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UBC Theses and Dissertations

Regulation of inflammatory and fibrotic mediators by adenovirus E1A in guinea pig lung cells Behzad, Ali Reza


Results from our laboratory have shown that guinea pigs with latent adenovirus infection develop excess lung inflammation and greater amounts of emphysema when chronically challenged with cigarette smoke. In this model the adenoviral E1A is expressed in peripheral lung epithelial (PLE) cells. We sought to establish PLE cell lines that stably express adenoviral E1A protein in culture and use these cells to investigate mechanisms by which E1A contributes to inflammatory and fibrotic responses. Primary PLE cultures were established on either plastic or on polycarbonate filters that were coated with extracellular matrix. Transfection of primary PLE cells grown on either substrate resulted in E1A-expressing PLE cell lines with epithelial characteristics of cytokeratin expression, cuboidal morphology and junctional complexes, but these cell lines failed to show more specific markers of PLE cells such as surfactant mRNA expression, lamellar bodies or microvilli. The suspicion that E1A transfection may have induced mesenchymal to epithelial transformation (MET) of contaminating normal lung fibroblasts (NLF) led us to compare E1A-PLE with E1A-NLF cell lines. E1A-expressing PLE and NLF cell lines showed similar epithelial characteristics and similar levels of mRNA and protein expression of IL-8 and MCP-1 before and after stimulation with LPS and TGF-pi and of CTGF in the absence of stimulation. These overlapping characteristics suggest that either E1A caused both PLE and NLF to converge to an intermediate phenotype or that E1A-expressing PLE cell lines are the result of E1A-induced MET of contaminating fibroblasts. E1A's enhancement of TGF-(31 mRNA expression in fibroblasts implicates this viral protein in the pathogenesis of fibrosis while the E1 A-induced suppression of IL-8 and MCP-1 may imply that E1A is acting as a negative regulator of inflammation. This suppression may reflect redirection of the host transcriptional apparatus by E1A to upregulate fibrotic

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