Advanced Ex Vivo Modeling of Pediatric Asthmatic Airway Epithelial Cells
Using primary cell lines from the upper and lower respiratory tracts in organotypic airway epithelial cell models of pediatric asthma
Apart from expensive biologics for severe asthma, treatment practices for most patients with asthma have remained largely unchanged over the past two decades, relying on combinations of bronchodilators and steroids to manage the disease. While 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, and current treatments are suboptimal in preventing viral triggered acute exacerbations. Developing improved human model systems to study the role of the airway epithelium in asthma is a key step towards creating novel treatment options to prevent acute exacerbations, airway remodeling and declines in lung function.
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. Utilizing a longstanding mechanistic translational study protocol and infrastructure to collect 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, innate immune responses to viral infection and augmentation of airway TH2 inflammation in asthma through the use of ex vivo organotypic airway model systems using the air-liquid interface culture technique. 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 in vitro and ex vivo settings.
Barriers to developing novel asthma treatments include the challenges of modeling the complex genetic and extra-cellular interactions that cause the disease. Over the past decade Dr. Debley’s laboratory has made significant contributions to current understanding of the role of the airway epithelium in asthma. “Alarmins” such as TSLP and IL-33 are excessively released by the epithelium in patients with asthma, augmenting TH2 inflammatory responses. Deficient or excessive epithelial type I and III interferon responses to viral infection may contribute to asthma exacerbations and/or declines in lung function among patients with asthma. TGF-β and VEGF are upregulated by the epithelium in asthma, promoting airway remodeling that results in lung function declines. Clinically, asthma is now recognized to include multiple sub-phenotypes/endotypes. However, understanding of the pathophysiology that drives specific endotypes is still limited. Dr. Debley’s advanced cellular model of the airway epithelium using cells from carefully phenotyped and genotyped donors can shed light on 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 (including human rhinovirus), pollens, 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
- Altman MC, Reeves SR, Parker AR, Whalen E, Misura KM, Barrow KA, James RG, Hallstrand TS, Ziegler SF, Debley JS. Interferon response to respiratory syncytial virus by bronchial epithelium from children with asthma is inversely correlated with pulmonary function. J Allergy Clin Immunol. 2018;142(2):451-459.
- James RG, Reeves SR, Barrow KA, White MP, Glukhova VA, Haghighi C, Seyoum D, Debley JS. Deficient Follistatin-like 3 Secretion by Asthmatic Airway Epithelium Impairs Fibroblast Regulation and Fibroblast-to-Myofibroblast Transition. Am J Respir Cell Mol Biol. 2018;59(1):104-113.
- Reeves SR, Kang I, Chan CK, Barrow KA, Kolstad TK, White MP, Ziegler SF, Wight TN, Debley JS. Asthmatic bronchial epithelial cells promote the establishment of a Hyaluronan-enriched, leukocyte-adhesive extracellular matrix by lung fibroblasts. Respir Res. 2018 Aug 2;19(1):146.
- Reeves SR, Barrow KA, Kolstad TK, White MP, Rich LM, Wight TN, Debley JS. Fibroblast gene expression following asthmatic bronchial epithelial cell conditioning correlates with epithelial donor lung function and exacerbation history. Sci Rep. 2018 Oct 25;8(1):15768.
To learn more about partnering with Seattle Children’s Research Institute on this or other projects, email the Office of Science-Industry Partnerships.