LAUSR

Introduction: Idiopathic pulmonary fibrosis is characterized by a vast remodeling of the alveolar compartment. Recent data indicate a role for airway basal cells in IPF. Methods: Bronchial epithelial cells of 30 patients with IPF and 18 age-matched healthy volunteers were harvested by bronchial brushes during routine diagnostic bronchoscopy. Airway basal cells were isolated in accordance to recently published protocols. Gene expression was analyzed by RNAseq using HiSeq/ Illumina platform. Cell function was tested by in vitro and in vivo assays. Results: RNAseq data revealed an abundant reprogramming of airway basal cells in IPF compared to healthy cells. Similarities between IPF and cancer as well as organ development in regards to underlying mechanisms/ pathways became evident by Ingenuity analyses. Involved upstream regulators and signaling pathways were identified. The pivotal role of these pathways in airway basal cell function was then tested in a 3D organoid model and a humanized mouse model. Airway basal cell proliferation and bronchosphere generation were inhibited by siRNA and small molecules blocking the involved pathways. Moreover, in a humanized mouse model using human IPF airway basal cells the blockade of these pathways resulted in less airway basal cell engraftment and reduced pulmonary fibrosis. Conclusion: airway basal cells derived from distal airways are reprogrammed in IPF which results in malfunction and mislead repair processes.