Analysis of transcriptional profile of lung fibroblasts derived from patients with progressive pulmonary fibrosis (PPF)

<bold>Background:</bold> A proportion of patients with interstitial lung diseases (ILDs) such as hypersensitivity pneumonitis (HP), sarcoidosis and pleuroparenchymal fibroelastosis (PPFE) exhibit progressive fibrosing phenotypes similar to idiopathic pulmonary fibrosis (IPF) which leads to decline in lung function, quality of life worsening and early mortality. The mechanisms mediating fibrogenesis in non-IPF PPF-ILDs still remains to be specified. <bold>Aim:</bold> To analyze transcriptomic signatures of fibroblasts/myofibroblasts isolated from patients with PPF in order to explore the mechanisms involved in pulmonary fibrosis. <bold>Methods:</bold> RNA sequencing was performed on human lung fibroblasts (HLFs) derived from patients with fibrosing HP (fHP, n=4), non-fibrosing HP (n=3), chronic sarcoidosis (n=4), PPFE (n=4) and IPF (n=14) treated or not with TGF-β1 (1 ng/ml) for 48 h. Transcriptome data were subjected to functional annotation, network, and pathway analyses. <bold>Results:</bold> Under basal condition, the transcriptional profile of non-IPF and IPF PPF HLFs was similar. After TGF-β stimulation, RNA sequencing identified 2084 differentially expressed genes in IPF, 1303 in f-HP, 248 in chronic sarcoidosis and 68 in PPFE. As well as in IPF HLFs, pathway analysis of the differentially expressed genes identified cellular adhesion, cytoskeletal anchoring, cell differentiation and extracellular matrix production as major biological process regulated by TGF-β. <bold>Conclusion:</bold> This analysis revealed shared and specific molecular and cellular pathways among, fHP, chronic sarcoidosis, PPFE and IPF providing a basis for understanding fibrogenesis and identifying potential common therapeutic targets.