Cellular Senescence: Pathogenic Mechanisms in Lung Fibrosis

Parimon, Tanyalak; Hohmann, Miriam S. N.; Yao, Changfu

doi:10.20944/preprints202105.0427.v1

Cited by 18 publications

(6 citation statements)

References 184 publications

(272 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pulmonary fibrosis serves as a prevalent interstitial lung disorder featured by chronic nonspecific inflammation of the interstitial lung and deposition of collagen, resulting in lung function impairment, and severely impaired the health and life quality of patients [ 1 ]. Unlike other kinds of lung disorders, the mechanisms of the progression of pulmonary fibrosis are still unclear [ 2 ]. Pulmonary fibrosis presents a high mortality rate and has been identified as a “tumor-like disease” [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

PM2.5 Exposure Induces Lung Injury and Fibrosis by Regulating Ferroptosis via TGF-β Signaling

et al. 2022

View full text Add to dashboard Cite

Background. Lung fibrosis is a severe lung disorder featured by chronic nonspecific inflammation of the interstitial lung and deposition of collagen, leading to lung dysfunction. It has been identified that ferroptosis is involved in the progression of lung injury. Particulate matter (PM2.5) is reported to be correlated with the incidence of pulmonary fibrosis. However, mechanisms underlying ferroptosis in PM2.5-related lung fibrosis is unclear. In this study, we aimed to explore the effect of PM2.5 on ferroptosis in lung fibrosis and the related molecular mechanisms. Methods. PM2.5-treated mouse model and cell model were established. Fibrosis and tissue damage were measured by Masson’s trichrome staining and HE staining. Fibrosis biomarkers, such as α-SMA, collagen I, and collagen III, were examined by histological analysis. The ferroptosis phenotypes, including the levels of iron, Fe2+, MDA, and GSH, were measured by commercial kits. ROS generation was checked by DCFH-DA. The oxidative stress indicators, 3-nitro-L-tyrosine (3 ′ -NT), 4-HNE, and protein carbonyl, were checked by enzyme linked immunosorbent assay (ELISA). The thiobarbituric acid reactive substances (TBARS) and GSH/GSSG ratio were assessed by TBARS assay kit and GSH/GSSG assay kit, respectively. TGF-β signaling was detected by Western blotting. Results. PM2.5 induced the lung injury and fibrosis in the mice model, along with elevated expression of fibrosis markers. PM2.5 enhanced oxidative stress in the lung of the mice. The SOD2 expression was reduced, and NRF2 expression was enhanced in the mice by the treatment with PM2.5. PM2.5 triggered ferroptosis, manifested as suppressed expression of GPX4 and SLC7A11, decreased levels of iron, Fe2+, and MDA, and increased GSH level in mouse model and cell model. The TGF-β and Smad3 signaling was inhibited by PM2.5. ROS inhibitor NAC reversed PM2.5-regulated ROS and ferroptosis in primary mouse lung epithelial cells. Conclusions. Therefore, we concluded that PM2.5 exposure induced lung injury and fibrosis by inducing ferroptosis via TGF-β signaling.

show abstract

Section: Introductionmentioning

confidence: 99%

PM2.5 Exposure Induces Lung Injury and Fibrosis by Regulating Ferroptosis via TGF-β Signaling

et al. 2022

View full text Add to dashboard Cite

show abstract

“…All three groups reported their presence in fibrotic regions of IPF lungs; an increase of AT2 cells in the transitional state was invariably accompanied by an increase in myofibroblasts. Our PPI network analyses suggested that AT2 senescence and progenitor arrested state in the setting of a ViP/sViP-immune response (cytokine storm contributed by PBMCs) may support a SASP phenotype, which is a pathological feature of aging and IPF lung(88, 89). It is possible that fibroblasts/myofibroblasts also contribute to this vicious cycle of inflammation and AT2 dysfunction.…”

