Adrenomedullin deficiency potentiates hyperoxic injury in fetal human pulmonary microvascular endothelial cells

Zhang, Shaojie; Patel, Ananddeep; Moorthy, Bhagavatula; Shivanna, Binoy

doi:10.1016/j.bbrc.2015.07.067

Cited by 16 publications

(17 citation statements)

References 52 publications

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“…While the observed beneficial effects of AM are seen at concentration that is 10-fold higher than its normal plasma levels, it is possible that the normal cell-specific AM concentration could be possibly much higher than its plasma concentration. Our findings in HPAECs complement our previous study, which showed that AM is necessary to protect human pulmonary microvascular endothelial cells against hyperoxic injury [43]. These findings indicate that AM signaling does play a pivotal role in the lung angiogenesis and development in human preterm infants.…”

Section: Resultssupporting

confidence: 89%

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

Menon

Shrestha

Shivanna

2017

Biochemical and Biophysical Research Communications

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Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of human infants that is characterized by disrupted lung angiogenesis. Adrenomedullin (AM) is a multifunctional peptide with angiogenic and vasoprotective properties. AM signals via its cognate receptors, calcitonin receptor-like receptor (Calcrl) and receptor activity-modifying protein 2 (RAMP2). Whether hyperoxia affects the pulmonary AM signaling pathway in neonatal mice and whether AM promotes lung angiogenesis in human infants are unknown. Therefore, we tested the following hypotheses: (1) hyperoxia exposure will disrupt AM signaling during the lung development period in neonatal mice; and (2) AM will promote angiogenesis in fetal human pulmonary artery endothelial cells (HPAECs) via extracellular signal-regulated kinases (ERK) 1/2 activation. We initially determined AM, Calcrl, and RAMP2 mRNA levels in mouse lungs on postnatal days (PND) 3, 7, 14, and 28. Next we determined the mRNA expression of these genes in neonatal mice exposed to hyperoxia (70% O2) for up to 14 d. Finally, using HPAECs, we evaluated if AM activates ERK1/2 and promotes tubule formation and cell migration. Lung AM, Calcrl, and RAMP2 mRNA expression increased from PND 3 and peaked at PND 14, a time period during which lung development occurs in mice. Interestingly, hyperoxia exposure blunted this peak expression in neonatal mice. In HPAECs, AM activated ERK1/2 and promoted tubule formation and cell migration. These findings support our hypotheses, emphasizing that AM signaling axis is a potential therapeutic target for human infants with BPD.

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Section: Resultssupporting

confidence: 89%

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

Menon

Shrestha

Shivanna

2017

Biochemical and Biophysical Research Communications

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“…ADM ameliorates hyperoxia-induced acute lung injury in rats by suppressing oxidative stress and inflammation 19 . ADM deficiency potentiates hyperoxic injury in primary foetal human pulmonary microvascular endothelial cells by increasing oxidative stress and inflammation 20 . ADM2, as a member of the ADM peptide family, causes a restorative effect on steroidogenesis in hydrogen peroxide-treated rat primary Leydig cells 6 .…”

Section: Introductionmentioning

confidence: 99%

Adrenomedullin protects Leydig cells against lipopolysaccharide-induced oxidative stress and inflammatory reaction via MAPK/NF-κB signalling pathways

Shi

et al. 2017

Sci Rep

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This study aimed to explore the possible benefits of adrenomedullin (ADM) in preventing oxidative stress and inflammation by using an in vitro primary culture model of rat Leydig cells exposed to lipopolysaccharide (LPS). Cell proliferation was detected through CCK-8 and BrdU incorporation assays. ROS were determined with a DCFDA kit, and cytokine concentrations were measured with ELISA assay kits. Protein production was examined by immunohistochemical staining and Western blot, and gene expression was observed through RT-qPCR. Results revealed that ADM significantly reduced LPS-induced cytotoxicity, and pretreatment with ADM significantly suppressed ROS overproduction and decreased 4-HNE and 8-OHdG expression levels and concentrations. ADM pretreatment also significantly attenuated the overactivation of enzymatic antioxidants, namely, superoxide dismutase, catalase, thioredoxin reductase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase. ADM supplementation reversed the significantly increased gene expression levels and concentrations of TNF-α, IL-1β, TGF-β1, MCP-1 and MIF. ADM pretreatment significantly inhibited the gene expression and protein production of TLR-2 and 4. Furthermore, ADM pretreatment markedly reduced the phosphorylation of JNK, ERK 1/2 and p38, phosphorylation and degradation of IκBα and nuclear translocation of p65. Our findings demonstrated that ADM protects Leydig cells from LPS-induced oxidative stress and inflammation, which might be associated with MAPK/NF-κB signalling pathways.

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“…The p-Akt, mTOR, p-MTOR and p-p70s6kinase expressions were increased in lung endothelial cells exposed to hyperoxia for 24 h ( Ahmad et al, 2006 ; Zhang et al, 2015 ). However, exposure of lung endothelial cells to 48 h of hyperoxia shows decline of Akt/mTOR pathway proteins ( Ahmad et al, 2006 ).…”

Section: Discussionmentioning

confidence: 99%

Alda-1 Attenuates Hyperoxia-Induced Acute Lung Injury in Mice

et al. 2021

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Acute lung injury (ALI), a milder form of acute respiratory distress syndrome (ARDS), is a leading cause of mortality in older adults with an increasing prevalence. Oxygen therapy, is a common treatment for ALI, involving exposure to a high concentration of oxygen. Unfortunately, hyperoxia induces the formation of reactive oxygen species which can cause an increase in 4-HNE (4-hydroxy 2 nonenal), a toxic byproduct of lipid peroxidation. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) serves as an endogenous shield against oxidative stress-mediated damage by clearing 4-HNE. Alda-1 [(N-(1, 3 benzodioxol-5-ylmethyl)-2, 6- dichloro-benzamide)], a small molecular activator of ALDH2, protects against reactive oxygen species-mediated oxidative stress by promoting ALDH2 activity. As a result, Alda-1 shields against ischemic reperfusion injury, heart failure, stroke, and myocardial infarction. However, the mechanisms of Alda-1 in hyperoxia-induced ALI remains unclear. C57BL/6 mice implanted with Alzet pumps received Alda-1 in a sustained fashion while being exposed to hyperoxia for 48 h. The mice displayed suppressed immune cell infiltration, decreased protein leakage and alveolar permeability compared to controls. Mechanistic analysis shows that mice pretreated with Alda-1 also experience decreased oxidative stress and enhanced levels of p-Akt and mTOR pathway associated proteins. These results show that continuous delivery of Alda-1 protects against hyperoxia-induced lung injury in mice.

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Adrenomedullin deficiency potentiates hyperoxic injury in fetal human pulmonary microvascular endothelial cells

Cited by 16 publications

References 52 publications

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

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

Adrenomedullin protects Leydig cells against lipopolysaccharide-induced oxidative stress and inflammatory reaction via MAPK/NF-κB signalling pathways

Alda-1 Attenuates Hyperoxia-Induced Acute Lung Injury in Mice

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