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).

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Biomedical Engineering
Schools of Engineering
United States
Zip Code
Robertson, Claire; Heidari, Andrew E; Chen, Zhongping et al. (2014) Mechanical analysis of arterial plaques in native geometry with OCT wall motion analysis. J Biomech 47:755-8
Merna, Nick; Robertson, Claire; La, Anh et al. (2013) Optical imaging predicts mechanical properties during decellularization of cardiac tissue. Tissue Eng Part C Methods 19:802-9
Robertson, Claire; Ikemura, Kenji; Krasieva, Tatiana B et al. (2013) Multiscale analysis of collagen microstructure with generalized image correlation spectroscopy and the detection of tissue prestress. Biomaterials 34:6127-32
Zhou, Jian; Alvarez-Elizondo, Martha B; Botvinick, Elliot et al. (2013) Adenosine A(1) and prostaglandin E receptor 3 receptors mediate global airway contraction after local epithelial injury. Am J Respir Cell Mol Biol 48:299-305
Zhou, Jian; Alvarez-Elizondo, Martha B; Botvinick, Elliot et al. (2012) Local small airway epithelial injury induces global smooth muscle contraction and airway constriction. J Appl Physiol 112:627-37
Jiang, Jingjing; George, Steven C (2011) TGF-ýý2 reduces nitric oxide synthase mRNA through a ROCK-dependent pathway in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 301:L361-7
George, Steven C; Hlastala, Michael P (2011) Airway gas exchange and exhaled biomarkers. Compr Physiol 1:1837-59
Robertson, Claire; Lee, Sang-Won; Ahn, Yeh-Chan et al. (2011) Investigating in vivo airway wall mechanics during tidal breathing with optical coherence tomography. J Biomed Opt 16:106011
Jiang, Jingjing; George, Steven C (2011) Modeling gas phase nitric oxide release in lung epithelial cells. Nitric Oxide 25:275-81
Raub, Christopher B; Mahon, Sari; Narula, Navneet et al. (2010) Linking optics and mechanics in an in vivo model of airway fibrosis and epithelial injury. J Biomed Opt 15:015004

Showing the most recent 10 out of 26 publications