Using primary cell lines from upper and lower respiratory tracts to develop air-liquid epithelial cell models of pediatric asthma
Treatment practices for asthma have remained largely unchanged over the past two decades, relying on combinations of bronchodilators and steroids to manage the disease. While the symptoms of asthma can in many instances be controlled with diligent medication use, the underlying pathology and potential long-term declines of lung function remain largely unaddressed. Developing improved human model systems to study the role of the airway epithelium in asthma is a key step towards creating novel treatment options that can prevent airway remodeling and declines in lung function as well as provide curative outcomes.
Dr. Debley has clinical expertise in asthma, cystic fibrosis, bronchopulmonary dysplasia, restrictive lung diseases of childhood and the management of acute and chronic respiratory failure. Through a long-term translational study involving the collection of bronchial and nasal epithelial cells from carefully characterized children with and without asthma, Dr. Debley is investigating the role airway epithelium plays in tissue remodeling and augmentation of airway inflammation in asthma through the use of an in vitro air-liquid interface model system. With this model, Dr. Debley is able to differentiate primary airway epithelial progenitor cells to achieve an ex vivo pseudo-stratified epithelial layer that includes ciliated apical cells and goblet cells characteristic of the in vivo airway. Furthermore, Dr. Debley has developed co-culturing techniques that incorporate fibroblasts and leukocytes into these differentiated epithelial culture models, which can reproduce complex cell-cell interactions in an in vitro and ex vivo setting.
Ongoing barriers to developing improved asthma treatments include the challenges of modeling the complex genetic and extra-cellular interactions that cause the disease. Alarmins such as TSLP and IL-33 are more readily released by the epithelium in patients with asthma, leading to increased and prolonged inflammatory responses. Additionally, TGF-β2 and VEGF tend to be upregulated by the epithelium of asthma patients, promoting airway remodeling that results in lung function declines. While specific phenotypic profiles are varied between patients and cannot be linked to any single genetic pathway, Dr. Debley’s advanced cellular model of the airway epithelium can shed light on some of the complex cellular mechanisms that drive asthma pathophysiology, as well as identify new therapeutic targets.
Dr. Debley is interested in collaborating with industry partners to help validate new therapeutic targets for asthma and other upper and lower airway diseases involving the epithelium. Besides the potential to conduct high-throughput pre-clinical screening of new drugs, this model allows the controlled study of pro-asthma stimuli including viral infection and pollen, smoke, and particulate exposure.
Stage of Development
- Pre-clinical in vitro
- Pre-clinical ex vivo
- Collaborative research opportunity
- Development opportunity
- Sponsored research agreement
- Consultation agreement
- High-throughput screening
- Tissue sample access
- Reeves S, Kolstad T, Lien T, … Debley J. Asthmatic airway epithelial cells differentially regulate fibroblast expression of extracellular matrix components. Journal of Allergy and Clinical Immunology. 2014;134(3):663-670.e1.
- Iwanaga K, Elliott M, Vedal S, Debley J. Urban particulate matter induces pro-remodeling factors by airway epithelial cells from healthy and asthmatic children. Inhalation Toxicology. 2013;25(12):653-660.
- Lopez-Guisa J, Powers C, File D, Cochrane E, Jimenez N, Debley J. Airway epithelial cells from asthmatic children differentially express proremodeling factors. Journal of Allergy and Clinical Immunology. 2012;129(4):990-997.e6.
- Lee H, Headley M, Loo Y, … Debley J et al. Thymic stromal lymphopoietin is induced by respiratory syncytial virus–infected airway epithelial cells and promotes a type 2 response to infection. Journal of Allergy and Clinical Immunology. 2012;130(5):1187-1196.e5.
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