Noncanonical WNT-5A signaling impairs endogenous lung repair in                    COPD

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT–β-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-β, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of β-catenin–driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal–epithelial cross talk in COPD pathogenesis, which is amenable to therapy.

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

PLoS ONE ◽

10.1371/journal.pone.0257281 ◽

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.

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Senescence of IPF Lung Fibroblasts Disrupt Alveolar Epithelial Cell Proliferation and Promote Migration in Wound Healing

Pharmaceutics ◽

10.3390/pharmaceutics12040389 ◽

2020 ◽

Vol 12 (4) ◽

pp. 389 ◽

Cited By ~ 3

Author(s):

Kaj E. C. Blokland ◽

David W. Waters ◽

Michael Schuliga ◽

Jane Read ◽

Simon D. Pouwels ◽

...

Keyword(s):

Cell Proliferation ◽

Epithelial Cell ◽

Wound Repair ◽

Alveolar Epithelial Cell ◽

Lung Parenchyma ◽

Repair Process ◽

Lung Fibroblasts ◽

Epithelial Cell Proliferation ◽

Alveolar Epithelial ◽

M Phase

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by excessive accumulation of lung fibroblasts (LFs) and collagen in the lung parenchyma. The mechanisms that underlie IPF pathophysiology are thought to reflect repeated alveolar epithelial injury leading to an aberrant wound repair response. Recent work has shown that IPF-LFs display increased characteristics of senescence including growth arrest and a senescence-associated secretory phenotype (SASP) suggesting that senescent LFs contribute to dysfunctional wound repair process. Here, we investigated the influence of senescent LFs on alveolar epithelial cell repair responses in a co-culture system. Alveolar epithelial cell proliferation was attenuated when in co-culture with cells or conditioned media from, senescence-induced control LFs or IPF-LFs. Cell-cycle analyses showed that a larger number of epithelial cells were arrested in G2/M phase when co-cultured with IPF-LFs, than in monoculture. Paradoxically, the presence of LFs resulted in increased A549 migration after mechanical injury. Our data suggest that senescent LFs may contribute to aberrant re-epithelialization by inhibiting proliferation in IPF.

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Pneumocystis Pneumonia Increases the Susceptibility of Mice to Sublethal Hyperoxia

Infection and Immunity ◽

10.1128/iai.71.10.5970-5978.2003 ◽

2003 ◽

Vol 71 (10) ◽

pp. 5970-5978 ◽

Cited By ~ 7

Author(s):

James M. Beck ◽

Angela M. Preston ◽

Steven E. Wilcoxen ◽

Susan B. Morris ◽

Eric S. White ◽

...

Keyword(s):

T Cells ◽

Epithelial Cell ◽

Cell Injury ◽

Alveolar Epithelial Cell ◽

Pulmonary Inflammation ◽

Alveolar Epithelial Cells ◽

Alveolar Epithelial ◽

Epithelial Cell Injury

ABSTRACT Patients with Pneumocystis pneumonia often develop respiratory failure after entry into medical care, and one mechanism for this deterioration may be increased alveolar epithelial cell injury. In vitro, we previously demonstrated that Pneumocystis is not cytotoxic for alveolar epithelial cells. In vivo, however, infection with Pneumocystis could increase susceptibility to injury by stressors that, alone, would be sublethal. We examined transient exposure to hyperoxia as a prototypical stress that does cause mortality in normal mice. Mice were depleted of CD4+ T cells and inoculated intratracheally with Pneumocystis. Control mice were depleted of CD4+ T cells but did not receive Pneumocystis. After 4 weeks, mice were maintained in normoxia, were exposed to hyperoxia for 4 days, or were exposed to hyperoxia for 4 days followed by return to normoxia. CD4-depleted mice with Pneumocystis pneumonia demonstrated significant mortality after transient exposure to hyperoxia, while all uninfected control mice survived this stress. We determined that organism burdens were not different. However, infected mice exposed to hyperoxia and then returned to normoxia demonstrated significant increases in inflammatory cell accumulation and lung cell apoptosis. We conclude that Pneumocystis pneumonia leads to increased mortality following a normally sublethal hyperoxic insult, accompanied by alveolar epithelial cell injury and increased pulmonary inflammation.

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Autophagy Decreases Alveolar Epithelial Cell Injury by Suppressing the NF-κB Signaling Pathway and Regulating the Release of Inflammatory Mediators

10.1101/328039 ◽

2018 ◽

Author(s):

Tao Fan ◽

Shuo Yang ◽

Zhixin Huang ◽

Wei Wang ◽

Shize Pan ◽

...

