COVID-19 lung disease shares driver AT2 cytopathic features with Idiopathic pulmonary fibrosis

Sinha, Saptarshi; Castillo, Vanessa; Espinoza, Celia R.; Tindle, Courtney; Fonseca, Ayden G.; Dan, Jennifer M.; Katkar, Gajanan D.; Das, Soumita; Sahoo, Debashis; Ghosh, Pradipta

doi:10.1016/j.ebiom.2022.104185

Cited by 26 publications

(24 citation statements)

References 133 publications

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“…Increased BAL cytotoxic T cells associate with epithelial damage and airways disease, while myeloid and B cell numbers correlate with the degree of chest CT abnormality [ 3 ]. Peripheral blood mononuclear cell signatures in COVID-19 lung disease and IPF have similar transcriptional signatures and prognostic value [ 14 ].…”

Section: Aetiopathogenesis Of Post-covid Ildmentioning

confidence: 99%

Understanding post-COVID-19 interstitial lung disease (ILD): a new fibroinflammatory disease entity

2022

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Section: Aetiopathogenesis Of Post-covid Ildmentioning

confidence: 99%

Understanding post-COVID-19 interstitial lung disease (ILD): a new fibroinflammatory disease entity

2022

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“…Some studies have found that the loss of epithelial progenitor cell function and/or numbers and cellular senescence are implicated in the pathogenies of IPF (Moss et al, 2022; Sinha et al, 2022; Yao et al, 2021). Senescent AT2 cells stimulated an influx of macrophages and the production of inflammatory cytokines, which causally implicates senescent macrophages and SASP in fibrotic pulmonary disease in recent findings.…”

Section: Resultsmentioning

confidence: 99%

Salvianolic acid B protects against pulmonary fibrosis by attenuating stimulating protein 1‐mediated macrophage and alveolar type 2 cell senescence

Li,

Chen,

et al. 2023

Phytotherapy Research

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Idiopathic pulmonary fibrosis (IPF), as the most common idiopathic interstitial pneumonia, is caused by a complex interaction of pathological mechanisms. Interestingly, IPF frequently occurs in the middle‐aged and elderly populations but rarely affects young people. Salvianolic acid B (SAB) exerts antioxidant, antiinflammatory, and antifibrotic bioactivities and is considered a promising drug for pulmonary disease treatment. However, the pharmacological effects and mechanisms of SAB on cellular senescence of lung cells and IPF development remain unclear. We used bleomycin (BLM)‐induced pulmonary fibrosis mice and different lung cells to investigate the antisenescence impact of SAB and explain its underlying mechanism by network pharmacology and the Human Protein Atlas database. Here, we found that SAB significantly prevented pulmonary fibrosis and cellular senescence in mice, and reversed the senescence trend and typical senescence‐associated secretory phenotype (SASP) factors released from lung macrophages and alveolar type II (AT2) epithelial cells, which further reduced lung fibroblasts activation. Additionally, SAB alleviated the epithelial–mesenchymal transition process of AT2 cells induced by transforming growth factor beta. By predicting potential targets of SAB that were then confirmed by chromatin immunoprecipitation‐qPCR technology, we determined that SAB directly hampered the binding of transcription factor stimulating protein 1 to the promoters of SASPs (P21 and P16), thus halting lung cell senescence. We demonstrated that SAB reduced BLM‐induced AT2 and macrophage senescence, and the subsequent release of SASP factors that activated lung fibroblasts, thereby dual‐relieving IPF. This study provides a new scientific foundation and perspective for pulmonary fibrosis therapy.

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“…13,14 However, the anti-fibrotic mechanism of H 2 S remains largely unknown. As one of the main senescent cells in fibrotic lungs, AT2 cells are critical in the pathogenesis of pulmonary fibrosis 29 and they appear to be targets of H 2 S. The previous study has indicated that H 2 S attenuates LPS-induced AT2 cell damage by activating PI3K/Akt/ mTOR signaling pathway. 30 Hydrogen sulfide is also found to attenuate mitochondrial dysfunction-induced cellular senescence by upregulating sirtuin 1 in human lung epithelial cell line A549.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen sulfide inhibits alveolar type II cell senescence and limits pulmonary fibrosis via promoting MDM2‐mediated p53 degradation

Wang,

Xu,

Zhang

et al. 2023

Acta Physiologica

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AimSenescence of alveolar type II (AT2) cells is an important driver of pulmonary fibrosis. This study aimed to investigate whether and how dysregulation of hydrogen sulfide (H2S) production affected AT2 cell senescence, and then explored the effect of H2S on the communication between AT2 and fibroblasts.MethodsICR mice were intratracheally administered with bleomycin (3 mg/kg). Sodium hydrosulfide (NaHS, 28 μmol/kg/d) was intraperitoneally injected for 2 weeks. The H2S‐generating enzyme cystathionine‐β‐synthase (CBS) knockout heterozygous (CBS+/−) mice were used as a low H2S production model.ResultsAnalysis of microarray datasets revealed downregulation of H2S‐generating enzymes in lung tissues of patients with pulmonary fibrosis. Decreased H2S production was correlated with higher levels of cell senescence markers p53 and p21 in bleomycin‐induced lung fibrosis. CBS+/− mice exhibited increased levels of p53 and p21. The numbers of AT2 cells positive for p53 and p21 were increased in CBS+/− mice as compared to control mice. H2S donor NaHS attenuated bleomycin‐induced AT2 cell senescence both in vivo and in vitro. H2S donor suppressed bleomycin‐induced senescence‐associated secretory phenotype (SASP) of AT2 cells via inhibiting p53/p21 pathway, consequently suppressing proliferation and myofibroblast transdifferentiation of fibroblasts. Mechanically, H2S suppressed p53 expression by enhancing the mouse double‐minute 2 homologue (MDM2)‐mediated ubiquitination and degradation of p53.ConclusionH2S inactivated p53‐p21 pathway, consequently suppressing AT2 cell senescence as well as cell communication between senescent AT2 cells and fibroblasts. Aberrant H2S synthesis may contribute to the development of pulmonary fibrosis through promoting the activation loop involving senescent AT2 cells and activated fibroblasts.

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COVID-19 lung disease shares driver AT2 cytopathic features with Idiopathic pulmonary fibrosis

Cited by 26 publications

References 133 publications

Understanding post-COVID-19 interstitial lung disease (ILD): a new fibroinflammatory disease entity

Understanding post-COVID-19 interstitial lung disease (ILD): a new fibroinflammatory disease entity

Salvianolic acid B protects against pulmonary fibrosis by attenuating stimulating protein 1‐mediated macrophage and alveolar type 2 cell senescence

Hydrogen sulfide inhibits alveolar type II cell senescence and limits pulmonary fibrosis via promoting MDM2‐mediated p53 degradation

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