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Transcriptome profiling of induced sputum identified up-regulated TNF-α/NF-κB signaling and down-regulated mitochondrial respiratory chain function in post-infectious Bronchiolitis obliterans

ABSTRACT: Post-infectious bronchiolitis obliterans (PiBO) is a chronic lung disease that occurs after severe lower respiratory infections and leads to persistent inflammation and fibrotic changes in the small airways. In the present study, gene expression analysis was used to identify differentially expressed genes (DEGs) in sputum cells derived from PiBO patients compared to healthy controls. Clinical history, lung function parameters, and induced sputum samples were collected from nine patients with PiBO and eight healthy controls. Multiplex immunohistochemistry (mIHC) as well as mRNA sequencing (MACE-Seq) were performed. Evaluation of the biological targets was done by KEGG pathway enrichment analysis. PiBO patients showed significantly reduced lung function parameters, an increased neutrophil count, and an altered macrophage profile in sputum. Transcriptome analysis revealed significant upregulation of the TNFα-dependent NFκB signalling pathway, as well as significant downregulation of the oxidative phosphorylation (OXPHOS). Linear regression analyses and mIHC showed a shift in macrophage polarization that appears to be responsible for the dysregulated gene expression. Notably, expression of these DEGs significantly correlated with FEV₁ lung function. These findings indicate a central role of macrophages in the immunopathology of PiBO and contribute to our understanding of the molecular mechanism involved in the disease process.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327957 | GEO | 2026/06/03

REPOSITORIES: GEO

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Project description:Background: Mesenchymal stromal cells (MSC) have been proposed as a future cell based therapy for lung diseases like bronchiolitis obliterans syndrome (BOS). Theoretically, it might be beneficial to use lung resident MSC already adapted to the pulmonary environment. We therefore aimed to compare lung MSC with the well-characterized bone marrow MSC. Furthermore, MSC isolated from lung-transplanted patients with BOS were compared to MSC isolated from good outcome recipients. Methods: MSC were isolated from bone marrow (BM) and adult/fetal lung tissues and compared by a comprehensive panel of assays. Results:The gene expression profiles of adult lung derived and fetal lung derived MSC were very similar compared to BM derived MSC, with only 235 and 338 genes, respectively, being significantly differently expressed. Out of the 235 genes that were significantly different between adult lung derived and BM derived MSC, 90 genes were higher expressed in the lung derived MSC. In case of fetal lung derived MSC, 166 genes were higher expressed compared to the BM derived MSC. Interestingly, only, 89 genes were found to be expressed differently when comparing BM derived MSC to both, fetal and adult lung derived MSC, indicating that these genes are lung specific. Next, we went on to evaluate if MSC isolated from biopsies of lung-transplanted patients with BOS differed compared to patients without BOS, i.e. good outcome recipients. Here we found that four genes (Sox9, FAR2, LOC728855 and NDUFS5) were significantly higher expressed in MSC isolated from BOS patients Conclusions: This data demonstrates that lung resident MSC possess lung specific properties that should be taken into considerations when using MSC for cell-based therapy in severe lung disorders like BOS. These results also show that MSC isolated from lung-transplanted patients with BOS do not have an altered phenotype. Comparison of gene expression of MSC isolated from bone marrow, adult lung and fetal lung.

Project description:Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality in allogeneic-hematopoietic stem cell transplantation with bronchiolitis obliterans syndrome (BOS) among the most lethal treatment-resistant complications. Despite approval of 4 second-line therapies, clinical response in moderate and severe BOS patients remains poor. Bromodomain and Extra terminal (BET) proteins are epigenetic readers driving oncogenic and inflammatory transcriptional programs in multiple cell types. We hypothesized that BET inhibition would be a feasible therapeutic option by restraining the direct inflammatory T cells as well as macrophage polarization to profibrotic phenotype known. We used an established BOS cGVHD model wherein we treated cGVHD mice with the translatable BET inhibitor: OPN-51107 (BETi). We found that under BETi, T and B cells had reduced germinal center (GC) trafficking ability, and GC activation resulting in reduced IgG1+ class switched B cells. Mice with cGVHD had elevated pathogenic IgM and IgG1 both in circulation and deposited onto lung tissue, which was attenuated under BET inhibition. Furthermore, antibodies produced in cGVHD were both allo- and auto-reactive. Single-cell RNA sequencing analysis revealed 22 distinct cell types in the BOS lung. In cGVHD mice, GSEA analysis revealed upregulation of anti-inflammatory Arginase1 and profibrotic Tgfb1 expression in alveolar macrophages (AM) and interstitial macrophages (IM), which was significantly reduced in BETi treated mice. Spectral flow cytometry confirmed that BETi targeted lung-infiltrating M2 macs, through diminishment of CD206+FcgR+ M2 IMs and AMs. Ultimately, this concluded in reduced collagen deposition and improved lung function in mice treated with BETi. We identify BET proteins as a key regulator of inflammation in BOS. BETi suppresses Tfh and GC B cells, thereby reducing Ab production and deposition. Within the lung, BETi selectively targets M2 IM macs to reduce FcgR and TGF-b expression, thereby regulating collagen deposition and fibrosis. These findings reveal a previously unrecognized mechanistic axis driving cGVHD and highlight BET inhibition as a promising therapeutic strategy.

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Transcriptome profiling of induced sputum identified up-regulated TNF-α/NF-κB signaling and down-regulated mitochondrial respiratory chain function in post-infectious Bronchiolitis obliterans

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