CCAAT/enhancer-binding protein (C/EBP) homologous protein promotes alveolar epithelial cell senescence via the nuclear factor-kappa B pathway in pulmonary fibrosis

2021 ◽  
pp. 106142
Author(s):  
Xiaoyan Jing ◽  
Wei Sun ◽  
Xiaoyu Yang ◽  
Hui Huang ◽  
Ping Wang ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Protein C ◽  
Nuclear Factor Kappa B ◽  
Alveolar Epithelial Cell ◽  
Cell Senescence ◽  
Nuclear Factor ◽  
Alveolar Epithelial ◽  
Homologous Protein ◽  
Enhancer Binding Protein

scholarly journals Efficacy of YAP1-gene Knockdown to Inhibit Alveolar-Epithelial-Cell Senescence and Alleviate Idiopathic Pulmonary Fibrosis (IPF)

2021 ◽  
Vol 18 (3 Suppl) ◽  
pp. 451-459
Author(s):  
WEI XU ◽  
WEIWEI SONG ◽  
YU WANG ◽  
YUMIN ZAN ◽  
MINGJIONG ZHANG ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Alveolar Epithelial Cell ◽  
Cell Senescence ◽  
Gene Knockdown ◽  
Alveolar Epithelial

scholarly journals Novel insights into surfactant protein C trafficking revealed through the study of a pathogenic mutant

2021 ◽  
pp. 2100267
Author(s):  
Jennifer A. Dickens ◽  
Eimear N. Rutherford ◽  
Susana Abreu ◽  
Joseph E. Chambers ◽  
Matthew O. Ellis ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Cell Surface ◽  
Protein C ◽  
Alveolar Epithelial Cell ◽  
Surfactant Protein ◽  
Surfactant Protein C ◽  
Alveolar Epithelial ◽  
Health And Disease

Alveolar epithelial cell dysfunction plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) but remains incompletely understood. Some monogenic forms of pulmonary fibrosis are associated with expression of mutant surfactant protein C (SFTPC). The commonest pathogenic mutant, I73T, mislocalises to the alveolar epithelial cell plasma membrane and displays a toxic-gain-of-function. Because the mechanisms explaining the link between this mutant and IPF are incompletely understood, we sought to interrogate SFTPC trafficking in health and disease to understand the functional significance of SFTPC-I73T relocalisation.We performed mechanistic analysis of SFTPC trafficking in a cell model that reproduces the in vivo phenotype and validated findings in human primary alveolar organoids.We show that wild-type SFTPC takes an unexpected indirect trafficking route via the plasma membrane and undergoes the first of multiple cleavage events before reaching the multivesicular body (MVB) for further processing. SFTPC-I73T takes this same route, but its progress is retarded both at the cell surface and due to failure of trafficking into the MVB. Unable to undergo onward trafficking, it is recycled to the plasma membrane as a partially cleaved intermediate.These data show for the first time that all SFTPC transits the cell surface during normal trafficking, and the I73T mutation accumulates at the cell surface through both retarded trafficking and active recycling. This understanding of normal SFTPC trafficking and how the I73T mutant disturbs it provides novel insight into SFTPC biology in health and disease, and in the contribution of the SFTPC mutant to IPF development.

scholarly journals PTEN loss regulates alveolar epithelial cell senescence in pulmonary fibrosis depending on Akt activation

Aging ◽  
2019 ◽  
Vol 11 (18) ◽  
pp. 7492-7509 ◽  
Author(s):  
Ting Qiu ◽  
Yaqiong Tian ◽  
Yujuan Gao ◽  
Miao Ma ◽  
Hui Li ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Alveolar Epithelial Cell ◽  
Cell Senescence ◽  
Pten Loss ◽  
Akt Activation ◽  
Alveolar Epithelial

ID: 140: KLOTHO, AN ANTI-AGING MOLECULE, REGULATES ALVEOLAR EPITHELIAL CELL MTDNA DAMAGE AND APOPTOSIS

2016 ◽  
Vol 64 (4) ◽  
pp. 961.1-961
Author(s):  
S Kim ◽  
P Cheresh ◽  
RP Jablonski ◽  
DW Kamp ◽  
M Eren ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Oxidative Dna Damage ◽  
Alveolar Epithelial Cell ◽  
Premature Aging ◽  
Protective Effects ◽  
Mtdna Damage ◽  
Alveolar Epithelial

