scholarly journals Pretreatment of aged mice with retinoic acid restores alveolar regeneration via upregulation of reciprocal PDGFRA signaling

2020 ◽  
Author(s):  
Jason J. Gokey ◽  
John Snowball ◽  
Jenna Green ◽  
Marion Waltamath ◽  
Jillian J. Spinney ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Differentiation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Alveolar Epithelial Cell ◽  
Aged Mice ◽  
Alveolar Epithelial ◽  
Epithelial Cell Differentiation ◽  
Lung Repair

AbstractObjectivesIdiopathic Pulmonary Fibrosis (IPF) primarily affects the aged population and is characterized by failure of alveolar regeneration leading to loss of alveolar type 1 cells (AT1). Aged mouse models of lung repair have demonstrated that regeneration fails with increased age. Mouse and rat lung repair models have shown retinoic acid (RA) treatment can restore alveolar regeneration. Herein we seek to determine the signaling mechanisms by which RA treatment prior to injury supports alveolar differentiation.DesignPartial pneumonectomy (PNX) lung injury model and next generation sequencing of sorted cell populations are used to uncover molecular targets regulating alveolar repair. In-vitro organoids generated from Mouse or IPF patient epithelial cells co-cultured with young, aged, or RA pretreated murine mesenchyme are used to test potential targets.Main outcome measurementsKnown alveolar epithelial cell differentiation markers, including HOPX and AGER for AT1 cells are used to assess outcome of treatments.ResultsGene expression analysis of sorted fibroblasts and epithelial cells isolated from lungs of young, aged, and RA treated aged mice predicted increased PDGFA signaling that coincided with regeneration and alveolar epithelial differentiation. Addition of PDGFA induced AT1 and AT2 alveolar differentiation in both mouse and human IPF lung organoids generated with aged fibroblasts and PDGFA monoclonal antibody blocked AT1 cell differentiation in organoids generated with young murine fibroblasts.ConclusionsOur data support the concept that reciprocal PDGFA signaling activates regenerative fibroblasts that support alveolar epithelial cell differentiation and repair, providing a potential therapeutic strategy to influence the pathogenesis of IPF.Key QuestionWhich epithelial-mesenchymal crosstalk pathways are activated by RA pretreatment of aged lungs that support realveolarization after partial pneumonectomy surgery?Bottom LineIncreased PDGFA/PDGFRA signaling in aged lungs promotes regenerative activation of interstitial matrixfibroblast which is required for AT2 to AT1 differentiation and alveolar regeneration.Read OnIn-vitro and in-vivo analysis demonstrated that PDGFA signaling supports alveolar matrixfibroblast and AT1 epithelial cell differentiation, both necessary for alveolar regeneration in aged lungs.

scholarly journals Pretreatment of aged mice with retinoic acid supports alveolar regeneration via upregulation of reciprocal PDGFA signalling

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-214986 ◽  
Author(s):  
Jason J Gokey ◽  
John Snowball ◽  
Jenna Green ◽  
Marion Waltamath ◽  
Jillian J Spinney ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Differentiation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Alveolar Epithelial Cell ◽  
Aged Mice ◽  
Alveolar Epithelial ◽  
Epithelial Cell Differentiation ◽  
Lung Repair ◽  
Murine Fibroblasts

ObjectivesIdiopathic pulmonary fibrosis (IPF) primarily affects the aged population and is characterised by failure of alveolar regeneration, leading to loss of alveolar type 1 (AT1) cells. Aged mouse models of lung repair have demonstrated that regeneration fails with increased age. Mouse and rat lung repair models have shown retinoic acid (RA) treatment can restore alveolar regeneration. Herein, we seek to determine the signalling mechanisms that become activated on RA treatment prior to injury, which support alveolar differentiation.DesignPartial pneumonectomy lung injury model and next-generation sequencing of sorted cell populations were used to uncover molecular targets regulating alveolar repair. In vitro organoids generated from epithelial cells of mouse or patient with IPF co-cultured with young, aged or RA-pretreated murine fibroblasts were used to test potential targets.Main outcome measurementsKnown alveolar epithelial cell differentiation markers, including HOPX and AGER for AT1 cells, were used to assess outcome of treatments.ResultsGene expression analysis of sorted fibroblasts and epithelial cells isolated from lungs of young, aged and RA-pretreated aged mice predicted increased platelet-derived growth factor subunit A (PDGFA) signalling that coincided with regeneration and alveolar epithelial differentiation. Addition of PDGFA induced AT1 and AT2 differentiation in both mouse and human IPF lung organoids generated with aged fibroblasts, and PDGFA monoclonal antibody blocked AT1 cell differentiation in organoids generated with young murine fibroblasts.ConclusionsOur data support the concept that RA indirectly induces reciprocal PDGFA signalling, which activates regenerative fibroblasts that support alveolar epithelial cell differentiation and repair, providing a potential therapeutic strategy to influence the pathogenesis of IPF.

