Hyperoxia exposure disrupts adrenomedullin signaling in newborn mice: Implications for lung development in premature infants

Menon, Renuka T.; Shrestha, Amrit Kumar; Shivanna, Binoy

doi:10.1016/j.bbrc.2017.04.112

Cited by 18 publications

(18 citation statements)

References 46 publications

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“…Hyperoxia exposure in the neonatal period results in impaired nephrogenesis via the downregulation of HIF-1 α [10], which is consistent with our observation that neonatal hyperoxia blunted the expression peak of HIF-1 α in the proximal tubules. A blunted expression peak in response to neonatal hyperoxia is also observed in other tissues [52]. HIF-1 α can trigger apoptosis in renal tubular epithelial cells [53], which is consistent with our observation that proximal tubular apoptosis is positively correlated to the expression of HIF-1 α on the 14th postnatal day.…”

Section: Discussionsupporting

confidence: 91%

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

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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.

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Section: Discussionsupporting

confidence: 91%

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

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“…For example, in endothelial cells, the antirheumatic drug leflunomide attenuated oxidative stress in fetal human pulmonary endothelial cells that was elicited by hyper-oxia, through superoxide dismutase 2 (Sod2) and catalase (Cat), although endothelial cell function was not addressed. Adrenomedullin was also demonstrated to attenuate the deleterious impact of hyperoxia in fetal human pulmonary artery endothelial cells, this time on extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, where endothelial cell functions such as tube formation were preserved (380). These data are in line with the suggestion from the same group that hyperoxia disrupted ERK1/2 signaling and ERK1/2-dependent angiogenesis in vitro (378).…”

Section: New Interventional Strategies To Drive Alveolarizationsupporting

confidence: 80%

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

Lignelli

Palumbo

Myti

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

111

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Bronchopulmonary dysplasia (BPD) is the most common cause of morbidity and mortality in preterm infants. A key histopathological feature of BPD is stunted late lung development, where the process of alveolarization—the generation of alveolar gas exchange units—is impeded, through mechanisms that remain largely unclear. As such, there is interest in the clarification both of the pathomechanisms at play in affected lungs, and the mechanisms of de novo alveoli generation in healthy, developing lungs. A better understanding of normal and pathological alveolarization might reveal opportunities for improved medical management of affected infants. Furthermore, disturbances to the alveolar architecture are a key histopathological feature of several adult chronic lung diseases, including emphysema and fibrosis, and it is envisaged that knowledge about the mechanisms of alveologenesis might facilitate regeneration of healthy lung parenchyma in affected patients. To this end, recent efforts have interrogated clinical data, developed new—and refined existing—in vivo and in vitro models of BPD, have applied new microscopic and radiographic approaches, and have developed advanced cell-culture approaches, including organoid generation. Advances have also been made in the development of other methodologies, including single-cell analysis, metabolomics, lipidomics, and proteomics, as well as the generation and use of complex mouse genetics tools. The objective of this review is to present advances made in our understanding of the mechanisms of lung alveolarization and BPD over the period 1 January 2017–30 June 2019, a period that spans the 50th anniversary of the original clinical description of BPD in preterm infants.

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“…Therefore, mice are one of the most commonly utilized laboratory animals to model human developmental lung disease such as BPD. We recently showed that neonatal hyperoxia exposure-induced alveolar and pulmonary vascular development abnormalities persists at four weeks of life (Menon et al, 2017). Because BPD infants have anatomical lung abnormalities that persist into adulthood, we evaluated the effects of neonatal hyperoxia exposure on alveolar and pulmonary vascular morphology in mice at eight weeks of age (equivalent to a human age of 21.5 years; (Dutta and Sengupta, 2016)).…”

Section: Resultsmentioning

confidence: 99%

Long-term pulmonary and cardiovascular morbidities of neonatal hyperoxia exposure in mice

Menon

Shrestha

Reynolds

et al. 2018

The International Journal of Biochemistry & Cell Biology

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Pulmonary hypertension (PH) frequently occurs in infants with bronchopulmonary dysplasia (BPD), causing increased mortality and right ventricular (RV) dysfunction that persists into adulthood. A first step in developing better therapeutic options is identifying and characterizing an appropriate animal model. Previously, we characterized the short-term morbidities of a model in which C57BL/6J wild-type (WT) mice were exposed to 70% O (hyperoxia) during the neonatal period. Here, we aimed to determine the long-term morbidities using lung morphometry, echocardiography (Echo), and cardiac magnetic resonance imaging (cMRI). The major highlight of this study is the use of the state-of-the art imaging technique, cMRI, in mice to characterize the long-term cardiac effects of neonatal hyperoxia exposure. To this end, WT mice were exposed to 21% O (normoxia) or hyperoxia for two weeks of life, followed by recovery in normoxia for six weeks. Alveolarization, pulmonary vascularization, pulmonary hypertension, and RV function were quantified at eight weeks. We found that hyperoxia exposure resulted in persistent alveolar and pulmonary vascular simplification. Furthermore, the Echo and cMRI studies demonstrated that hyperoxia-exposed mice had signs of PH and RV dysfunction as indicated by increased RV pressure, mass, and end-systolic and -diastolic volumes, and decreased RV stroke volume and ejection fractions. Taken together, our results demonstrate that neonatal hyperoxia exposure in mice cause cardiopulmonary morbidities that persists into adulthood and provides evidence for the use of this model to develop novel therapies for BPD infants with PH.

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Hyperoxia exposure disrupts adrenomedullin signaling in newborn mice: Implications for lung development in premature infants

Cited by 18 publications

References 46 publications

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

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

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

Long-term pulmonary and cardiovascular morbidities of neonatal hyperoxia exposure in mice

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