Hyperoxia-induced NF-κB activation occurs via a maturationally sensitive atypical pathway

Wright, Clyde J.; Zhuang, Tiangang; La, Ping; Guang, Yang; Dennery, Phyllis A.

doi:10.1152/ajplung.90499.2008

Cited by 26 publications

(26 citation statements)

References 71 publications

(74 reference statements)

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“…In addition to this canonical pathway, an atypical pathway of NF-κB activation results from specific phosphorylation of IκBα on tyrosine 42 (54). This occurs after stimulation with pervanadate, nerve growth factor, hydrogen peroxide and ischemia-reperfusion (54-56) and, as most recently demonstrated, with hyperoxia (57). This latter pathway represents an intriguing molecular target for modulating the pulmonary response to hyperoxia.…”

Section: Hyperoxic Gene Regulationmentioning

confidence: 88%

Manipulation of Gene Expression by Oxygen: A Primer From Bedside to Bench

Wright

Dennery

2009

Pediatr Res

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For nearly 100 y, pediatricians have regularly used oxygen to treat neonatal and childhood diseases. During this time, it has become clear that oxygen is toxic and that overzealous use can lead to significant morbidity. As we have learned more about the appropriate clinical indications for oxygen therapy, studies at the bench have begun to elucidate the molecular mechanisms by which cells respond to hyperoxia. In this review, we discuss transcription factors whose activity is regulated by oxygen, including nuclear factor, erythroid 2-related factor 2 (Nrf2), activator protein 1 (AP-1), p53, nuclear factor B (NF-B), signal transducers and activators of transcription protein (STAT), and ccat/enhancer binding protein (CEBP). Special attention is paid to the mechanisms by which hyperoxia affects these transcription factors in the lung. Finally, we identify downstream targets of these transcription factors, with a focus on heme oxygenase-1. A better understanding of how oxygen affects various signaling pathways could lead to interventions aimed at preventing hyperoxic injury. O xygen therapy has a long and tortuous history in Neonatology. The pendulum has swung from a liberal use of supplemental oxygen in the early 20th century, to limited application in the 1950s based on the association with retinopathy of prematurity. Today, clinical studies are focused on addressing which neonatal pathologic states require treatment with oxygen, and what level of oxygen administration is safe. In concert with these clinical studies, much work has been done at the bench to ascertain how oxygen affects gene expression. This is of particular relevance in neonates because changes in gene expression at critical times in development can have long-lasting effects and subsequent consequences on lung structure and function. This review will address lessons learned and new insights as to the effects of hyperoxia on pulmonary gene expression. EVOLUTIONARY PERSPECTIVEResponses to atmospheric oxygen have evolved in eukaryotes during the last 1.5 billion years (1). The ability of organisms to reduce oxygen to water critically altered cellular metabolism and energy production, but also resulted in the formation of toxic reactive oxygen species (ROS) via the mitochondrial respiratory chain. These radicals are electron donors, which can damage DNA, RNA, protein, and lipids. They can also propagate deleterious reactions throughout cells and tissues resulting in death and apoptosis. In addition, these ROS can alter gene expression by modulating transcription factor activation, which then impact downstream targets. In oxygen breathing animals, only three tissues-the cornea, the skin, and the respiratory tract epithelium-are exposed to 21% Received January 8, 2009; accepted February 3, 2009 Abbreviations: AP-1, activator protein 1; ARE, antioxidant response elements; Bach1, basic leucine zipper transcription factor 1; BPD, bronchopulmonary dysplasia; C/EBP, ccat/enhancer binding protein; ENaC, epithelium sodium channel; HO-1, heme oxygenase...

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Section: Hyperoxic Gene Regulationmentioning

confidence: 88%

Manipulation of Gene Expression by Oxygen: A Primer From Bedside to Bench

Wright

Dennery

2009

Pediatr Res

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“…A 32 P-labeled oligonucleotide with the consensus sequence for NF-B (5=-AGTT-GAGGGGACTTTCCCAGGC-3=) (Promega) was used as a probe to evaluate NF-B binding ability as described previously (60,62). To identify nonspecific binding of nuclear proteins, competition reactions were performed by addition of either 50-fold excess of the nonradiolabeled NF-B consensus sequence or 50-fold excess of nonradiolabeled mutated NF-B consensus sequence (5=-AGTTGAGGC-GACTTTCCCAGGC-3=) (Santa Cruz Biotechnology) to the reaction mixtures before electrophoresis.…”

