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Comparative transcriptional analysis of lung fibroblasts from young and aged mice identifies PIM1/NFATc1 axis as a driver of persistent fibrosis

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by the accumulation of myofibroblasts leading to the progressive scarring of the lung. To identify transcriptional gene programs driving persistent fibrosis in aged lungs, we performed a comparative RNA-seq analysis of fibroblasts freshly isolated from young and aged mouse lungs 30 days post-bleomycin injury. We discovered that lung fibroblasts isolated from young animals at this time point post-injury were transcriptionally similar to those isolated from uninjured mice. In contrast, aged lung fibroblasts isolated at the same time point exhibited a sustained pro-fibrotic state characterized by the elevated expression of genes implicated in inflammation, extracellular matrix remodeling, and cell survival. We identified the protein kinase pro-viral integration site of Moloney murine leukemia virus 1 (PIM1) and its direct target Nuclear Factor of Activated T Cells-1 (NFATc1) as putative drivers of the sustained profibrotic gene signatures observed in aged lung fibroblasts post-injury. PIM1 and NFATc1 transcripts were highly enriched in a pathogenic fibroblast population recently discovered in IPF lungs, and their protein expression was detected in fibroblastic foci. Overexpression of PIM1 in normal human lung fibroblasts potentiated their fibrogenic activation and this effect was dependent on NFATc1. Pharmacological inhibition of PIM1 in IPF-derived lung fibroblasts attenuated their activation and sensitized them to apoptotic stimuli. Finally, inhibition of PIM1 strongly reduced the expression of ECM remodeling and pro-survival genes and blocked the secretion of collagen in IPF lung explants ex vivo. Targeting PIM1/NFATc1 axis in pathogenic lung fibroblasts may represent a therapeutic strategy to limit their activation and promote fibrosis resolution in IPF.

ORGANISM(S): Mus musculus

PROVIDER: GSE191208 | GEO | 2022/01/01

REPOSITORIES: GEO

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Project description:Objective: Pulmonary complications in systemic sclerosis (SSc), including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality. We compared the molecular fingerprint of SSc lung tissues and matching primary lung fibroblasts to those of normal donors, and patients with idiopathic pulmonary fibrosis (IPF) and idiopathic pulmonary arterial hypertension (IPAH). Methods: Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively. Results: We identified a consensus of 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. Enriched function groups in SSc-PF and IPF lungs included fibrosis, insulin-like growth factor signaling and caveolin-mediated endocytosis. Functional groups shared by SSc-PAH and IPAH lungs included antigen presentation, chemokine activity, and IL-17 signaling. Conclusion: Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts of patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease- (SSc) and phenotype- (PF vs PAH) specific. These signatures provide new insights into pathogenesis and potential therapeutic targets for SSc lung disease. Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively.

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Comparative transcriptional analysis of lung fibroblasts from young and aged mice identifies PIM1/NFATc1 axis as a driver of persistent fibrosis

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