Integrated analysis of single-cell and bulk RNA sequencing reveals pro-fibrotic PLA2G7high macrophages in pulmonary fibrosis

Wang, Junyi; Jiang, Manling; Xiong, Anying; Zhang, Lei; Luo, Li; Liu, Yao; Liu, Shengbin; Qin, Ran; Wu, Dehong; Xiong, Ying; He, Xiang; Leung, Elaine Lai-Han; Li, Guoping

doi:10.1016/j.phrs.2022.106286

Cited by 21 publications

(12 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent advancements in single-cell RNA sequencing technology have helped us understand the heterogeneity of cell subpopulations and their transcriptomic changes in healthy individuals as well as patients with pulmonary brosis (4,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Our study highlights the effect of nintedanib treatment on speci c cell subpopulations in patients with pulmonary brosis and emphasizes the need for multicenter and large-scale combination analyses to gain further insight into the mechanisms of new pulmonary brosis drugs.…”

Section: Discussionmentioning

confidence: 83%

Expression profiles of nintedanib-targeting molecules in progressive fibrotic interstitial lung diseases (non-IPF-PF) and IPF

Zhang

Wang

et al. 2023

Preprint

View full text Add to dashboard Cite

Background: Idiopathic pulmonary fibrosis (IPF) and other types of progressive fibrotic interstitial lung diseases (non-IPF-PF), such as chronic hypersensitivity pneumonitis (cHP), systemic sclerosis (SSc), non-specific interstitial pneumonia (NSIP), and sarcoidosis, are common interstitial lung diseases. Nintedanib is one of the two approved therapies that can significantly slow the progression of IPF. However, the potential of nintedanib in non-IPF-PF has not been fully evaluated. Methods: We reanalyzed the single-cell data of IPF and non-IPF-PF and identified the main target genes of nintedanib (FGFR1, FGFR2, FGFR3, FLT1, FLT4, KDR, and PDGFRA) by subgroup classification and functional analysis of gene expression profiles in both IPF and non-IPF-PF. Results: We found that the main target genes of nintedanib were upregulated in IPF and various cell subpopulations of non-IPF-PF, including cHP, SSc, NSIP, and sarcoidosis, with Fgfr1 being the most elevated subpopulation. In fibroblasts, Fgfr1 was found to be elevated in both IPF and cHP. We identified nintedanib-sensitive cell subpopulations by analyzing the expression profiles of fibroblasts after nintedanib treatment. We also found that nintedanib could inhibit the nintedanib-sensitive gene set in mice treated with nintedanib in vivo. Furthermore, we demonstrated that key regulatory genes of nintedanib were positively correlated with survival in lung adenocarcinoma, providing further support for the potential anti-tumor activity of nintedanib in vivo. Conclusion: Our findings provide comprehensive evidence of the target expression of nintedanib in non-IPF-PF and IPF, highlighting the potential of nintedanib for the treatment of non-IPF-PF.

show abstract

Section: Discussionmentioning

confidence: 83%

Expression profiles of nintedanib-targeting molecules in progressive fibrotic interstitial lung diseases (non-IPF-PF) and IPF

Zhang

Wang

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…We analyzed the impact of anti brotic drugs on the transcriptome of a rat model of TGF-β1-induced lung brosis. Nintedanib, sorafenib, and pirfenidone effectively reversed the expression of lung brosisrelated genes including syndecan-2 (SDC2) 56 , platelet activating factor acetyl hydrolase (PLA2G7) 57 , and serpin family G member 1 (SERPING1) 58 common to COVID-19, IPF, and TGF-β1-induced lung brosis transcriptomes.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, ABCA1 upregulation and increased cholesterol e ux could be compensatory responses to decreased surfactant synthesis in brotic lung tissue. A recent single cell RNA-Seq study disclosed that PLA2G7 is upregulated in macrophages and is linked to broblast-to-myo broblast transition 57 , in addition to being a potential PCPF driver 61 . A drug screening assay showed that the PLA2G7 inhibitor darapladib is a therapeutic candidate for COVID-19 62 .…”

Section: Discussionmentioning

confidence: 99%

Integrative single-cell transcriptome analysis reveals new insights into post-COVID-19 pulmonary fibrosis and potential therapeutic targets