Section: Methodsmentioning

confidence: 99%

Sustained hyperoxia-induced NF-κB activation improves survival and preserves lung development in neonatal mice

McKenna

Michaelis

Agboke

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Oxygen toxicity contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). Neonatal mice exposed to hyperoxia develop a simplified lung structure that resembles BPD. Sustained activation of the transcription factor NF-κB and increased expression of protective target genes attenuate hyperoxia-induced mortality in adults. However, the effect of enhancing hyperoxia-induced NF-κB activity on lung injury and development in neonatal animals is unknown. We performed this study to determine whether sustained NF-κB activation, mediated through IκBβ overexpression, preserves lung development in neonatal animals exposed to hyperoxia. Newborn wild-type (WT) and IκBβ-overexpressing (AKBI) mice were exposed to hyperoxia (>95%) or room air from day of life (DOL) 0-14, after which all animals were kept in room air. Survival curves were generated through DOL 14. Lung development was assessed using radial alveolar count (RAC) and mean linear intercept (MLI) at DOL 3 and 28 and pulmonary vessel density at DOL 28. Lung tissue was collected, and NF-κB activity was assessed using Western blot for IκB degradation and NF-κB nuclear translocation. WT mice demonstrated 80% mortality through 14 days of exposure. In contrast, AKBI mice demonstrated 60% survival. Decreased RAC, increased MLI, and pulmonary vessel density caused by hyperoxia in WT mice were significantly attenuated in AKBI mice. These findings were associated with early and sustained NF-κB activation and expression of cytoprotective target genes, including vascular endothelial growth factor receptor 2. We conclude that sustained hyperoxia-induced NF-κB activation improves neonatal survival and preserves lung development. Potentiating early NF-κB activity after hyperoxic exposure may represent a therapeutic intervention to prevent BPD.

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“…NFjB inhibition decreases Nox4 expression in PPHN PASMC (187), and it attenuates monocrotaline-induced pulmonary arterial hypertension in rats (96,154), suggesting a potential role for NFjB in pulmonary vascular ROS generation. Hyperoxia selectively activates NFjB in fetal, but not adult, lung fibroblasts (195), suggesting that NFjB could also play a role in the development of neonatal PH due to hyperoxic lung injury. NFjB activity is regulated through its interaction with the regulatory protein IjB.…”

Section: Nadph Oxidasesmentioning

confidence: 99%

Role of Reactive Oxygen Species in Neonatal Pulmonary Vascular Disease

Wedgwood

Steinhorn

2014

Antioxidants & Redox Signaling

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Significance: Abnormal lung development in the perinatal period can result in severe neonatal complications, including persistent pulmonary hypertension (PH) of the newborn and bronchopulmonary dysplasia. Reactive oxygen species (ROS) play a substantive role in the development of PH associated with these diseases. ROS impair the normal pulmonary artery (PA) relaxation in response to vasodilators, and ROS are also implicated in pulmonary arterial remodeling, both of which can increase the severity of PH. Recent Advances: PA ROS levels are elevated when endogenous ROS-generating enzymes are activated and/or when endogenous ROS scavengers are inactivated. Animal models have provided valuable insights into ROS generators and scavengers that are dysregulated in different forms of neonatal PH, thus identifying potential therapeutic targets. Critical Issues: General antioxidant therapy has proved ineffective in reversing PH, suggesting that it is necessary to target specific signaling pathways for successful therapy. Future Directions: Development of novel selective pharmacologic inhibitors along with nonantioxidant therapies may improve the treatment outcomes of patients with PH, while further investigation of the underlying mechanisms may enable earlier detection of the disease.

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Hyperoxia-induced NF-κB activation occurs via a maturationally sensitive atypical pathway

Cited by 26 publications

References 71 publications

Manipulation of Gene Expression by Oxygen: A Primer From Bedside to Bench

Manipulation of Gene Expression by Oxygen: A Primer From Bedside to Bench

Sustained hyperoxia-induced NF-κB activation improves survival and preserves lung development in neonatal mice

Role of Reactive Oxygen Species in Neonatal Pulmonary Vascular Disease

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