An in vitro airway wall model of remodeling

Departments of 1 Biomedical Engineering and 3 Chemical Engineering, Northwestern University, Evanston 60208; and 2 Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University and Veterans Affairs Chicago Health Care System - Lakeside Division, Chicago, Illinois 60611 Submitted 8 January 2003 ; accepted in final form 23 April 2003 Recent studies have shown that mechanical forces on airway epithelial cells can induce upregulation of genes involved in airway remodeling in diseases such as asthma. However, the relevance of these responses to airway wall remodeling is still unclear since 1 ) mechanotransduction is highly dependent on environment (e.g., matrix and other cell types) and 2 ) inflammatory mediators, which strongly affect remodeling, are also present in asthma. To assess the effects of mechanical forces on the airway wall in a relevant three-dimensional inflammatory context, we have established a tissue culture model of the human airway wall that can be induced to undergo matrix remodeling. Our model contains differentiated human bronchial epithelial cells characterized by tight junctions, cilia formation, and mucus secretion atop a collagen gel embedded with human lung fibroblasts. We found that addition of activated eosinophils and the application of 50% strain to the same system increased the epithelial thickness compared with either condition alone, suggesting that mechanical strain affects airway wall remodeling synergistically with inflammation. This integrated model more closely mimics airway wall remodeling than single-cell, conditioned media, or even two-dimensional coculture systems and is relevant for examining the importance of mechanical strain on airway wall remodeling in an inflammatory environment, which may be crucial for understanding and treating pathologies such as asthma. asthma; human bronchial epithelial cells; eosinophils; mechanical stress; airway inflammation Address for reprint requests and other correspondence: M. A. Swartz, Dept. of Biomedical Engineering, Northwestern Univ., 2145 N. Sheridan Rd., Evanston, IL 60208-3107 (E-mail: m-swartz2{at}northwestern.edu ).