Deficient retinoid-driven angiogenesis may contribute to failure of adult human lung regeneration in emphysema

Ng-Blichfeldt, John-Poul; Alçada, Joana; Montero, M. Ángeles; Dean, Charlotte; Griesenbach, Uta; Griffiths, Mark; Hind, Matthew

doi:10.1136/thoraxjnl-2016-208846

Cited by 27 publications

(23 citation statements)

References 55 publications

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“…On the contrary, degradation of endogenous RA by increased CYP26A1, which occurs in emphysema, impairs endothelial cell repair and may contribute to chronic lung disease. This supports the clinical importance of maintaining an adequate vitamin A status for the conservation of lung function in humans [ 168 ].…”

Section: Vitamin a Deficiency And The Lungsupporting

confidence: 72%

Vitamin A Deficiency and the Lung

et al. 2018

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Vitamin A (all-trans-retinol) is a fat-soluble micronutrient which together with its natural derivatives and synthetic analogues constitutes the group of retinoids. They are involved in a wide range of physiological processes such as embryonic development, vision, immunity and cellular differentiation and proliferation. Retinoic acid (RA) is the main active form of vitamin A and multiple genes respond to RA signalling through transcriptional and non-transcriptional mechanisms. Vitamin A deficiency (VAD) is a remarkable public health problem. An adequate vitamin A intake is required in early lung development, alveolar formation, tissue maintenance and regeneration. In fact, chronic VAD has been associated with histopathological changes in the pulmonary epithelial lining that disrupt the normal lung physiology predisposing to severe tissue dysfunction and respiratory diseases. In addition, there are important alterations of the structure and composition of extracellular matrix with thickening of the alveolar basement membrane and ectopic deposition of collagen I. In this review, we show our recent findings on the modification of cell-junction proteins in VAD lungs, summarize up-to-date information related to the effects of chronic VAD in the impairment of lung physiology and pulmonary disease which represent a major global health problem and provide an overview of possible pathways involved.

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Section: Vitamin a Deficiency And The Lungsupporting

confidence: 72%

Vitamin A Deficiency and the Lung

et al. 2018

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“…Studies in mice revealed that RA is a critical regulator of both embryonic lung development and post-natal alveolarization [ [15] , [16] , [17] , [18] , [19] ]. In vitro , ATRA stimulated human lung microvascular angiogenesis [ 20 ] and induced lung fibroblast elastin synthesis [ 21 ]. In man, epidemiological evidence revealed associations between vitamin A deficiency and reduced lung function in children that was alleviated by maternal vitamin A supplementation [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid signaling balances adult distal lung epithelial progenitor cell growth and differentiation

et al. 2018

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BackgroundDespite compelling data describing pro-regenerative effects of all-trans retinoic acid (ATRA) in pre-clinical models of chronic obstructive pulmonary disease (COPD), clinical trials using retinoids for emphysema patients have failed. Crucial information about the specific role of RA signaling in adult rodent and human lung epithelial progenitor cells is largely missing.MethodsAdult lung organoid cultures were generated from isolated primary mouse and human lung epithelial cells, and incubated with pharmacological pathway modulators and recombinant proteins. Organoid number and size were measured, and differentiation was assessed with quantitative immunofluorescence and gene expression analyses.FindingsWe unexpectedly found that ATRA decreased lung organoid size, whereas RA pathway inhibition increased mouse and human lung organoid size. RA pathway inhibition stimulated mouse lung epithelial proliferation via YAP pathway activation and epithelial-mesenchymal FGF signaling, while concomitantly suppressing alveolar and airway differentiation. HDAC inhibition rescued differentiation in growth-augmented lung organoids.InterpretationIn contrast to prevailing notions, our study suggests that regenerative pharmacology using transient RA pathway inhibition followed by HDAC inhibition might hold promise to promote lung epithelial regeneration in diseased adult lung tissue.FundThis project is funded by the Lung Foundation Netherlands (Longfonds) grant 6.1.14.009 (RG, MK, JS, PSH) and W2/W3 Professorship Award by the Helmholtz Association, Berlin, Germany (MK).

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“…LIFs generate all-trans retinoic acid (ATRA) that acts autocrinally to upregulate elastin gene expression and synthesis, thus playing a crucial role in the induction of septal eruption [116,119,120]. Moreover, ATRA acts paracrinally to induce proliferation of the adjacent AEC2 [121,122], gene expression [115], and angiogenesis in microvascular endothelial cells [123]. After birth, esters start to disappear from the lung and are converted into active forms, like retinol and RA [98,104,124].…”

Section: Alveolar Phasementioning

confidence: 99%

“…Moreover, and considering retinoic acid role in the later phases, RA might be a suitable candidate to improve some chronic diseases in the adult by promoting regenerating/repair events. rarα −/− (↓ alveolar number and surface area) rarβ −/− (early & faster septation; ↓ surface area) rarγ −/− (↓ elastic tissue, ↓ alveoli number, ↑ distance between the alveolar walls) rxrα −/− (embryonic lethality) rarγ −/− , rxrα +/− (↓ elastic tissue at the alveolar septa) [88,94,97,104,[107][108][109][110][111][112]123,126,127,130,134] ↓, decrease; ↑, increase.…”

Section: Final Remarksmentioning

confidence: 99%

Retinoic Acid: A Key Regulator of Lung Development

et al. 2020

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Retinoic acid (RA) is a key molecular player in embryogenesis and adult tissue homeostasis. In embryo development, RA plays a crucial role in the formation of different organ systems, namely, the respiratory system. During lung development, there is a spatiotemporal regulation of RA levels that assures the formation of a fully functional organ. RA signaling influences lung specification, branching morphogenesis, and alveolarization by regulating the expression of particular target genes. Moreover, cooperation with other developmental pathways is essential to shape lung organogenesis. This review focuses on the events regulated by retinoic acid during lung developmental phases and pulmonary vascular development; also, it aims to provide a snapshot of RA interplay with other well-known regulators of lung development.

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Deficient retinoid-driven angiogenesis may contribute to failure of adult human lung regeneration in emphysema

Abstract: RA regulates lung microvascular angiogenesis; the endothelium produces CYP26A1 which is increased in emphysema, possibly leading to reduced RA availability. These data highlight a role for RA in maintenance of the human pulmonary microvascular endothelium.

Cited by 27 publications

References 55 publications

Vitamin A Deficiency and the Lung

Vitamin A Deficiency and the Lung

Retinoic acid signaling balances adult distal lung epithelial progenitor cell growth and differentiation

Retinoic Acid: A Key Regulator of Lung Development

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