scholarly journals Erratum: Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis

2021 ◽  
Vol 204 (1) ◽  
pp. 113-113
Keyword(s):  
Pulmonary Fibrosis ◽  
Alveolar Type

scholarly journals Senescence of alveolar stem cells drives progressive pulmonary fibrosis

2019 ◽  
Author(s):  
Changfu Yao ◽  
Xiangrong Guan ◽  
Gianni Carraro ◽  
Tanyalak Parimon ◽  
Xue Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Chronic Disease ◽  
Pulmonary Fibrosis ◽  
Cellular Senescence ◽  
Adult Mouse ◽  
Alveolar Type ◽  
Epithelial Stem Cells ◽  
Organ Function ◽  
P53 Activation

AbstractTissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ function leading to morbidity and mortality. In the lung, idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Here, we show that alveolar type 2 (AT2) stem cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of epithelial stem cells serves as a proximal driver of Tgfβ activation and progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation, senescence, or downstream Tgfβ activation, block fibrogenesis.

scholarly journals Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis

2021 ◽  
Vol 118 (20) ◽  
pp. e2101100118
Author(s):  
Satoshi Watanabe ◽  
Nikolay S. Markov ◽  
Ziyan Lu ◽  
Raul Piseaux Aillon ◽  
Saul Soberanes ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Alveolar Epithelium ◽  
Protein Translation ◽  
Alveolar Type ◽  
Fatal Disease ◽  
Epithelial Repair ◽  
Old Mice

Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy, we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.

scholarly journals Alveolar Type 2 Epithelial Cell Quality Control Responses to Pulmonary Fibrosis Related SFTPC Mutations Are Dysfunctional And Substrate Specific

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Michael F. Beers ◽  
Luis Rodriguez ◽  
Arie Hawkins ◽  
Scott J. Russo ◽  
Yaniv Tomer ◽  
...  
Keyword(s):  
Quality Control ◽  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Alveolar Type

scholarly journals Mesenchymal stromal cells attenuate alveolar type 2 cells senescence through regulating NAMPT-mediated NAD metabolism

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiaofan Lai ◽  
Shaojie Huang ◽  
Sijia Lin ◽  
Lvya Pu ◽  
Yaqing Wang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Potential ◽  
Alveolar Type ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Nad Metabolism

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive deadly fibrotic lung disease with high prevalence and mortality worldwide. The therapeutic potential of mesenchymal stem cells (MSCs) in pulmonary fibrosis may be attributed to the strong paracrine, anti-inflammatory, anti-apoptosis and immunoregulatory effects. However, the mechanisms underlying the therapeutic effects of MSCs in IPF, especially in terms of alveolar type 2 (AT2) cells senescence, are not well understood. The purpose of this study was to evaluate the role of MSCs in NAD metabolism and senescence of AT2 cells in vitro and in vivo. Methods MSCs were isolated from human bone marrow. The protective effects of MSCs injection in pulmonary fibrosis were assessed via bleomycin mouse models. The senescence of AT2 cells co-cultured with MSCs was evaluated by SA-β-galactosidase assay, immunofluorescence staining and Western blotting. NAD+ level and NAMPT expression in AT2 cells affected by MSCs were determined in vitro and in vivo. FK866 and NAMPT shRNA vectors were used to determine the role of NAMPT in MSCs inhibiting AT2 cells senescence. Results We proved that MSCs attenuate bleomycin-induced pulmonary fibrosis in mice. Senescence of AT2 cells was alleviated in MSCs-treated pulmonary fibrosis mice and when co-cultured with MSCs in vitro. Mechanistic studies showed that NAD+ and NAMPT levels were rescued in AT2 cells co-cultured with MSCs and MSCs could suppress AT2 cells senescence mainly via suppressing lysosome-mediated NAMPT degradation. Conclusions MSCs attenuate AT2 cells senescence by upregulating NAMPT expression and NAD+ levels, thus exerting protective effects in pulmonary fibrosis.

Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis

2020 ◽  
Author(s):  
Changfu Yao ◽  
Xiangrong Guan ◽  
Gianni Carraro ◽  
Tanyalak Parimon ◽  
Xue Liu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Alveolar Type

Defective surfactant biosynthesis and ultrastructural abnormalities of alveolar type 2 cells in pulmonary fibrosis of conditional Nedd4-2mice

2019 ◽  
Author(s):  
Dominik Leitz ◽  
Julia Duerr ◽  
Jan Hegermann ◽  
Lars Knudsen ◽  
Surafel Mulugeta ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Alveolar Type

scholarly journals AP-3–dependent targeting of flippase ATP8A1 to lamellar bodies suppresses activation of YAP in alveolar epithelial type 2 cells

2021 ◽  
Vol 118 (20) ◽  
pp. e2025208118
Author(s):  
Seunghyi Kook ◽  
Ping Wang ◽  
Shufang Meng ◽  
Christopher S. Jetter ◽  
Jennifer M. S. Sucre ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Protein A ◽  
Alveolar Type ◽  
Transcriptional Coactivator ◽  
Lamellar Bodies ◽  
Recycling Endosomes ◽  
Alveolar Epithelial ◽  
Early Endosomes ◽  
Lysosome Related Organelles

Lamellar bodies (LBs) are lysosome-related organelles (LROs) of surfactant-producing alveolar type 2 (AT2) cells of the distal lung epithelium. Trafficking pathways to LBs have been understudied but are likely critical to AT2 cell homeostasis given associations between genetic defects of endosome to LRO trafficking and pulmonary fibrosis in Hermansky Pudlak syndrome (HPS). Our prior studies uncovered a role for AP-3, defective in HPS type 2, in trafficking Peroxiredoxin-6 to LBs. We now show that the P4-type ATPase ATP8A1 is sorted by AP-3 from early endosomes to LBs through recognition of a C-terminal dileucine-based signal. Disruption of the AP-3/ATP8A1 interaction causes ATP8A1 accumulation in early sorting and/or recycling endosomes, enhancing phosphatidylserine exposure on the cytosolic leaflet. This in turn promotes activation of Yes-activating protein, a transcriptional coactivator, augmenting cell migration and AT2 cell numbers. Together, these studies illuminate a mechanism whereby loss of AP-3–mediated trafficking contributes to a toxic gain-of-function that results in enhanced and sustained activation of a repair pathway associated with pulmonary fibrosis.

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