Airway epithelial injury occurs following inhalation of toxic agents, infection, intubation, and in a chronic repetitive disease such as asthma which impacts approximately 10% of the population in the United States. The wound repair response of the epithelium can induce changes in the structure and mechanical properties of the underlying connective tissue that can alter normal lung function. In bronchial asthma, alterations in the airway mucosa become more prominent as the disease progresses, and are correlated with disease severity, symptoms, and lung function (i.e., fixed airflow obstruction). The bronchial epithelium is known to modulate the development of the lung parenchyma during embryogenesis and these signaling pathways are likely "re- awakened" during chronic inflammatory diseases such as asthma resulting in pathological tissue growth. Our central hypothesis is that the wounded and inflamed epithelium secretes soluble mediators which diffuse into the underlying stroma at biologically active concentrations to significantly influence the mechanical properties of the matrix.
Our specific aims are structured to specifically address the role of the epithelium in modulating the mechanical and optical properties of the subepithelial matrix: 1) utilizing both physical (compressive and scrape) and chemical (IL-13) injuries to the normal human bronchial epithelium in vitro, characterize the resulting impact on the optical and mechanical properties of the subepithelial matrix;2) characterize the relationship between optical endpoints and the mechanical properties of both acellular and cellularized collagen gels in which collagen content, microstructure, and transforming growth factor-2 are systematically altered;3) quantify changes in the optical and mechanical properties of the tracheal mucosa in a rabbit model of repeated airway epithelial injury. The proposal combines novel tissue engineering techniques which mimic the anatomical arrangement of the epithelium and lamina propria, conventional biological techniques to assess protein expression, non-traditional minimally-invasive optical techniques (multiphoton laser scanning microscopy and optical coherence tomography) to assess bulk and microscopic changes in the matrix, and an in vivo model of tracheal epithelial injury. Completion of these aims will provide insight into the underlying mechanisms of airway remodeling, and provide a platform for non-invasive diagnostics for not only the airway, but other epithelial tissues subject to chronic or acute injury (e.g., cornea, skin).
Airway injury, manifested primarily by asthma, is one of the most prevalent chronic diseases in the United States. Diagnosis and management remain challenging due to the chronic repetitive nature of the disease that leads to tissue remodeling. The proposal seeks to understand the link between the biological mechanisms that trigger changes in the mechanical and optical properties in the airway mucosa. The results should provide a platform for drug discovery and non-invasive diagnostics.
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