Influence of Inhaled Nitric Oxide and Hyperoxia on Na,K-ATPase Expression and Lung Edema in Newborn Piglets

Youssef, JihanA.; Thibeault, DonaldW.; Rezaiekhaligh, MohammadH.; Mabry, SherryM.; Norberg, MichaelI.; Truog, WilliamE.

doi:10.1159/000014096

Cited by 17 publications

(13 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is clear that apoptosis or DNA fragmentation affects cell survival by activating death signals, but it is less evident why lung apoptosis or DNA fragmentation significantly affects survival during acute exposure to hyperoxia. Perhaps apoptosis and subsequent Na + /K + ATPase dysfunction and ATP depletion lead to increased lung edema and mortality, as suggested by others (56).…”

Section: Figurementioning

confidence: 78%

Maturational differences in lung NF-κB activation and their role in tolerance to hyperoxia

Guang¹,

Abate²,

George³

et al. 2004

J. Clin. Invest.

View full text Add to dashboard Cite

Neonatal rodents are more tolerant to hyperoxia than adults. We determined whether maturational differences in lung NF-κB activation could account for the differences. After hyperoxic exposure (O 2 > 95%), neonatal (<12 hours old) lung NF-κB binding was increased and reached a maximum between 8 and 16 hours, whereas in adults no changes were observed. Additionally, neonatal NF-κB/luciferase transgenic mice (incorporating 2 NF-κB consensus sequences driving luciferase gene expression) demonstrated enhanced in vivo NF-κB activation after hyperoxia in real time. In the lungs of neonates, there was a propensity toward NF-κB activation as evidenced by increased lung I-κB kinase protein levels, I-κBα phosphorylation, β-transducin repeat-containing protein levels, and total I-κBα degradation. Increased lung p-JNK immunoreactive protein was observed only in the adult lung. Inhibition of pI-κBα by BAY 11-7085 resulted in decreased Bcl-2 protein levels in neonatal lung homogenates and decreased cell viability in lung primary cultures after hyperoxic exposure. Furthermore, neonatal p50-null mutant (p50 -/-) mice showed increased lung DNA degradation and decreased survival in hyperoxia compared with WT mice. These data demonstrate that there are maturational differences in lung NF-κB activation and that enhanced NF-κB may serve to protect the neonatal lung from acute hyperoxic injury via inhibition of apoptosis.

show abstract

Section: Figurementioning

confidence: 78%

Maturational differences in lung NF-κB activation and their role in tolerance to hyperoxia

Guang¹,

Abate²,

George³

et al. 2004

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…Reactive oxygen and nitrogen species have been shown to be involved in the development of epithelial injury in pathologic situations, including LPS-/sepsis-induced lung injury as well as viral pneumonia, in which RONS are produced in large quantities by alveolar phagocytes (77). Studies in rabbit and piglet lungs further elucidated that RONS affect AFC and edema persistence by inhibiting both the activity of ENaC and alveolar epithelial NKA (78,79).…”

Section: Reactive Oxygen and Nitrogen Species (Rons)mentioning

confidence: 99%

Inflammatory Responses Regulating Alveolar Ion Transport during Pulmonary Infections

et al. 2017

View full text Add to dashboard Cite

The respiratory epithelium is lined by a tightly balanced fluid layer that allows normal O2 and CO2 exchange and maintains surface tension and host defense. To maintain alveolar fluid homeostasis, both the integrity of the alveolar–capillary barrier and the expression of epithelial ion channels and pumps are necessary to establish a vectorial ion gradient. However, during pulmonary infection, auto- and/or paracrine-acting mediators induce pathophysiological changes of the alveolar–capillary barrier, altered expression of epithelial Na,K-ATPase and of epithelial ion channels including epithelial sodium channel and cystic fibrosis membrane conductance regulator, leading to the accumulation of edema and impaired alveolar fluid clearance. These mediators include classical pro-inflammatory cytokines such as TGF-β, TNF-α, interferons, or IL-1β that are released upon bacterial challenge with Streptococcus pneumoniae, Klebsiella pneumoniae, or Mycoplasma pneumoniae as well as in viral infection with influenza A virus, pathogenic coronaviruses, or respiratory syncytial virus. Moreover, the pro-apoptotic mediator TNF-related apoptosis-inducing ligand, extracellular nucleotides, or reactive oxygen species impair epithelial ion channel expression and function. Interestingly, during bacterial infection, alterations of ion transport function may serve as an additional feedback loop on the respiratory inflammatory profile, further aggravating disease progression. These changes lead to edema formation and impair edema clearance which results in suboptimal gas exchange causing hypoxemia and hypercapnia. Recent preclinical studies suggest that modulation of the alveolar–capillary fluid homeostasis could represent novel therapeutic approaches to improve outcomes in infection-induced lung injury.

