Human bronchial epithelial cells_Passage 3 vs. passage 0 . Homo sapiens

Squamous metaplasia is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether squamous metaplasia actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry and fibroblast culture of lung samples from COPD patients, genome-wide analysis of a model of squamous metaplasia, and in vitro modeling of human airway epithelial-mesenchymal interactions, we have produced evidence that squamous metaplasia, through the increased secretion of IL-1, induces a fibrotic response of adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-b activation in amplifying squamous metaplasia and driving IL-1-dependent profibrotic mesenchymal responses. Finally, we show that squamous metaplasia correlates with increasing severity of COPD and fibroblast expression of the integrin avb8, which is the major mediator of airway fibroblast TGF-b activation, correlates with disease severity and small airway wall thickening in COPD. Keywords: genome-wide differential expression study Overall design: A dye-swap design of three two-channel arrays