Moderate hyperoxia induces senescence in developing human lung fibroblasts

You, Kai; Parikh, Pavan; Khandalavala, Karl; Wicher, S.A.; Manlove, L.; Yang, Binxia; Roesler, Annie; Roos, B.; Teske, J.J.; Britt, Rodney D.; Pabelick, Christina M.; Prakash, Y. S.

doi:10.1152/ajplung.00067.2019

Cited by 41 publications

(37 citation statements)

References 59 publications

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“…In the ensuing section, we will highlight several emerging and proposed mechanisms. Cellular senescence of ASM induced by hyperoxia leads to secretion of pro-inflammatory and pro-fibrotic mediators factors that has been proposed to contribute to pediatric airway disease in the context of sequelae of preterm birth (220,221).…”

Section: Cells Implicated In Inflammagingmentioning

confidence: 99%

Airway Remodeling in Asthma

et al. 2020

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Asthma is an inflammatory disease of the airways that may result from exposure to allergens or other environmental irritants, resulting in bronchoconstriction, wheezing, and shortness of breath. The structural changes of the airways associated with asthma, broadly referred to as airway remodeling, is a pathological feature of chronic asthma that contributes to the clinical manifestations of the disease. Airway remodeling in asthma constitutes cellular and extracellular matrix changes in the large and small airways, epithelial cell apoptosis, airway smooth muscle cell proliferation, and fibroblast activation. These pathological changes in the airway are orchestrated by crosstalk of different cell types within the airway wall and submucosa. Environmental exposures to dust, chemicals, and cigarette smoke can initiate the cascade of pro-inflammatory responses that trigger airway remodeling through paracrine signaling and mechanostimulatory cues that drive airway remodeling. In this review, we explore three integrated and dynamic processes in airway remodeling: (1) initiation by epithelial cells; (2) amplification by immune cells; and (3) mesenchymal effector functions. Furthermore, we explore the role of inflammaging in the dysregulated and persistent inflammatory response that perpetuates airway remodeling in elderly asthmatics.

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Section: Cells Implicated In Inflammagingmentioning

confidence: 99%

Airway Remodeling in Asthma

et al. 2020

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“…Interestingly, in the absence of p21, mortality and alveolar cell death was increased, and repair of the hyperoxia-injured lung was hampered [ 12 , 46 , 47 ]. Moderate hyperoxia (40% FiO 2 ) upregulated p53 and p21 in human fetal lung fibroblasts and airway smooth muscle cells [ 48 , 49 ]. In this study, we show that the p21 upregulation in the acute phase after hyperoxia exposure could be mediated through H3K27ac gain.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic response to hyperoxia in the neonatal lung is sexually dimorphic

et al. 2020

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Sex as a biological variable plays a critical role both during lung development and in modulating postnatal hyperoxic lung injury and repair. The molecular mechanisms behind these sex-specific differences need to be elucidated. Our objective was to determine if the neonatal lung epigenomic landscape reconfiguration has profound effects on gene expression and could underlie sex-biased differences in protection from or susceptibility to diseases. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia (95% FiO, PND 1–5: saccular stage) or room air and euthanized on PND 7 and 21. Pulmonary gene expression was studied using RNA-seq on Illumina HiSeq 2500 platform and quantified. Epigenomic landscape was assessed using Chromatin Immunoprecipitation (ChIP-Seq) of the H3K27ac histone modification mark, associated with active genes, enhancers, and super-enhancers. These data were then integrated, pathways identified and validated. Sex-biased epigenetic modulation of gene expression leads to differential regulation of biological processes in the developing lung at baseline and after exposure to hyperoxia. The female lung exhibits a more robust epigenomic response for the H3K27ac mark in response to hyperoxia. Epigenomic changes distribute over genomic and epigenomic domains in a sex-specific manner. The differential epigenomic responses also enrich for key transcription regulators crucial for lung development. In addition, by utilizing H3K27ac as the target epigenomic change we were also able to identify new epigenomic reprogramming at super-enhancers. Finally, we report for the first time that the upregulation of p21 (Cdkn1a) in the injured neonatal lung could be mediated through gain of H3K27ac. These data demonstrate that modulation of transcription via epigenomic landscape alterations may contribute to the sex-specific differences in preterm neonatal hyperoxic lung injury and repair.

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“…Many molecular pathways that are associated with aging are also altered in the neonatal BPD lung (51,52). Hyperoxia is known to induce a senescent phenotype in many cell types including airway smooth muscle cells and fibroblasts (53)(54)(55).…”

Section: Role Of Gdf15 In Chronic Lung Disease: Neonatal and Pediatricmentioning

confidence: 99%

Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan

et al. 2020

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Growth Differentiation Factor 15 (GDF15) is a divergent member of transforming growth factor-beta (TGF-β) superfamily and is ubiquitously expressed, under normal physiological conditions. GDF15 expression increases during many pathological states and serves a marker of cellular stress. GDF15 has multiple and even paradoxical roles within a pathological condition, as its effects can be dose- and time-dependent and vary based on the targeted tissues and downstream pathways. GDF15 has emerged as one of the most recognized proteins as part of the senescence associated secretory phenotype. Cellular senescence plays a major role in many lung diseases across the life-span from bronchopulmonary dysplasia in the premature neonate to COPD and idiopathic pulmonary fibrosis in aged adults. GDF15 levels have been reported to be as a useful biomarker in chronic obstructive pulmonary disease, lung fibrosis and pulmonary arterial hypertension and predict disease severity, decline in lung function and mortality. Glial-cell-line-derived neurotrophic factor family receptor alpha-like (GFRAL) in the brain stem has been identified as the only validated GDF15 receptor and mediates GDF15-mediated anorexia and wasting. The mechanisms and pathways by which GDF15 exerts its pulmonary effects are being elucidated. GDF15 may also have an impact on the lung based on the changes in circulating levels or through the central action of GDF15 activating peripheral metabolic changes. This review focuses on the role of GDF15 in different lung diseases across the lifespan and its role in cellular senescence.

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Moderate hyperoxia induces senescence in developing human lung fibroblasts

Cited by 41 publications

References 59 publications

Airway Remodeling in Asthma

Airway Remodeling in Asthma

Epigenetic response to hyperoxia in the neonatal lung is sexually dimorphic

Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan

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