EXTRACELLULAR MATRIX-DRIVEN ALVEOLAR EPITHELIAL CELL DIFFERENTIATION IN VITRO

2005 ◽  
Vol 31 (5) ◽  
pp. 461-482 ◽  
Author(s):  
Colin E. Olsen ◽  
Brant E. Isakson ◽  
Gregory J. Seedorf ◽  
Richard L. Lubman ◽  
Scott Boitano
Keyword(s):  
Extracellular Matrix ◽  
Cell Differentiation ◽  
Epithelial Cell ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial ◽  
Epithelial Cell Differentiation

YAP Regulates NFI/KLF5 Transcriptional and Epigenetic Networks Directing Alveolar Epithelial Cell Differentiation

2020 ◽  
Author(s):  
Jason J. Gokey ◽  
John Snowball ◽  
Anusha Sridharan ◽  
Parvathi Sudha ◽  
Joseph A. Kitzmiller ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cell ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial ◽  
Epithelial Cell Differentiation

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

2005 ◽  
Vol 288 (2) ◽  
pp. L342-L349 ◽  
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.

Effect of cigarette smoke and its condensates on alveolar epithelial cell injury in vitro

1994 ◽  
Vol 266 (1) ◽  
pp. L92-L100 ◽  
Author(s):  
S. Lannan ◽  
K. Donaldson ◽  
D. Brown ◽  
W. MacNee
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Cell Injury ◽  
Cell Attachment ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
Alveolar Epithelial

The oxidant-antioxidant balance in the airspaces of the lungs may be critical in protecting the lungs from the effects of cigarette smoke. We studied the effect of cigarette smoke and its condensates on the detachment, attachment, and proliferation of the A549 human alveolar epithelial cell line, in an in vitro model of cell injury and regeneration and the protective effects of antioxidants. Whole and vapor phase cigarette smoke decreased 51Cr-labeled A549 cell attachment, increased cell detachment, and decreased cell proliferation, as assessed by [3H]thymidine uptake. Freshly isolated rat type II alveolar epithelial cells showed an enhanced susceptibility to smoke-induced cell lysis when compared with the A549 cell line. Reduced glutathione (GSH) (400 microM) protected against the effects of cigarette smoke exposure on cell attachment, proliferation, and detachment. Depletion of intracellular GSH with buthionine sulfoxamine enhanced the epithelial cell detachment injury produced by smoke condensates. We conclude that cigarette smoke and its condensates cause an oxidant-induced injury to A549 human type II alveolar epithelial cells. Both intra- and extracellular GSH have important roles in protecting epithelial cells from the injurious effects of cigarette smoke.

scholarly journals Modulation of T1α expression with alveolar epithelial cell phenotype in vitro

1998 ◽  
Vol 275 (1) ◽  
pp. L155-L164 ◽  
Author(s):  
Zea Borok ◽  
Spencer I. Danto ◽  
Richard L. Lubman ◽  
Yuxia Cao ◽  
Mary C. Williams ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Shape ◽  
Alveolar Epithelial Cell ◽  
Cell Phenotype ◽  
Alveolar Type ◽  
Type I ◽  
Soluble Factors ◽  
Alveolar Epithelial

T1α is a recently identified gene expressed in the adult rat lung by alveolar type I (AT1) epithelial cells but not by alveolar type II (AT2) epithelial cells. We evaluated the effects of modulating alveolar epithelial cell (AEC) phenotype in vitro on T1α expression using either soluble factors or changes in cell shape to influence phenotype. For studies on the effects of soluble factors on T1α expression, rat AT2 cells were grown on polycarbonate filters in serum-free medium (MDSF) or in MDSF supplemented with either bovine serum (BS, 10%), rat serum (RS, 5%), or keratinocyte growth factor (KGF, 10 ng/ml) from either day 0 or day 4 through day 8 in culture. For studies on the effects of cell shape on T1α expression, AT2 cells were plated on thick collagen gels in MDSF supplemented with BS. Gels were detached on either day 1(DG1) or day 4 (DG4) or were left attached until day 8. RNA and protein were harvested at intervals between days 1 and 8 in culture, and T1α expression was quantified by Northern and Western blotting, respectively. Expression of T1α progressively increases in AEC grown in MDSF ± BS between day 1 and day 8 in culture, consistent with transition toward an AT1 cell phenotype. Exposure to RS or KGF from day 0 prevents the increase in T1α expression on day 8, whereas addition of either factor from day 4 through day 8 reverses the increase. AEC cultured on attached gels express high levels of T1α on days 4 and 8. T1α expression is markedly inhibited in both DG1 and DG4 cultures, consistent with both inhibition and reversal of the transition toward the AT1 cell phenotype. These results demonstrate that both soluble factors and alterations in cell shape modulate T1α expression in parallel with AEC phenotype and provide further support for the concept that transdifferentiation between AT2 and AT1 cell phenotypes is at least partially reversible.

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