Kim

Lim

Kim

et al. 2023

Preprint

View full text Add to dashboard Cite

The global COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in a significant number of patients experiencing persistent symptoms, including post-COVID pulmonary fibrosis (PCPF). This study aimed to identify novel therapeutic targets for PCPF using single-cell RNA-Sequencing data from lung tissues of COVID-19 patients, idiopathic pulmonary fibrosis (IPF) patients, and a rat TGF-β1-induced fibrosis model treated with antifibrotic drugs. Patients with COVID-19 had lower alveolar macrophage counts than healthy controls, whereas patients with COVID-19 and IPF presented with elevated monocyte-derived macrophage counts. A differential gene expression analysis showed that macrophages play a crucial role in IPF and COVID-19 development and progression, and fibrosis- and inflammation-associated genes were upregulated in both conditions. Pathway analysis revealed upregulation of inflammation and proteolysis and downregulation of ribosome biogenesis and respiratory gas exchange. Cholesterol efflux and glycolysis were augmented in both macrophage types. The study suggests that antifibrotic drugs may reverse critical lung fibrosis mediators in COVID-19. The results help clarify the molecular mechanisms underlying pulmonary fibrosis in patients with severe COVID-19 and IPF and highlight the potential efficacy of antifibrotic drugs in COVID-19 therapy. Thus, the study's results may have significant implications for the development of new treatment strategies for PCPF.

show abstract

“…ABCA1 prevents lung inflammation and fibrosis by promoting surfactant production 46 . A recent single‐cell RNA‐seq study disclosed that PLA2G7 is upregulated in macrophages and is linked to fibroblast‐to‐myofibroblast transition, 43 in addition to being a potential PCPF driver 47 . A drug screening assay showed that the PLA2G7 inhibitor darapladib is a therapeutic candidate for COVID‐19 48 .…”

Section: Discussionmentioning

confidence: 99%

“…41 These results in spatial levels, support that fibroblast and infiltrated macrophages were key pathology players in PCPFs. and pirfenidone effectively reversed the expression of lung fibrosisrelated genes, including syndecan-2 (SDC2), 42 PLA2G7, 43 and serpin family G member 1 (SERPING1), 44 common to COVID-19, IPF, and TGF-β1-induced lung fibrosis transcriptomes.…”

Section: Discussionmentioning

confidence: 99%

Integrative single‐cell transcriptome analysis provides new insights into post‐COVID‐19 pulmonary fibrosis and potential therapeutic targets

Kim,

Lim

et al. 2023

Journal of Medical Virology

View full text Add to dashboard Cite

The global COVID‐19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 virus has resulted in a significant number of patients experiencing persistent symptoms, including post‐COVID pulmonary fibrosis (PCPF). This study aimed to identify novel therapeutic targets for PCPF using single‐cell RNA‐sequencing data from lung tissues of COVID‐19 patients, idiopathic pulmonary fibrosis (IPF) patients, and a rat transforming growth factor beta‐1‐induced fibrosis model treated with antifibrotic drugs. Patients with COVID‐19 had lower alveolar macrophage counts than healthy controls, whereas patients with COVID‐19 and IPF presented with elevated monocyte‐derived macrophage counts. A comparative transcriptome analysis showed that macrophages play a crucial role in IPF and COVID‐19 development and progression, and fibrosis‐ and inflammation‐associated genes were upregulated in both conditions. Functional enrichment analysis revealed the upregulation of inflammation and proteolysis and the downregulation of ribosome biogenesis. Cholesterol efflux and glycolysis were augmented in both macrophage types. The study suggests that antifibrotic drugs may reverse critical lung fibrosis mediators in COVID‐19. The results help clarify the molecular mechanisms underlying pulmonary fibrosis in patients with severe COVID‐19 and IPF and highlight the potential efficacy of antifibrotic drugs in COVID‐19 therapy. Collectively, all these findings may have significant implications for the development of new treatment strategies for PCPF.

show abstract

Integrated analysis of single-cell and bulk RNA sequencing reveals pro-fibrotic PLA2G7high macrophages in pulmonary fibrosis

Cited by 21 publications

References 48 publications

Expression profiles of nintedanib-targeting molecules in progressive fibrotic interstitial lung diseases (non-IPF-PF) and IPF

Expression profiles of nintedanib-targeting molecules in progressive fibrotic interstitial lung diseases (non-IPF-PF) and IPF

Integrative single-cell transcriptome analysis reveals new insights into post-COVID-19 pulmonary fibrosis and potential therapeutic targets

Integrative single‐cell transcriptome analysis provides new insights into post‐COVID‐19 pulmonary fibrosis and potential therapeutic targets

Contact Info

Product

Resources

About