Airway wall thickening has been identified as a major independent predictor of the severity of physiologic airway obstruction in COPD patients. Similarly, loss of epithelial integrity and airway wall thickening are associated with bronchiolitis obliterans syndrome (BOS), which is the primary and late chronic complication after lung transplantation. Effective treatments for COPD and BOS are currently limited. A better understanding of the pathogenesis of the loss of epithelial integrity and subsequent peribronchiolar fibrosis is needed if new and effective therapeutic strategies are to be developed to improve long-term survival in patients with COPD and after lung transplantation.
Our laboratory has developed a novel conditional transgenic mouse model to induce diphtheria toxin mediated cell death specifically in bronchiolar Clara cells. After acute epithelial injury, a squamous epithelium covers the basement membrane, and bronchiolar cells regenerate within 10 days. After chronic Clara cell death and possible exhaustion of bronchiolar stem cells, the bronchiolar epithelium develops a persistent squamous phenotype, and the associated mesenchyme increases in thickness. This novel mouse model enables studies of 1) bronchiolar stem cells, 2) molecular mechanisms responsible for bronchiolar regeneration after acute injury and 3) airway wall fibrosis after chronic injury.
The goals of this project are to identify bronchiolar stem cells and signaling pathways that are activated to induce proper bronchiolar repair, and to identify a cellular process and signaling pathways that lead to epithelial regeneration, aberrant tissue repair and fibrosis.
This work has been published:
Perl AK, Riethmacher D, Whitsett JA. Conditional Depletion of Airway Progenitor Cells Induces Peribronchiolar Fibrosis. Am J Respir Crit Care Med. 2011.
This project is currently funded with an American Lung Association research grant (2008-2011).