Twist: a regulator of epithelial-mesenchymal transition in lung fibrosis.
BACKGROUND
Several studies have implicated viral infection as an important factor in the pathogenesis of IPF and related fibrotic lung disorders. Viruses are thought to cause epithelial cell injury and promote epithelial-mesenchymal transition (EMT), a process whereby differentiated epithelial cells undergo transition to a mesenchymal phenotype, and considered a source of fibroblasts in the setting of lung injury. We have demonstrated an association between the epithelial injury caused by chronic herpes virus infection with the murine gamma-herpes virus, MHV68, and lung fibrosis. We hypothesize that EMT in this model of virus-induced pulmonary fibrosis is driven by the expression of the transcription factor Twist.


RESULTS
In vitro MHV68 infection of murine lung epithelial cells induced expression of Twist, and mesenchymal markers. Stable overexpression of Twist promoted EMT in MLE15 lung epithelial cells. Transient knockdown expression of Twist resulted in preservation of epithelial phenotype after in vitro MHV68 infection. In concordance, high expression of Twist was found in lung epithelial cells of MHV68 infected mice, but not in mock infected mice. Alveolar epithelial cells from lung tissue of idiopathic pulmonary fibrosis (IPF) patients were strongly positive for Twist. These cells demonstrated features of EMT with low expression of E-cadherin and upregulation of the mesenchymal marker N-cadherin. Finally, IPF tissue with high Twist protein levels was also positive for the herpesvirus, EBV.


CONCLUSIONS
We conclude that Twist contributes to EMT in the model of virus-induced pulmonary fibrosis. We speculate that in some IPF cases, gamma-herpes virus infection with EBV might be a source of injury precipitating EMT through the expression of Twist.
Pozharskaya
Veronika
V
Division of Pulmonary, Allergy/Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.
Torres-González
Edilson
E
Rojas
Mauricio
M
Gal
Anthony
A
Amin
Minal
M
Dollard
Sheila
S
Roman
Jesse
J
Stecenko
Arlene A
AA
Mora
Ana L
AL
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation; D006564:Herpesviridae / Q000378:metabolism; D006566:Herpesviridae Infections / Q000821:virology*; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000473:pathology*; D051879:Twist-Related Protein 1 / Q000378:metabolism*
D015820:Cadherins; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse