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TIme-cource single-cell RNA-seq analysis of bleomycin and LPS-induced lung injury and fibrosis

ABSTRACT: Pulmonary fibrosis (PF) is a progressive fibrotic disease with a poor prognosis and suboptimal therapeutic options. To construct comprehensive single-cell atlas and identify disease-relevant cell subsets and gene signatures of the murine models of PF pathogenesis and lung repair, time-course singel-cell RNA-seq analysis of bleomycin (BLM) and LPS-induced lung injury/fibrosis models were performed. We sampled mouse lungs of untreated, day3, 7, 14, 28, 42, 63 (BLM model, 1.25 mg/kg), day3, 7, 14 (3 mg/kg), and day7, 14, 42 (LPS model, 1mg/ml, 50ul/head) with 5 biological replicates (except BLM 3mg/kg at day 14 which includes 2 biological replicate) and processed by using TAS-Seq protocol (Shichino et al. Commnue Biol 2022). We found that some of the early phase-specific markers, and repair phase-specific cell subsets and associated gene signatures. Of these, we found that Sftpb was an early marker of lung injury that was specifically expressed on AT2 cells, and SFTPC protein also highly expressed in the serum extracellular vesicles from prognosis-worsen PF-ILD patients. Our dataset might useful to clarify lung injury and repair mechanisms.

ORGANISM(S): Mus musculus

PROVIDER: GSE264278 | GEO | 2024/10/09

REPOSITORIES: GEO

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Project description:Acute inflammatory exacerbations (AIEs) represent immune-driven deteriorations of many chronic lung conditions, including COPD, asthma, and pulmonary fibrosis (PF). The first line of therapy is represented by broad-spectrum immunomodulation. Among the several inflammatory populations mobilizing during AIEs, eosinophils have been identified as promising indicators of an active inflammatory exacerbation. To better study the eosinophil-parenchymal crosstalk during AIE-PF, this work leverages a clinically relevant model of inflammatory exacerbations triggered by mutation in the alveolar epithelial type 2 cell Surfactant Protein-C gene [SP-CI73T]. Unbiased single-cell sequencing analysis of controls and SP-CI73T mutants at a time coordinated with peak eosinophilia (14 d) defined heightened inflammatory activation, chemotaxis, and survival signaling (IL-6, IL-4/13, STAT3, Glucocorticoid Receptor, mTOR, and MYC) in eosinophils. To study the impact of eosinophils in inflammatory exacerbations, the SP-CI73T line was crossed with eosinophil lineage deficient mice (GATA1Δdbl, SP-CI73TGATA1KO). Time course analysis (7-42 d) demonstrated improved lung histology, survival, and reduced inflammation in SP-CI73TGATA1KO cohorts. Spectral flow cytometry of tissue digests confirmed eosinophil depletion in GATA1KO mice and the absence of a compensatory shift in neutrophils and immature monocyte recruitment. Eosinophil deletion was seen to boost accumulation of total monocyte-derived macrophages, 14 d post-injury, while declines in CD3+CD4+ lymphocyte abundance observed during SP-CI73T-induced injury were limited in SP-CI73TGATA1KO mice. Histochemical analysis 14 d post-injury revealed atypical inflammatory cell activation in SP-CI73TGATA1KO mice, with reduced numbers of Arg-1+ and iNOS+ cells, but increases in mcp1 and tgfb1 mRNA expression in BAL cells and tissue. To study corticosteroid efficacy in highly eosinophilic exacerbations, SP-CI73T mice received dexamethasone (1 mg/kg daily, i.p) starting 5 d post-induction. Dexamethasone successfully reduced total and eosinophil (CD11b+SigF+CD11c-) counts at 14 d and was linked to reduced evidence of structural damage and perivascular infiltrate. Together, these results illustrate the deleterious role of eosinophils in inflammatory events preceding lung fibrosis and demonstrate the efficacy of corticosteroid treatment in highly eosinophilic exacerbations induced by mutant SP-CI73T.

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TIme-cource single-cell RNA-seq analysis of bleomycin and LPS-induced lung injury and fibrosis

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