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This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/L451    most recent 00376.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Malizia, A. P. Articles by Egan, J. J. Search for Related Content PubMed PubMed Citation Articles by Malizia, A. P. Articles by Egan, J. J.

Alveolar epithelial cell injury with Epstein-Barr virus upregulates TGFβ1 expression

¹Advanced Lung Disease and Lung Transplant Program, and ²Genome Research Unit, School of Medicine and Medical Science, University College Dublin, Mater Misericordiae University Hospital; and ³School of Biotechnology, Dublin City University, Dublin, Ireland

Submitted 11 September 2007 ; accepted in final form 7 July 2008

Idiopathic pulmonary fibrosis (IPF) is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation, and ECM protein deposition. Epstein-Barr virus (EBV) has previously been localized to alveolar epithelial cells of IPF patients and is associated with a poor prognosis. In this study, we utilized a microarray-based differential gene expression analysis strategy to identify molecular drivers of EBV-associated lung fibrosis. Two cell lines, primary human alveolar epithelial cells type 2 and A549 cells, were infected with EBV. EBV lytic phase induction increased active and total transforming growth factor-β1 (TGFβ1) transcript expression in association with reduced cell proliferation and increased caspase 3/7 activity. Exposing EBV-infected cells to ganciclovir resulted in TGFβ1 deregulation and reduced expression of EBV early response genes, BRLF1 and BZLF1. We targeted the BRLF1 and BZLF1 gene products, Rta and Zta, by silencing RNA, and this resulted in the normalization of TGFβ1 transcript and cell proliferation levels. Our study using a viral cell line model complements existing human and animal model data and further provides evidence to suggest that viral epithelial cell injury may play a role in IPF.

idiopathic pulmonary fibrosis; transforming growth factor-β1; epithelial injury; ganciclovir