scholarly journals Cigarette-Decreased NAD+/SIRT1 of Alveolar Type 2 Cells Aggravates Pulmonary Fibrosis by Promoting Cellular Senescence Through Autophagy Inhibition and Mitochondrial Oxidative Stress Induction

2020 ◽  
Author(s):  
Y. Zhang ◽  
Y. Meng
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Fibrosis ◽  
Cellular Senescence ◽  
Alveolar Type ◽  
Mitochondrial Oxidative Stress ◽  
Stress Induction ◽  
Autophagy Inhibition

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 The Essential Element Manganese, Oxidative Stress, and Metabolic Diseases: Links and Interactions

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Longman Li ◽  
Xiaobo Yang
Keyword(s):  
Oxidative Stress ◽  
Metabolic Diseases ◽  
Essential Element ◽  
Ros Generation ◽  
Oxygen Species ◽  
Mitochondrial Oxidative Stress ◽  
Nonalcoholic Fatty Liver ◽  
The Past ◽  
The Relationship

Manganese (Mn) is an essential element that is involved in the synthesis and activation of many enzymes and in the regulation of the metabolism of glucose and lipids in humans. In addition, Mn is one of the required components for Mn superoxide dismutase (MnSOD) that is mainly responsible for scavenging reactive oxygen species (ROS) in mitochondrial oxidative stress. Both Mn deficiency and intoxication are associated with adverse metabolic and neuropsychiatric effects. Over the past few decades, the prevalence of metabolic diseases, including type 2 diabetes mellitus (T2MD), obesity, insulin resistance, atherosclerosis, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), and hepatic steatosis, has increased dramatically. Previous studies have found that ROS generation, oxidative stress, and inflammation are critical for the pathogenesis of metabolic diseases. In addition, deficiency in dietary Mn as well as excessive Mn exposure could increase ROS generation and result in further oxidative stress. However, the relationship between Mn and metabolic diseases is not clear. In this review, we provide insights into the role Mn plays in the prevention and development of metabolic diseases.

scholarly journals Akt is required for Rac1 mediated mitochondrial oxidative stress and pulmonary fibrosis

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Jennifer Casey ◽  
Shubha Murthy ◽  
Alan J Ryan ◽  
A. Brent Carter
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Fibrosis ◽  
Mitochondrial Oxidative Stress

scholarly journals Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin

Aging ◽  
2012 ◽  
Vol 4 (1) ◽  
pp. 3-12 ◽  
Author(s):  
Michael C. Velarde ◽  
James M. Flynn ◽  
Nicholas U. Day ◽  
Simon Melov ◽  
Judith Campisi
Keyword(s):  
Oxidative Stress ◽  
Cellular Senescence ◽  
Mitochondrial Oxidative Stress

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.

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