Adenine nucleotide translocase regulates airway epithelial metabolism, surface hydration and ciliary function

Kliment, Corrine R.; Nguyen, Jennifer M. K.; Kaltreider, Mary Jane; Lu, Ya Wen; Claypool, Steven M.; Radder, Josiah E.; Sciurba, Frank C.; Zhang, Yingze; Gregory, Alyssa D.; Iglesias, Pablo A.; Sidhaye, Venkataramana K.; Robinson, Douglas N.

doi:10.1242/jcs.257162

Cited by 22 publications

(26 citation statements)

References 60 publications

(97 reference statements)

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“…A Matlab (R2018b, The MathWorks, Inc., MA, USA) program ( Sisson et al, 2003 ) was used to determine average CBF per video. Refer to earlier studies ( Kliment et al, 2021 ; Chandrala et al, 2019 ) for more details on CBF analysis.…”

Section: Methodsmentioning

confidence: 99%

Epithelial plasticity in COPD results in cellular unjamming due to an increase in polymerized actin

Ghosh

Nishida

Chandrala

et al. 2022

Journal of Cell Science

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The airway epithelium is subjected to insults such as cigarette smoke (CS), a primary cause of Chronic Obstructive Pulmonary Disease (COPD) and serves as an excellent model to study cell plasticity. Both CS-exposed and COPD-patient derived epithelia (CHBE) display quantitative evidence of cellular plasticity, with loss of specialized apical features and a transcriptional profile suggestive of partial epithelial to mesenchymal transition, albeit with distinct cell motion indicative of cellular unjamming. These injured/diseased cells have an increased fraction of polymerized actin, due to loss of the actin-severing protein, cofilin-1. Decreasing polymerized actin restores the jammed state in both CHBE and CS exposed epithelia, indicating that the fraction of polymerized actin is critical in unjamming the epithelia. Kinetic energy spectral analysis suggests that loss of cofilin-1 results in unjamming, similar to that seen with both CS exposure and in CHBE cells. Our data suggest that in response to chronic injury, although epithelial cells display evidence of pEMT, their movement is more consistent with cellular unjamming. Inhibitors of actin polymerization rectify the unjamming features of the monolayer.

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Section: Methodsmentioning

confidence: 99%

Epithelial plasticity in COPD results in cellular unjamming due to an increase in polymerized actin

Ghosh

Nishida

Chandrala

et al. 2022

Journal of Cell Science

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“…Five areas were imaged per insert. A Matlab (R2020a) script (validated against SAVA (38)) was used to determine average CBF and % moving cilia per video to generate a heatmap(39).…”

Section: Methodsmentioning

confidence: 99%

Knockout of E-cadherin in adult mouse epithelium results in emphysema and airway disease

Ghosh

Loube

Thapa³

et al. 2021

Preprint

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Chronic obstructive pulmonary disease (COPD) is a devastating lung disease, characterized by a progressive decline in lung function, alveolar loss (emphysema), and airflow limitation due to excessive mucus secretion (chronic bronchitis), that can occur even after the injurious agent is removed. It is slated to rise to the 3rd leading cause of death due to chronic disease by 2030 globally, and the 4th leading cause of death due to chronic disease in the USA. While there is substantial evidence indicating loss of E-cadherin in the lung epithelium of patients with COPD, it is not known if this is causal to the disease. We investigated if loss of E-cadherin can result in lung disease using in both in vitro models of primary, differentiated human cells and in mouse models. Using a cell type-specific promoter using Cre/LoxP mice system to knock-out E-cadherin in ciliated and alveolar epithelial cell (Type 1 and Type 2) populations in adult mouse models, we determined that loss of E-cadherin caused airspace enlargement, as well as increased airway hyperresponsiveness indicating that it does have a causative role in causing COPD. Strategies to upregulate CDH1 (encodes for E-cadherin) in CHBEs and cigarette-smoke injured NHBEs can rescue the dysfunctional epithelium.

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“…and increases lineage output, we employed C57BL/6 mice exposed to cigarette smoke for six months, an established mouse model of COPD 40,47 . These mice contained significantly heightened numbers of lymphocytes, such as B and T cells, in the bone marrow while myeloid cell content decreased (Suppl.…”

Section: Additionally To Understand If Copd Elevates Vegfr Expression In Hematopoietic Progenitorsmentioning

confidence: 99%

“…Patients with OSA and COPD, characterized by alveolar hypoxia, displayed increased circulating myeloid cell numbers. We used two independent mouse models of hypoxia to understand the effect of hypoxia in HSPC proliferation: C57BL/6 mice exposed to A) 10% O2 for three weeks, an established mouse model of chronic hypoxia [36][37][38] and B) cigarette smoke for six months, a COPD mouse model 39,40 . Mice under chronic hypoxic conditions and exposed to cigarette smoke had elevated numbers of neutrophils, monocytes and macrophages in the blood and lungs suggesting augmented hematopoiesis.…”

Section: Introductionmentioning

confidence: 99%

VEGF receptor promotes hypoxia-induced hematopoietic progenitor proliferation and differentiation

Florentin

O'Neil

Vasamsetti

et al. 2021

Preprint

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Intermittent or chronic hypoxia is associated with morbidity and mortality in many diseases such as obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD), respectively. We found exaggerated inflammation with heightened numbers of inflammatory leukocytes in these patients compared with age-matched controls. Chronically hypoxic mice exhibited similar trend and induced proliferation of hematopoietic stem and progenitor cells (HSPC), precursors of inflammatory leukocytes. Consistently, a transcriptomic analysis of human HSPC exposed to hypoxic conditions revealed elevated expression of genes involved in progenitor mobilization. Additionally, bone marrow cells in mice under hypoxic conditions expressed high amount of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFr) and its target genes in hypoxic conditions. In silico and ChIP experiments demonstrated that HIF-1⍺ binds to the promoter region of VEGFr. These results indicate that VEGF signaling in HSPC is an important mediator of their proliferation and differentiation in hypoxia-induced inflammation and represents a potential therapeutic target to prevent aberrant inflammation in hypoxia-associated diseases.

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Adenine nucleotide translocase regulates airway epithelial metabolism, surface hydration and ciliary function

Cited by 22 publications

References 60 publications

Epithelial plasticity in COPD results in cellular unjamming due to an increase in polymerized actin

Epithelial plasticity in COPD results in cellular unjamming due to an increase in polymerized actin

Knockout of E-cadherin in adult mouse epithelium results in emphysema and airway disease

VEGF receptor promotes hypoxia-induced hematopoietic progenitor proliferation and differentiation

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