Inhibition of lung epithelial cell proliferation by hyperoxia. Posttranscriptional regulation of proliferation-related genes.

Clément, Annick; Edeas, Marvin; Chadelat, Katarina; Brody, Jerome S.

doi:10.1172/jci116056

Cited by 47 publications

(22 citation statements)

References 41 publications

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“…The median PI of lungs from preterm infants was increased 2.2-fold. This observation is in contradiction to results obtained in cell culture experiments, in which hyperoxia inhibited the proliferation of fibroblasts [5], smooth muscle cells [4] and epithelial cells [19]. The cessation of proliferation is believed to represent a basic protective mechanism that prevents the replication of damaged template DNA.…”

Section: Discussioncontrasting

confidence: 71%

“…The cessation of proliferation is believed to represent a basic protective mechanism that prevents the replication of damaged template DNA. Molecules such as p21 WAF/CIP1 and p53, which promote cell cycle arrest, are upregulated during hyperoxia [20] and the messenger ribonucleic acids (mRNAs) encoding the cell cycle proteins histone and thymidine kinase are not translated under hyperoxic conditions [19]. However, in rat lung and in lung explant cultures, under hyperoxic conditions, increased proliferation, especially of alveolar type II cells and fibroblasts, was observed [10,11].…”

Section: Discussionmentioning

confidence: 99%

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Apoptosis and proliferation in lungs of ventilated and oxygen-treated preterm infants

May¹,

Strobel²,

Preisshofen³

et al. 2004

European Respiratory Journal

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. ABSTRACT: Apoptosis and proliferation and the effect of exogenous surfactant on these processes were investigated in the lungs of mechanically ventilated/oxygen-treated preterm infants with respiratory distress syndrome and stillborn foetuses.Apoptotic and proliferation indices were determined in lung tissue sections from 27 ventilated/oxygen-treated preterm infants and 29 stillborn foetuses. The effect of exogenous surfactant on apoptosis and proliferation was studied in 16 ventilated preterm infants; 11 untreated infants served as control. Apoptotic and proliferating cells were identified by double labelling combining terminal deoxynucleotidyltransferasemediated deoxyuridine triphosphate nick end-labelling or Ki-67 with cell marker proteins. Pathways to cell death were explored by immunolabelling of cleaved caspases-3, -8 and -9.In the lungs of ventilated/oxygen-treated preterm infants, the numbers of apoptotic and proliferating cells increased significantly compared to the respective numbers in the lungs of stillborn foetuses. Apoptosis was detected in alveolar epithelial cells, whereas epithelial, endothelial and smooth muscle cells proliferated. Surfactant treatment reduced apoptosis induced by ventilation/oxygen-treatment; however, the decrease was not significant. Caspases-8 and -9 do not contribute to ventilation-induced apoptosis, whereas caspase-3 is involved.In conclusion, ventilation/oxygen-treatment induces epithelial cell apoptosis and proliferation of epithelial, endothelial and smooth muscle cells in the lungs of preterm infants. Apoptosis and proliferation are involved in several processes during embryonal and foetal life and play an important role in normal cell turnover and tissue development.Although they have been implicated as mechanisms of obtaining correct cell number, they are involved in pathological processes. In the lung, these processes can result from oxygen injury caused by high oxygen concentrations. However, oxygen therapy is often necessary for patients suffering from pulmonary diseases. This is particularly true for preterm infants and neonates suffering from respiratory distress syndrome (RDS), who require supraphysiological concentrations of oxygen to maintain adequate blood oxygen tensions.In animal models, it has been demonstrated that apoptosis is significantly increased in lungs exposed to hyperoxia [1][2][3]. In addition, it could be shown that hyperoxia induces increased expression of genes encoding apoptosis-promoting proteins [1,2]. Proliferation, however, ceases as a consequence of hyperoxia in cell culture experiments with alveolar epithelial cells, fibroblasts and tracheal smooth muscle cells [4][5][6].Exogenous surfactant therapy remains an established treatment of RDS. Recently, it has become increasingly obvious that exogenous surfactant preparations have significant effects on cell physiology and inflammatory processes in the lung comprising suppression of pro-inflammatory cytokines, superoxide production and regulation of the pulmonary host defence [7,8]. Ho...

