Airway epithelium mediated structural cell remodeling

The epithelium lining our airway can be labeled as one of the most 'influential' cells in the human body, forming a barrier against inhaled agonists and coordinating external signals with internal responses of the airway. Lying adjacent to the normal human bronchial epithelial cells (NHBE) are structural cells, namely normal human lung fibroblasts (NHLF) in the lamina propria and human airway smooth muscle cells (HASM) in the submucosa. Airway diseases, e.g. asthma and COPD, initiate with an attack on the airway epithelium causing it to be altered or injured and this altered epithelium can in turn send signals deeper into the airway affecting the structural cells. Such communication prevalent during lung development is proposed to be reactivated and uncontrolled in disease. This study identifies novel epithelium derived mediators and highlights the importance of the communication between the epithelium (normal or altered) and the underlying structural cells.;Altered NHBE, marked by increased mucus production, TGFbeta2 levels and decreased cilia on chronic treatment with IL-13, were co-cultured with NHLF to study NHBE-NHLF communication. Co-culture of 1-day post withdrawal of IL-13 from chronically pre-treated NHBE results in elevated, collagen secretion and SHG signal from the NHLF. Furthermore this increase was reversed by using a TGFbeta2 antibody and lost in co-culture with extended periods of withdrawal of IL-13 from the chronically pretreated NHBE, suggesting a plasticity of the airway epithelium.;Uninjured and injured NHBE co-cultured with HASM to study NHBE-HASM communication results in increased HASM proliferation. IL-6, IL-8, MCP-1, MMP-9 are identified as novel HASM proliferation stimulants using respective neutralizing antibodies, MMP-9 chemical and siRNA inhibition. Furthermore augmented HASM proliferation and submucosal MMP-9 expression was also observed in an in vivo rabbit tracheal scrape model.;Next the diffusion process of epithelial derived mediators reaching the HASM was characterized to examine the importance of NHBE-HASM distance and thickness of the fibrotic layer as diffusion resistance.;In summary we conclude that epithelium mediated structural cell remodeling can be a serious contributor in development and propagation of airway remodeling in asthma and COPD. Making the epithelium as well as its secreted factors attractive targets for therapeutic intervention.