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

Roesler, A.M.; Ravix, Jovanka; Bartman, Colleen M.; Patel, Brijeshkumar S.; Schiliro, Marta; Roos, B.; Nesbitt, Lisa; Pabelick, Christina M.; Martin, Richard J.; MacFarlane, Peter M.; Prakash, Y. S.

doi:10.3389/fphys.2021.585895

Cited by 9 publications

(4 citation statements)

References 53 publications

(126 reference statements)

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“…In ASM, calcium release from the sarcoplasmic reticulum drives cellular contraction, and calcium exchange between the mitochondrion and sarcoplasmic reticulum is important for regulating contraction as well as other cellular functions, including ATP production from oxidative phosphorylation and subsequent ROS production [ 70 , 78 ]. Our data showing increased oxidative damage and altered mitochondrial morphology in response to various O 2 conditions or antioxidants build on our previously published work showing increased intracellular calcium response to agonists in human fASM exposed to hyperoxia [ 79 ]. It is now worth investigating whether ROS can be targeted to help mitigate elevated [Ca 2+ ] i in various O 2 conditions.…”

Section: Discussionsupporting

confidence: 84%

Intermittent Hypoxia-Hyperoxia and Oxidative Stress in Developing Human Airway Smooth Muscle

et al. 2021

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Premature infants are frequently and intermittently administered supplemental oxygen during hypoxic episodes, resulting in cycles of intermittent hypoxia and hyperoxia. The relatively hypoxic in utero environment is important for lung development while hyperoxia during the neonatal period is recognized as detrimental towards the development of diseases such as bronchopulmonary dysplasia and bronchial asthma. Understanding early mechanisms that link hypoxic, hyperoxic, and intermittent hypoxic-hyperoxic exposures to altered airway structure and function are key to developing advanced therapeutic approaches in the clinic. Changes in oxygen availability can be detrimental to cellular function and contribute to oxidative damage. Here, we sought to determine the effect of oxygen on mitochondria in human fetal airway smooth muscle cells exposed to either 5% O2, 21% O2, 40% O2, or cycles of 5% and 40% O2 (intermittent hypoxia-hyperoxia). Reactive oxygen species production, altered mitochondrial morphology, and changes in mitochondrial respiration were assessed in the context of the antioxidant N-acetylcysteine. Our findings show developing airway smooth muscle is differentially responsive to hypoxic, hyperoxic, or intermittent hypoxic-hyperoxic exposure in terms of mitochondrial structure and function. Cycling O2 decreased mitochondrial branching and branch length similar to hypoxia and hyperoxia in the presence of antioxidants. Additionally, hypoxia decreased overall mitochondrial respiration while the addition of antioxidants increased respiration in normoxic and O2-cycling conditions. These studies show the necessity of balancing oxidative damage and antioxidant defense systems in the developing airway.

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Section: Discussionsupporting

confidence: 84%

Intermittent Hypoxia-Hyperoxia and Oxidative Stress in Developing Human Airway Smooth Muscle

et al. 2021

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“…We previously established a model of moderate hyperoxia exposure in neonatal mice (Bartman et al., 2024 ; Faksh et al., 2016 ; Roesler et al., 2021 ; Vogel et al., 2019 ; Wang et al., 2014 ). Briefly, newborn mouse pups (postnatal day 0, P0) are exposed to either 21% O 2 (room air) or 50% O 2 (moderate hyperoxia chamber) from P0‐P7.…”

Section: Resultsmentioning

confidence: 99%

“…Studies show that altered airway structure and function in neonates contributes to childhood asthma: children less than 3 years old with thickened airways display recurrent wheeze prior to the emergence of pediatric asthma (Baldwin & Roche, 2002 ; O'Reilly et al., 2013 ; Saglani et al., 2007 ). Additionally, in vitro studies using human fetal ASM exposed to moderate O 2 show increased intracellular calcium, proliferation, extracellular matrix deposition, and cellular senescence (Britt Jr. et al., 2015 ; Hartman et al., 2012 ; Parikh et al., 2018 ; Roesler et al., 2021 ). Similarly, in vivo studies using a neonatal mouse model of moderate hyperoxia exposure show increased ASM thickness, collagen deposition, AHR following methacholine (MCh) challenge, and sex differences in response to O 2 (Bartman et al., 2024 ; Faksh et al., 2016 ; Wang et al., 2014 ).…”