RationaleConvincing evidence has emerged that impaired alveolar epithelial cell (AEC) injury and repair resulting from ‘exaggerated’ lung aging and mitochondrial dysfunction are critical determinants of the lung fibrogenic potential of toxic agents, including asbestos fibers, but the mechanisms underlying these findings is unknown. We showed that the extent of AEC mitochondrial DNA (mtDNA) damage and apoptosis are critical determinants of asbestos-induced pulmonary fibrosis (Cheresh et al AJRCMB 2014, Kim et al JBC 2014). Klotho is an age-inhibiting gene and Klotho-deficient mice demonstrate a premature aging phenotype that includes a reduced lifespan, arteriosclerosis, and lung oxidative DNA damage, and that Klotho attenuates hyperoxic-induced AEC DNA damage and apoptosis (Ravikumar et al AJP-Lung 2014). We reason that Klotho has an important role in limiting pulmonary fibrosis by protecting the AECs from oxidative stress.MethodsQuantitative PCR-based measurement of mtDNA damage was assessed following transient transfection with wild-type Klotho, Klotho siRNA or AKT siRNA in A549 and/or MLE-12 cells for 48 hrs followed by exposure to either amosite asbestos (25 µg/cm2) or H2O2 (200 µM) for 24 hrs. Apoptosis was assessed by cleaved caspase-9/3 levels and DNA fragmentation assay. Murine pulmonary fibrosis was analyzed in male 8–10 week old WT (C3H/C57B6J) mice or Klotho heterozygous knockout (Kl+/−) mice following intratracheal instillation of a single dose of 100 µg crocidolite asbestos or titanium dioxide (negative control) using histology (fibrosis score by Masson's trichrome staining) and lung collagen (Sircoll assay).ResultsCompared to control, amosite asbestos or H2O2 reduces Klotho mRNA/protein expression. Notably, silencing of Klotho promotes oxidative stress-induced AEC mtDNA damage and apoptosis whereas Klotho-enforced expression (EE) and Euk-134, a mitochondrial ROS scavenger, are protective. Interestingly, Kl+/− mice have increased asbestos-induced lung fibrosis. Also, we find that inhibition or silencing of AKT augments oxidant-induced AEC mtDNA damage and apoptosis.ConclusionsOur data demonstrate a crucial role for AEC AKT signaling in mediating the mtDNA damage protective effects of Klotho. Given the importance of AEC aging and apoptosis in pulmonary fibrosis, we reason that Klotho/AKT axis is an innovative therapeutic target for preventing common lung diseases of aging (i.e. IPF, COPD, lung cancer, etc.) for which more effective management regimens are clearly needed.FundingNIH-RO1 ES020357-01A1 (DK) and VA Merit (DK).

scholarly journals GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257281
Author(s):  
Silvia Speca ◽  
Caroline Dubuquoy ◽  
Christel Rousseaux ◽  
Philippe Chavatte ◽  
Pierre Desreumaux ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Alveolar Epithelial Cell ◽  
Lung Fibroblasts ◽  
Epithelial Cell Line ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Ppar Γ

The development of more effective, better tolerated drug treatments for progressive pulmonary fibrosis (of which idiopathic pulmonary fibrosis is the most common and severe form) is a research priority. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a key regulator of inflammation and fibrosis and therefore represents a potential therapeutic target. However, the use of synthetic PPAR-γ agonists may be limited by their potentially severe adverse effects. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, we have demonstrated that the non-racemic selective PPAR-γ modulator GED-0507 is able to reduce body weight loss, ameliorate clinical and histological features of pulmonary fibrosis, and increase survival rate without any safety concerns. Here, we focused on the biomolecular effects of GED-0507 on various inflammatory/fibrotic pathways. We demonstrated that preventive and therapeutic administration of GED-0507 reduced the BLM-induced mRNA expression of several markers of fibrosis, including transforming growth factor (TGF)-β, alpha-smooth muscle actin, collagen and fibronectin as well as epithelial-to-mesenchymal transition (EMT) and expression of mucin 5B. The beneficial effect of GED-0507 on pulmonary fibrosis was confirmed in vitro by its ability to control TGFβ-induced myofibroblast activation in the A549 human alveolar epithelial cell line, the MRC-5 lung fibroblast line, and primary human lung fibroblasts. Compared with the US Food and Drug Administration-approved antifibrotic drugs pirfenidone and nintedanib, GED-0507 displayed greater antifibrotic activity by controlling alveolar epithelial cell dysfunction, EMT, and extracellular matrix remodeling. In conclusion, GED-0507 demonstrated potent antifibrotic properties and might be a promising drug candidate for the treatment of pulmonary fibrosis.

scholarly journals β-catenin induces A549 alveolar epithelial cell mesenchymal transition during pulmonary fibrosis

2014 ◽  
Vol 11 (4) ◽  
pp. 2703-2710 ◽  
Author(s):  
PING SONG ◽  
JIN-XU ZHENG ◽  
JIAO XU ◽  
JI-ZHU LIU ◽  
LI-YAN WU ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Alveolar Epithelial Cell ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial

scholarly journals Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis

2020 ◽  
Vol 22 (8) ◽  
pp. 934-946 ◽  
Author(s):  
Yoshihiko Kobayashi ◽  
Aleksandra Tata ◽  
Arvind Konkimalla ◽  
Hiroaki Katsura ◽  
Rebecca F. Lee ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Alveolar Epithelial Cell ◽  
Cell State ◽  
Alveolar Epithelial
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