Epithelial progenitor cell dysfunction in fibrotic lung disease

点击翻译按钮获取中文摘要

ABSTRACT Fibrotic lung diseases including usual interstitial pneumonia/idiopathic pulmonary fibrosis (IPF) and chronic lung allograft dysfunction (CLAD) are associated with defects in epithelial maintenance and repair that lead to irreversible declines in lung function and death. However, little is known of mechanisms leading to defective epithelial maintenance and remodeling in lung tissue of these patients. Over the previous funding period we demonstrated that loss of alveolar type 2 (AT2) cells in lung tissue of patients with end-stage IPF is associated with distal airway basal and secretory cell hyperplasia. Using state-of-the-art 3D culture models and genomics approaches we found that alveolar epithelial progenitor (AT2) cells from lungs of IPF patients have reduced colony-forming and clonogenic potentials and accompanying upregulation of the p53 pathway. Alveolar progenitor cell dysfunction in mouse models was found to be a potent regulator of small airway basal cell expansion similar to that observed in lungs of IPF patients. Basal cell expansion could be activated by interleukin 22, a cytokine that was induced following alveolar injury and whose elevated abundance has been associated with fibrotic lung disease. Goals of the present application are to determine cellular mechanisms that contribute to either regeneration or remodeling and molecular pathways that guide cells along either of these pathways with the long-term expectation that novel therapies can be developed to promote normal tissue repair and/or block fibrosis. Our experimental plan will address the overarching hypothesis that p53-dependent alveolar progenitor cell dysfunction drives airway and parenchymal remodeling through a mechanism involving IL23-mediated innate immune stimulation and elevated IL22 production. This hypothesis will be tested in two aims that will define roles for p53 signaling in regulation of alveolar progenitor cells and define roles for IL22 in the regulation of basal cell expansion and recruitment to regions of alveolar injury. Completion of aims will yield novel insights into the molecular regulation of airway epithelial progenitor cells that will guide development of new therapies to treat patients with chronic lung disease.