Section: Introductionmentioning

confidence: 99%

BMAL1 sex‐specific effects in the neonatal mouse airway exposed to moderate hyperoxia

Bartman,

Nesbitt,

Lee

et al. 2024

Physiological Reports

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Supplemental O2 (hyperoxia) is a critical intervention for premature infants (<34 weeks) but consequently is associated with development of bronchial airway hyperreactivity (AHR) and asthma. Clinical practice shifted toward the use of moderate hyperoxia (<60% O2), but risk for subsequent airway disease remains. In mouse models of moderate hyperoxia, neonatal mice have increased AHR with effects on airway smooth muscle (ASM), a cell type involved in airway tone, bronchodilation, and remodeling. Understanding mechanisms by which moderate O2 during the perinatal period initiates sustained airway changes is critical to drive therapeutic advancements toward treating airway diseases. We propose that cellular clock factor BMAL1 is functionally important in developing mouse airways. In adult mice, cellular clocks target pathways highly relevant to asthma pathophysiology and Bmal1 deletion increases inflammatory response, worsens lung function, and impacts survival outcomes. Our understanding of BMAL1 in the developing lung is limited, but our previous findings show functional relevance of clocks in human fetal ASM exposed to O2. Here, we characterize Bmal1 in our established mouse neonatal hyperoxia model. Our data show that Bmal1 KO deleteriously impacts the developing lung in the context of O2 and these data highlight the importance of neonatal sex in understanding airway disease.

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“…For example, studies using human fetal airway smooth muscle have shown dose-dependent effects with moderate oxygen increasing proliferation and higher levels (>60%) driving apoptosis ( 102 ). Furthermore, studies on human fetal airway smooth muscle have shown moderate hyperoxia increases airway hyperreactivity via intracellular calcium response to bronchoconstrictor agonists ( 102 , 142 , 143 ). In vivo studies using moderate hyperoxia in a neonatal mouse model have demonstrated structural and functional changes similar to those seen in asthma and reactive airway disease: increased airway hyperreactivity in response to methacholine challenge as well as increased ASM thickness and collagen deposition in the airway ( 100 , 132 ).…”

Section: Oxygen and Pediatric Airway Diseasementioning

confidence: 99%

Oxygen and mechanical stretch in the developing lung: risk factors for neonatal and pediatric lung disease

et al. 2023

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Chronic airway diseases, such as wheezing and asthma, remain significant sources of morbidity and mortality in the pediatric population. This is especially true for preterm infants who are impacted both by immature pulmonary development as well as disproportionate exposure to perinatal insults that may increase the risk of developing airway disease. Chronic pediatric airway disease is characterized by alterations in airway structure (remodeling) and function (increased airway hyperresponsiveness), similar to adult asthma. One of the most common perinatal risk factors for development of airway disease is respiratory support in the form of supplemental oxygen, mechanical ventilation, and/or CPAP. While clinical practice currently seeks to minimize oxygen exposure to decrease the risk of bronchopulmonary dysplasia (BPD), there is mounting evidence that lower levels of oxygen may carry risk for development of chronic airway, rather than alveolar disease. In addition, stretch exposure due to mechanical ventilation or CPAP may also play a role in development of chronic airway disease. Here, we summarize the current knowledge of the impact of perinatal oxygen and mechanical respiratory support on the development of chronic pediatric lung disease, with particular focus on pediatric airway disease. We further highlight mechanisms that could be explored as potential targets for novel therapies in the pediatric population.

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

Cited by 9 publications

References 53 publications

Intermittent Hypoxia-Hyperoxia and Oxidative Stress in Developing Human Airway Smooth Muscle

Intermittent Hypoxia-Hyperoxia and Oxidative Stress in Developing Human Airway Smooth Muscle

BMAL1 sex‐specific effects in the neonatal mouse airway exposed to moderate hyperoxia

Oxygen and mechanical stretch in the developing lung: risk factors for neonatal and pediatric lung disease

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