show abstract

“…Animal models have also showed the adverse effects of prolonged hyperoxia on the developing pulmonary circulation. Endothelial cells are especially prone to oxidant injury, and the absence of VEGF, an important endothelial cell survival factor, may further increase susceptibility of the endothelium to hyperoxic injury (43). NO plays an integral role in VEGF signaling, not only by modulating vasorelaxation and permeability but also by playing an important role in the angiogenesis in vitro and in vivo (44).…”

Section: No Improves Alveolarization In Bpdmentioning

confidence: 99%

Inhaled Nitric Oxide Enhances Distal Lung Growth after Exposure to Hyperoxia in Neonatal Rats

et al. 2005

View full text Add to dashboard Cite

Exposure of newborn rats to hyperoxia impairs alveolarization and vessel growth, causing abnormal lung structure that persists during infancy. Recent studies have shown that impaired angiogenesis due to inhibition of vascular endothelial growth factor (VEGF) signaling decreases alveolar and vessel growth in the developing lung, and that nitric oxide (NO) mediates VEGFdependent angiogenesis. The purpose of this study was to determine whether hyperoxia causes sustained reduction of lung VEGF, VEGF receptor, or endothelial NO synthase (eNOS) expression during recovery, and whether inhaled NO improves lung structure in infant rats after neonatal exposure to hyperoxia. Newborn rat pups were randomized to hyperoxia [fraction of inspired oxygen (FiO 2 ), 1.00] or room air exposure for 6 d, and then placed in room air with or without inhaled NO (10 ppm) for 2 wk. Rats were then killed for studies, which included measurements of body weight, lung weight, right ventricular hypertrophy (RVH), morphometric analysis of alveolarization (by mean linear intercept (MLI), radial alveolar counts (RAC), and vascular volume (Vv), and immunostaining and Western blot analysis. In comparison with controls, neonatal hyperoxia reduced body weight, increased MLI, and reduced RAC in infant rats. Lung VEGF, VEGFR-2, and eNOS protein expression were reduced after hyperoxia. Inhaled NO treatment after hyperoxia increased body weight and improved distal lung growth, as demonstrated by increased RAC and Vv and decreased MLI. We conclude that neonatal hyperoxia reduced lung VEGF expression, which persisted during recovery in room air, and that inhaled NO restored distal lung growth in infant rats after neonatal hyperoxia. BPD is the chronic lung disease of infancy that follows ventilator and oxygen therapy for acute respiratory failure after premature birth (1). Traditionally, BPD has been defined by the presence of persistent respiratory signs and symptoms, the need for supplemental oxygen to treat hypoxemia, and an abnormal chest radiograph at 36 wk corrected age. Over the years, the clinical course of premature infants with BPD has changed, reflecting the effects of improved survival of babies who are less mature and have lower birth weights, as well as changes in therapeutic strategies, such as surfactant therapy and modes of mechanical ventilation (2,3). Infants with BPD now have less severe initial acute respiratory disease, and at autopsy, lung histology is predominantly characterized by arrested lung development, including impaired alveolar and vascular growth (4).Although mechanisms that impair lung growth in BPD are poorly understood, recent studies suggest that disruption of VEGF function plays a pivotal role in the pathogenesis of BPD. Bhatt et al. (5) have shown decreased lung VEGF mRNA and protein expression, as well as a reduction of the VEGF receptor, flt-1 (VEGFR-1), in the lungs of infants with fatal BPD. In addition, VEGF protein levels are reduced in the tracheal aspirates obtained from premature newborns with BPD, as well a...

show abstract

Influence of Inhaled Nitric Oxide and Hyperoxia on Na,K-ATPase Expression and Lung Edema in Newborn Piglets

Cited by 17 publications

References 54 publications

Maturational differences in lung NF-κB activation and their role in tolerance to hyperoxia

Maturational differences in lung NF-κB activation and their role in tolerance to hyperoxia

Inflammatory Responses Regulating Alveolar Ion Transport during Pulmonary Infections

Inhaled Nitric Oxide Enhances Distal Lung Growth after Exposure to Hyperoxia in Neonatal Rats

Contact Info

Product

Resources

About