| First Author | Kramer EL | Year | 2018 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 315 |
| Issue | 3 | Pages | L456-L465 |
| PubMed ID | 29877096 | Mgi Jnum | J:265153 |
| Mgi Id | MGI:6199298 | Doi | 10.1152/ajplung.00530.2017 |
| Citation | Kramer EL, et al. (2018) Subacute TGFbeta expression drives inflammation, goblet cell hyperplasia, and pulmonary function abnormalities in mice with effects dependent on CFTR function. Am J Physiol Lung Cell Mol Physiol 315(3):L456-L465 |
| abstractText | Cystic fibrosis (CF) produces variable lung disease phenotypes that are, in part, independent of the CF transmembrane conductance regulator ( CFTR) genotype. Transforming growth factor-beta (TGFbeta) is the best described genetic modifier of the CF phenotype, but its mechanism of action is unknown. We hypothesized that TGFbeta is sufficient to drive pathognomonic features of CF lung disease in vivo and that CFTR deficiency enhances susceptibility to pathological TGFbeta effects. A CF mouse model and littermate controls were exposed intratracheally to an adenoviral vector containing the TGFbeta1 cDNA (Ad-TGFbeta), empty vector, or PBS only. Studies were performed 1 wk after treatment, including lung mechanics, collection of bronchoalveolar lavage fluid, and analysis of lung histology, RNA, and protein. CF and non-CF mice showed similar weight loss, inflammation, goblet cell hyperplasia, and Smad pathway activation after Ad-TGFbeta treatment. Ad-TGFbeta produced greater abnormalities in lung mechanics in CF versus control mice, which was uniquely associated with induction of phosphoinositide 3-kinase and mitogen-activated protein kinase signaling. CFTR transcripts were reduced, and epithelial sodium channel transcripts were increased in CF and non-CF mice, whereas the goblet cell transcription factors, forkhead ortholog A3 and SAM-pointed domain-containing ETS-like factor, were increased in non-CF but not CF mice following Ad-TGFbeta treatment. Pulmonary TGFbeta1 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 multifunctional impact of TGFbeta on pulmonary pathology in vivo and identify cellular-response differences that may impact CF lung pathology. |
