Effects of Hyperoxia on the Developing Airway and Pulmonary Vasculature

Pabelick, Christina M.; Thompson, Michael A.; Britt, Rodney D.

doi:10.1007/978-3-319-63245-2_11

Cited by 12 publications

(7 citation statements)

References 138 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mechanisms in the context of inflammation (Hartman et al, 2012), hypercontractility (Faksh et al, 2016), and fibrosis (Vogel et al, 2017) have been explored to some extent. In this regard, there is increasing recognition that O 2 effects in specific cell types and the types of changes are dependent on extent of exposure structure/function, where with higher levels of O 2 promote bronchopulmonary dysplasia (Wang et al, 2014;Pabelick et al, 2017), but even moderate hyperoxia can contribute to bronchial changes. For example, at a cellular level, we previously showed that increasing levels of O 2 result in progressively greater enhancement of [Ca 2+ ] i and mitochondrial fragmentation, but interestingly, cell proliferation is increased until >60% O 2 levels are reached when cell death is predominant (Hartman et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle

et al. 2021

Self Cite

View full text Add to dashboard Cite

Supplemental O2 (hyperoxia), necessary for maintenance of oxygenation in premature infants, contributes to neonatal and pediatric airway diseases including asthma. Airway smooth muscle (ASM) is a key resident cell type, responding to hyperoxia with increased contractility and remodeling [proliferation, extracellular matrix (ECM) production], making the mechanisms underlying hyperoxia effects on ASM significant. Recognizing that fetal lungs experience a higher extracellular Ca2+ ([Ca2+]o) environment, we previously reported that the calcium sensing receptor (CaSR) is expressed and functional in human fetal ASM (fASM). In this study, using fASM cells from 18 to 22 week human fetal lungs, we tested the hypothesis that CaSR contributes to hyperoxia effects on developing ASM. Moderate hyperoxia (50% O2) increased fASM CaSR expression. Fluorescence [Ca2+]i imaging showed hyperoxia increased [Ca2+]i responses to histamine that was more sensitive to altered [Ca2+]o, and promoted IP3 induced intracellular Ca2+ release and store-operated Ca2+ entry: effects blunted by the calcilytic NPS2143. Hyperoxia did not significantly increase mitochondrial calcium which was regulated by CaSR irrespective of oxygen levels. Separately, fASM cell proliferation and ECM deposition (collagens but not fibronectin) showed sensitivity to [Ca2+]o that was enhanced by hyperoxia, but blunted by NPS2143. Effects of hyperoxia involved p42/44 ERK via CaSR and HIF1α. These results demonstrate functional CaSR in developing ASM that contributes to hyperoxia-induced contractility and remodeling that may be relevant to perinatal airway disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…The mechanisms responsible for airway dysfunction and thickening in preterm infants that lead to subsequent recurrent wheezing and asthma remain incompletely understood. Although hyperoxia can be expected to induce oxidant stress and thus activate a number of pathways relating to inflammation (13), hypercontractility (9), and fibrosis (8), antioxidants per se have not been shown to be effective (34). Furthermore, the extent of hyperoxia exposure (O 2 concentration and/or duration) clearly colors the picture of which cell types are affected and what structure/function changes occur, with the understanding that high levels of O 2 promote bronchopulmonary dysplasia (14,34).…”

