Background. Cystic fibrosis (CF) produces variable lung disease phenotypes that are in part independent of CFTR genotype. Transforming growth factor beta (TGFβ) is the best described genetic modifier of the CF phenotype, but its mechanism of action is unknown. We hypothesized that TGFβ is sufficient to drive pathognomonic features of CF lung disease in vivo and that CFTR deficiency enhances susceptibility to pathologic TGFβ effects.Methods. A CF mouse model and littermate controls were exposed intratracheally to an adenoviral vector containing the TGFβ1 cDNA (Ad-TGFβ), empty vector, or PBS only. Studies were performed one week after treatment, including lung mechanics, collection of bronchoalveolar lavage fluid (BALF), and analysis of lung histology, RNA, and protein. Results. CF and non-CF mice showed similar weight loss, inflammation, goblet cell hyperplasia, and Smad pathway activation after Ad-TGFβ treatment. Ad-TGFβ produced greater abnormalities in lung mechanics in CF vs control mice, which was uniquely associated with induction of PI3K and MAPK signaling. CFTR transcripts were reduced and ENaC transcripts were increased in CF and non-CF mice, while the goblet cell transcription factors FoxA3 and SPDEF were increased in non-CF but not CF mice following Ad-TGFβ treatment.Conclusion. Pulmonary TGFβ1 expression was sufficient to produce pulmonary remodeling and abnormalities in lung mechanics that were associated with both shared and unique cell signaling pathway activation in CF and non-CF mice. These results highlight the multi-functional impact of TGFβ on pulmonary pathology in vivo and identify cellular response differences that may impact CF lung pathology.
AJP - Lung Cellular and Molecular Physiology – The American Physiological Society
Published: Dec 13, 2017
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