Background: Interstitial lung disease is a major cause of morbidity and mortality in systemic sclerosis (SSc), with\r\ninsufficiently effective treatment options. Progression of pulmonary fibrosis involves expanding populations of\r\nfibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of SSc lung fibroblast gene\r\nexpression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes\r\nleading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of\r\nfibroblasts isolated from SSc lung biopsies at the time of diagnosis, compared with those from control lungs.\r\nMethods: We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary\r\nfibroblasts cultured from 8 patients with pulmonary fibrosis associated with SSc (SSc-ILD), with those from control\r\nlung tissue peripheral to resected cancer (n=10). Fibroblast cultures from 3 patients with idiopathic pulmonary\r\nfibrosis (IPF) were included as a further comparison. Genes differentially expressed were identified using two\r\nseparate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were\r\nconsidered. Microarray expression data was verified by qRT-PCR and/or western blot analysis.\r\nResults: A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from SSc-ILD and/\r\nor IPF compared to control lung, with a large overlap in the expression profiles of both diseases. We observed\r\nincreased expression of a TGF-�Ÿ response signature including fibrosis associated genes and myofibroblast markers,\r\nwith marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes,\r\nincluding antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This\r\nexpression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and\r\nwas also independent of disease group.\r\nConclusions: This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from\r\nfibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical\r\naspects of the profibrotic fibroblast phenotype, identifying an area in pulmonary fibrosis that requires further\r\ninvestigation.
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