Section: Discussionmentioning

confidence: 99%

Hyperoxia-induced Cellular Senescence in Fetal Airway Smooth Muscle Cells

Parikh

Britt

Manlove³

et al. 2019

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

Supplemental O 2 (hyperoxia; 30-90% O 2 ) is a necessary intervention for premature infants, but it contributes to development of neonatal and pediatric asthma, necessitating better understanding of contributory mechanisms in hyperoxia-induced changes to airway structure and function. In adults, environmental stressors promote formation of senescent cells that secrete factors (senescence-associated secretory phenotype), which can be inflammatory and have paracrine effects that enhance chronic lung diseases. Hyperoxia-induced changes in airway structure and function are mediated in part by effects on airway smooth muscle (ASM). In the present study, using human fetal ASM cells as a model of prematurity, we ascertained the effects of clinically relevant moderate hyperoxia (40% O 2 ) on cellular senescence. Fetal ASM exposed to 40% O 2 for 7 days exhibited elevated concentrations of senescence-associated markers, including b-galactosidase; cell cycle checkpoint proteins p16, p21, and p-p53; and the DNA damage marker p-gH2A.X (phosphorylated g-histone family member X). The combination of dasatinib and quercetin, compounds known to eliminate senescent cells (senolytics), reduced the number of hyperoxia-exposed b-galactosidase-, p21-, p16-, and p-gH2A.X-positive ASM cells. The senescenceassociated secretory phenotype profile of hyperoxia-exposed cells included both profibrotic and proinflammatory mediators. Naive ASM exposed to media from hyperoxia-exposed senescent cells exhibited increased collagen and fibronectin and higher contractility. Our data show that induction of cellular senescence by hyperoxia leads to secretion of inflammatory factors and has a functional effect on naive ASM. Cellular senescence in the airway may thus contribute to pediatric airway disease in the context of sequelae of preterm birth.

show abstract

“…Despite close monitoring, mounting evidence from various clinical and experimental observations suggests that neonatal hyperoxia causes systemic injury to several organs. Hyperoxia is a key contributor to neonatal and pediatric lung diseases, including airway disease (wheezing and asthma) and bronchopulmonary dysplasia [6]. Chronic exposure to hyperoxia causes oxidative stress and contributes to the pathogenesis of injury in the preterm as well as full-term brain, with a dramatic deterioration of brain function in later life [7].…”

Section: Introductionmentioning

confidence: 99%

Proximal Tubular Development Is Impaired with Downregulation of MAPK/ERK Signaling, HIF-1α, and Catalase by Hyperoxia Exposure in Neonatal Rats

You

2019

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Supplemental oxygen therapy (hyperoxia) is a widely used treatment for alveolar hypoxia in preterm infants. Despite being closely monitored, hyperoxia exposure is believed to undermine neonatal nephrogenesis and renal function caused by elevated oxidative stress. Previous studies have mostly focused on the hyperoxia-induced impairment of glomerular development, while the long-term impact of neonatal hyperoxia on tubular development and the regulatory component involved in this process remain to be clarified. Here, we examined tubular histology and apoptosis, along with the expression profile of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling, hypoxia-inducible factor 1α (HIF-1α), and catalase, following hyperoxia exposure in neonatal rats. Hematoxylin and eosin (H&E) staining revealed the early disappearance of the nephrogenic zone, as well as dilated lumens and reduced epithelial cells, of mature proximal tubules following neonatal hyperoxia. A robust increase in tubular cell apoptosis caused by neonatal hyperoxia was found using a TUNEL assay. Moreover, neonatal hyperoxia altered renal MAPK/ERK signaling activity and downregulated the expression of HIF-1α and catalase in the proximal tubules throughout nephrogenesis from S-shaped bodies to mature proximal tubules. Cell apoptosis in the proximal tubules was positively correlated with HIF-1α expression on the 14th postnatal day. Our data indicates that proximal tubular development is impaired by neonatal hyperoxia, which is accompanied by altered MAPK/ERK signaling as well as downregulated HIF-1α and catalase. Therapeutic management that targets MAPK/ERK signaling, HIF-1α, or catalase may serve as a protective agent against hyperoxia-induced oxidative damage to neonatal proximal tubules.

show abstract

Effects of Hyperoxia on the Developing Airway and Pulmonary Vasculature

Cited by 12 publications

References 138 publications

Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle

Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle

Hyperoxia-induced Cellular Senescence in Fetal Airway Smooth Muscle Cells

Proximal Tubular Development Is Impaired with Downregulation of MAPK/ERK Signaling, HIF-1α, and Catalase by Hyperoxia Exposure in Neonatal Rats

Contact Info

Product

Resources

About