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Section: Discussioncontrasting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Apoptosis and proliferation in lungs of ventilated and oxygen-treated preterm infants

May¹,

Strobel²,

Preisshofen³

et al. 2004

European Respiratory Journal

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“…1A) due to Rev-erba autoregulation (1). Since hyperoxia inhibits cell proliferation (15), cell number was determined at each time point of the incubation (Fig. 1B) and luciferase activity was normalized to cell numbers (Fig.…”

Section: Resultsmentioning

confidence: 99%

Oxidative Stress and Inflammation Modulate Rev-erbα Signaling in the Neonatal Lung and Affect Circadian Rhythmicity

Guang

Wright

Hinson

et al. 2014

Antioxidants & Redox Signaling

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Aims: The response to oxidative stress and inflammation varies with diurnal rhythms. Nevertheless, it is not known whether circadian genes are regulated by these stimuli. We evaluated whether Rev-erba, a key circadian gene, was regulated by oxidative stress and/or inflammation in vitro and in a mouse model. Results: A unique sequence consisting of overlapping AP-1 and nuclear factor kappa B (NFjB) consensus sequences was identified on the mouse Rev-erba promoter. This sequence mediates Rev-erba promoter activity and transcription in response to oxidative stress and inflammation. This region serves as an NrF2 platform both to receive oxidative stress signals and to activate Rev-erba, as well as an NFjB-binding site to repress Rev-erba with inflammatory stimuli. The amplitude of the rhythmicity of Rev-erba was altered by pre-exposure to hyperoxia or disruption of NFjB in a cell culture model of circadian simulation. Oxidative stress overcame the inhibitory effect of NFjB binding on Rev-erba transcription. This was confirmed in neonatal mice exposed to hyperoxia, where hyperoxiainduced lung Rev-erba transcription was further increased with NFjB disruption. Interestingly, this effect was not observed in similarly exposed adult mice. Innovation: These data provide novel mechanistic insights into how key circadian genes are regulated by oxidative stress and inflammation in the neonatal lung. Conclusion: Rev-erba transcription and circadian oscillation are susceptible to oxidative stress and inflammation in the neonate. Due to Rev-erba's role in cellular metabolism, this could contribute to lung cellular function and injury from inflammation and oxidative stress. Antioxid. Redox Signal. 21, 17-32.

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“…For autoradiography of labeled nuclei, cells were incubated for 24 h in medium containing 2 Ci/ml [methyl- 3 H]thymidine (60-70 Ci/mmol), as previously described (9). The plates were then washed three times with cold PBS, fixed with methanol, air dried, and coated with NTB-2 liquid emulsion (Eastman Kodak, Rochester, NY).…”

Section: Proliferation Studiesmentioning

confidence: 99%

Protective role of retinoic acid from antiproliferative action of TNF-α on lung epithelial cells

Besnard

Nabeyrat

Henrion‐Caude

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Tumor necrosis factor (TNF)-α is a key molecule in lung inflammation. We have established the insulin-like growth factor binding protein 2 (IGFBP-2) as a marker associated with the growth arrest of lung alveolar epithelial cells (AEC). Here, we studied the effects of TNF-α on AEC proliferation and the putative protective role of retinoic acid (RA). We documented an antiproliferative action of TNF-α that was reversible only at 24 h and then became irreversible with induction of apoptosis. TNF-α treatment was associated with a dramatic induction of IGFBP-2. To discover the mechanism of action of IGFBP-2, we further tested the mitogenic potential of IGF-I to counteract TNF-α inhibition. Addition of IGF-I to the TNF-α containing medium did not stimulate proliferation, whereas des(1–3)IGF-I, an analog of IGF-I that bears low affinity for IGFBPs, was able to restore cell growth. Interestingly, we observed that RA abrogated TNF-α-induced growth arrest and that this effect was associated with a dramatic decrease in IGFBP-2 expression. These results suggest a protective role of RA from TNF-α antiproliferative action, through mechanisms involving modulation of IGFBP-2 production.

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Inhibition of lung epithelial cell proliferation by hyperoxia. Posttranscriptional regulation of proliferation-related genes.

Cited by 47 publications

References 41 publications

Apoptosis and proliferation in lungs of ventilated and oxygen-treated preterm infants

Apoptosis and proliferation in lungs of ventilated and oxygen-treated preterm infants

Oxidative Stress and Inflammation Modulate Rev-erbα Signaling in the Neonatal Lung and Affect Circadian Rhythmicity

Protective role of retinoic acid from antiproliferative action of TNF-α on lung epithelial cells

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