Section: Discussionmentioning

confidence: 91%

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

Sinha

Castillo

Espinoza

et al. 2021

Preprint

View full text Add to dashboard Cite

STRUCTURED ABSTRACTBackgroundIn the aftermath of Covid-19, a long-haul form of mysterious and progressive fibrotic lung disease has emerged, i.e., post-COVID-19 lung disease (PCLD), for which we currently lack insights into pathogenesis, disease models, or treatment options.MethodUsing an AI-guided approach, we analyzed > 1000 human lung transcriptomic datasets associated with various lung conditions using two viral pandemic (ViP and sViP) and one covid lung gene signatures. Upon identifying similarities between COVID-19 and idiopathic pulmonary fibrosis (IPF), we subsequently dissected the basis for such similarity from molecular, cytopathic, and immunologic perspectives using a panel of IPF-specific gene signatures, alongside signatures of alveolar type II (AT2) cytopathies and of prognostic monocyte-driven processes that are known drivers of IPF. To pinpoint the AT2 processes that are shared points of convergence between COVID-19 and IPF, transcriptome-derived findings were used to construct protein – protein interaction (PPI) network. Key findings were validated in hamster and human adult lung organoid (ALO) pre-clinical models of COVID-19 using immunohistochemistry and qPCR.FindingsWe found that COVID-19 resembles IPF at a fundamental level; it recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric) and the AT2 cytopathic changes, e.g., injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP). These immunocytopathic features were induced in pre-clinical COVID models (ALO and hamster) and reversed with effective anti-CoV-2 therapeutics in hamsters. PPI-network analyses pinpointed ER stress as one of the shared early triggers of both diseases, and IHC studies validated the same in the lungs of deceased subjects with COVID-19 and SARS-CoV-2-challenged hamster lungs. Lungs from tg-mice, in which ER stress is induced specifically in the AT2 cells, faithfully recapitulate the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2.InterpretationLike IPF, COVID-19 may be driven by injury-induced ER stress that culminates into progenitor state arrest and SASP in AT2 cells. The ViP signatures in monocytes may be key determinants of prognosis. The insights, signatures, disease models identified here are likely to spur the development of therapies for patients with IPF and other fibrotic interstitial lung disease.FundingThis work was supported by the National Institutes for Health grants R01-GM138385 and AI155696 and funding from the Tobacco-Related disease Research Program (R01RG3780).One Sentence SummarySevere COVID-19 triggers cellular processes seen in fibrosing Interstitial Lung DiseasePANEL: RESEARCH IN CONTEXTEvidence before this studyIn its aftermath, the COVID-19 pandemic has left many survivors, almost a third of those who recovered, with a mysterious long-haul form of the disease which culminates in a fibrotic form of interstitial lung disease (post-COVID-19 ILD). Post-COVID-19 ILD remains a largely unknown entity. Currently we lack insights into the core cytopathic features that drives this condition.Added value of this studyUsing an AI-guided approach, which involves the use of a sets of gene signatures, protein-protein network analysis, and a hamster model of COVID-19, we have revealed here that COVID-19 -lung fibrosis resembles IPF, the most common form of ILD, at a fundamental level—showing similar gene expression patterns in the lungs and blood, and dysfunctional AT2 processes (ER stress, telomere instability, progenitor cell arrest and senescence). These findings are insightful because AT2 cells are known to contain an elegant quality control network to respond to intrinsic or extrinsic stress; a failure of such quality control results in diverse cellular phenotypes, of which ER stress appears to be a point of convergence, which appears to be sufficient to drive downstream fibrotic remodeling in the lung.Implications of all the available evidenceBecause unbiased computational methods identified the shared fundamental aspects of gene expression and cellular processes between COVID-19 and IPF, the impact of our findings is likely to go beyond COVID-19 or any viral pandemic. The insights, tools (disease models, gene signatures, and biomarkers), and mechanisms identified here are likely to spur the development of therapies for patients with IPF and other fibrotic interstitial lung disease, all of whom have limited or no treatment options. to dissect the validate prognostic biomarkers to assess and track the risk of pulmonary fibrosis and develop therapeutics to halt fibrogenic progression.

show abstract

“…Consequences of “macrophageing” may be the reduced ability of the macrophages to remove other senescent cells and to interact with adaptive immune cells (including antigen presentation). It is worth mentioning that SASP is not only proinflammatory, but, especially at early stages of development of this phenotype, also immunosuppressive (due to secretion of TGF-β1 and TGF-β3), dampening the efficiency immune responses, as well as profibrotic, leading to more severe lung fibrosis ( Ito et al, 2017 , Nacarelli et al, 2019 , Parimon et al, 2021 ). These features very likely participate in increased severity of COVID-19 in the elderly.…”

Section: Cellular Senescence Immunosenescence and Inflammaging - How ...mentioning

confidence: 99%

Immunosenescence and COVID-19

Witkowski

Fülöp

Bryl

2022

Mechanisms of Ageing and Development

View full text Add to dashboard Cite

Cellular Senescence: Pathogenic Mechanisms in Lung Fibrosis

Cited by 18 publications

References 184 publications

PM2.5 Exposure Induces Lung Injury and Fibrosis by Regulating Ferroptosis via TGF-β Signaling

PM2.5 Exposure Induces Lung Injury and Fibrosis by Regulating Ferroptosis via TGF-β Signaling

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

Immunosenescence and COVID-19

Contact Info

Product

Resources

About