Keyword(s):

Epithelial Cell ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Alveolar Epithelial Cell ◽

Ischemia Reperfusion ◽

Left Lung ◽

Alveolar Epithelial ◽

Group Blocking

AbstractTo research the impact of autophagy on alveolar epithelial cell inflammation and its possible mechanism in early stages of hypoxia, we established a cell hypoxia-reoxygenation model and orthotopic left lung ischemia-reperfusion model. Rat alveolar epithelial cells stably expressing GFP-LC3 were treated with an autophagy inhibitor (3-methyladenine, 3-MA) or autophagy promoter (rapamycin), followed by hypoxia-reoxygenation treatment at 2, 4 and 6h in vitro. In vivo, twenty-four male Sprague-Dawley rats were randomly divided into four groups (model group: no blocking of hilum in the left lung; control group: blocking of hilum in the left lung for 1h with DMSO lavage; 3-MA group: blocking of hilum in the left lung for 1h with 100ml/kg of 3-MA (5μmol/L) solution lavage; rapamycin group: blocking of hilum in the left lung for 1h with 100ml/kg of rapamycin (250nmol/L) solution lavage) to establish an orthotopic left lung ischemia model. This study demonstrated that rapamycin significantly suppressed the NF-κB signaling pathway, restrained the expression of pro-inflammatory factors. A contrary result was confirmed by 3-MA pretreatment. These findings indicate that autophagy reduces ischemia-reperfusion injury by repressing inflammatory signaling pathways in the early stage of hypoxia in vitro and in vivo. This could be a new protective method for lung ischemia-reperfusion injury.

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Protective effect of IL-6 on alveolar epithelial cell death induced by hydrogen peroxide

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00016.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. L342-L349 ◽

Cited By ~ 32

Author(s):

Hiroshi Kida ◽

Mitsuhiro Yoshida ◽

Shigenori Hoshino ◽

Koji Inoue ◽

Yukihiro Yano ◽

...

Keyword(s):

Gene Expression ◽

Cell Death ◽

Epithelial Cell ◽

Epithelial Cells ◽

Alveolar Epithelial Cell ◽

Alveolar Epithelial Cells ◽

Lung Fibroblasts ◽

Alveolar Epithelial ◽

Epithelial Cell Death

The goal of this study was to examine whether IL-6 could directly protect lung resident cells, especially alveolar epithelial cells, from reactive oxygen species (ROS)-induced cell death. ROS induced IL-6 gene expression in organotypic lung slices of wild-type (WT) mice. ROS also induced IL-6 gene expression in mouse primary lung fibroblasts, dose dependently. The organotypic lung slices of WT were more resistant to ROS-induced DNA fragmentation than those of IL-6-deficient (IL-6−/−) mice. WT resistance against ROS was abrogated by treatment with anti-IL-6 antibody. TdT-mediated dUTP nick end labeling stain and electron microscopy revealed that DNA fragmented cells in the IL-6−/− slice included alveolar epithelial cells and endothelial cells. In vitro studies demonstrated that IL-6 reduced ROS-induced A549 alveolar epithelial cell death. Together, these data suggest that IL-6 played an antioxidant role in the lung by protecting lung resident cells, especially alveolar epithelial cells, from ROS-induced cell death.

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Faculty Opinions recommendation of Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1040287.497449 ◽

2006 ◽

Author(s):

Mina J Bissell

Keyword(s):

Extracellular Matrix ◽

Epithelial Cell ◽

Pulmonary Fibrosis ◽

Alveolar Epithelial Cell ◽

Mesenchymal Transition ◽

Alveolar Epithelial

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Development of novel in vitro human alveolar epithelial cell models to study distal lung biology and disease

10.1101/2020.12.25.424415 ◽

2020 ◽

Author(s):

Evelyn Tran ◽

Tuo Shi ◽

Xiuwen Li ◽

Adnan Y. Chowdhury ◽

Du Jiang ◽

...

Keyword(s):

Epithelial Cell ◽

Cell Lines ◽

Alveolar Epithelial Cell ◽

Cellular Heterogeneity ◽

Lung Fibroblasts ◽

Alveolar Epithelial ◽

Chronic Lung Diseases ◽

Distal Lung ◽

Lung Progenitor

ABSTRACTMany acute and chronic lung diseases affect the distal lung alveoli. Although airway-derived human cell lines exist, alveolar epithelial cell (AEC)-derived lines are needed to better model these diseases. We have generated and characterized novel immortalized cell lines derived from human AECs. They grow as epithelial monolayers expressing lung progenitor markers SOX9 and SOX2, with little to no expression of mature AEC markers. Co-cultured in 3-dimensions (3D) with lung fibroblasts, the cells form NKX2-1+ organoids expressing mature AEC markers AQP5 and GPRC5A. Single-cell RNA sequencing of an AEC line in 2D versus 3D revealed increased cellular heterogeneity and induction of cytokine and lipoprotein signaling, consistent with organoid formation. Activating WNT and FGF pathways resulted in larger organoids. Our approach appears to yield lung progenitor lines that retain a genetic and structural memory of their alveolar cell lineage despite long-term expansion and whose differentiation may be modulated under various 3D conditions. These cell lines provide a valuable new system to model the distal lung in vitro.

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