithelial Signaling as a Driver of Airway Remodeling in Asthmatic Children

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 DESCRIPTION (provided by applicant): Epidemiologic studies have revealed that asthmatic children have lower lung function during childhood that persists into adulthood compared to healthy children. Bronchial biopsies from asthmatic children demonstrate that features of airway remodeling, including excessive sub-epithelial extracellular matrix deposition (e.g. collagens, hyaluronan), are already present in early childhood. Together, these data suggest that early structural changes in the asthmatic airway may contribute to lung function declines that manifest early in the natural history of asthma. Although inhaled corticosteroids reduce morbidity, treatment does not alter the natural history of asthma nor prevent decline in lung function. Improved understanding of mechanisms that drive airway remodeling is fundamental to the development of future clinical interventions to alter the natural course of asthma and prevent lung function decline. Airway epithelial cells are the first point of contact between the environment and the host lung. Evidence from animal models and human bronchial biopsies suggest that the bronchial epithelium secretes a number of proteins that may regulate lung fibroblasts and airway remodeling. Our group has demonstrated that primary airway epithelial cells from asthmatic children intrinsically exhibit greater expression of candidate pro-remodeling factors, when compared to healthy epithelial cells. We have also reported that in co-culture airway epithelial cells from healthy children markedly down-regulate lung fibroblast expression of extracellular matrix components involved in airway remodeling. In contrast, this down-regulation is significantly less when fibroblasts are co-cultured with asthmatic epithelial cells. Preliminary data from our human airway epithelial cell model systems suggest prostaglandin E2 (PGE2) and the activin inhibitor follistatin-like-3 (FSTL3) as epithelial-secreted proteins that ma tonically inhibit fibroblast function. We propose to use innovative airway epithelial cell/fibroblat co-culture model systems with primary bronchial epithelial cells from well-characterized asthmatic and healthy children to test our hypothesis that in normal airways a balance of epithelial-derived stimulatory and inhibitory factors regulates fibroblasts and inhibits airway interstitial extracellular matrix deposition involved in airway remodeling. We will test our hypothesis that expression of these factors is dysregulated in asthma, specifically with increased TGFß2 and activin A, as well as decreased PGE2 and FSTL3 expression by asthmatic epithelial cells, leading to increased fibroblast proliferation and extracellular matrix expression. Finally, we will test our hypotheses that fibroblast proliferation and expression of extracellular matrix constituents and epithelial secretion of TGFß2, activin A, PGE2 and FSTL3, in asthmatic co-cultures are associated with asthma severity, asthma exacerbations, and/or lung function among the asthmatic children who donated airway epithelial cells used in co-culture experiments.