Inhibiting NF-κB in the developing lung disrupts angiogenesis and alveolarization

Iosef, Cristiana; Alastalo, Tero-Pekka; Hou, Yanli; Chen, Chih-Hsin; Adams, Eloa S.; Lyu, Shu‐Chen; Cornfield, David N.; Alvira, Cristina M.

doi:10.1152/ajplung.00230.2011

Cited by 107 publications

(118 citation statements)

References 78 publications

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“…63,64 Disrupted nuclear factor kappa B (NFkB) signaling appears to contribute to this process through both inflammatory and noninflammatory pathways. [65][66][67] Pulmonary dendritic cells are increased in both chorioamnionitis and BPD. 68 Although they are pro-angiogenic in nature, dendritic cells appear to promote dysmorphic vascular growth in these patients.…”

Section: Pathophysiology Of Ph In Bpdmentioning

confidence: 99%

Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia

Baker

Abman

Mourani

2014

Pediatric Allergy, Immunology, and Pulmonology

112

100

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Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is a significant contributor to perinatal morbidity and mortality. Premature birth disrupts pulmonary vascular growth and initiates a cascade of events that result in impaired gas exchange, abnormal vasoreactivity, and pulmonary vascular remodeling that may ultimately lead to pulmonary hypertension (PH). Even infants who appear to have mild BPD suffer from varying degrees of pulmonary vascular disease (PVD). Although recent studies have enhanced our understanding of the pathobiology of PVD and PH in BPD, much remains unknown with respect to how PH should be properly defined, as well as the most accurate methods for the diagnosis and treatment of PH in infants with BPD. This article will provide neonatologists and primary care providers, as well as pediatric cardiologists and pulmonologists, with a review of the pathophysiology of PH in preterm infants with BPD and a summary of current clinical recommendations for managing PH in this population.

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Section: Pathophysiology Of Ph In Bpdmentioning

confidence: 99%

Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia

Baker

Abman

Mourani

2014

Pediatric Allergy, Immunology, and Pulmonology

112

100

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“…Specifically, NF-kB regulates the induction of IL-11 and MnSOD, as well as constitutive expression of VEGFR2 (21,34). Expression of these factors attenuates hyperoxic lung injury (11,12,35,36).…”

Section: Antiapoptotic and Antioxidant Nf-kb Target Gene Expression Imentioning

confidence: 99%

IκBβ-Mediated NF-κB Activation Confers Protection against Hyperoxic Lung Injury

Michaelis

Agboke

Liu

et al. 2014

Am J Respir Cell Mol Biol

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Supplemental oxygen is frequently used in an attempt to improve oxygen delivery; however, prolonged exposure results in damage to the pulmonary endothelium and epithelium. Although NF-kB has been identified as a redox-responsive transcription factor, whether NF-kB activation exacerbates or attenuates hyperoxic lung injury is unclear. We determined that sustained NF-kB activity mediated by IkBb attenuates lung injury and prevents mortality in adult mice exposed to greater than 95% O 2 . Adult wild-type mice demonstrated evidence of alveolar protein leak and 100% mortality by 6 days of hyperoxic exposure, and showed NF-kB nuclear translocation that terminated after 48 hours. Furthermore, these mice showed increased expression of NF-kB-regulated proinflammatory and proapoptotic cytokines. In contrast, mice overexpressing the NF-kB inhibitory protein, IkBb (AKBI), demonstrated significant resistance to hyperoxic lung injury, with 50% surviving through 8 days of exposure. This was associated with NF-kB nuclear translocation that persisted through 96 hours of exposure. Although induction of NFkB-regulated proinflammatory cytokines was not different between wild-type and AKBI mice, significant up-regulation of antiapoptotic proteins (BCL-2, BCL-XL) was found exclusively in AKBI mice. We conclude that sustained NF-kB activity mediated by IkBb protects against hyperoxic lung injury through increased expression of antiapoptotic genes.Keywords: NF-kB; IkB; hyperoxic lung injury; apoptosis; inflammation Clinical RelevanceOxygen therapy is commonly employed in an attempt to improve oxygen delivery, and yet prolonged exposure results in lung injury. No pharmacologic strategies to attenuate hyperoxic lung injury have been identified. We show that enhancing hyperoxia-induced NF-kB activity attenuates lung injury, and thus represents a potential therapeutic target.The first studies demonstrating the lethal effect of inspiring high concentrations of oxygen were published over a century ago (1). Due to this toxicity, hyperoxic exposure has been widely used in animal studies to induce and study acute lung injury (2). Despite this, no pharmacologic therapies to attenuate hyperoxic lung injury have been identified.Hyperoxia induces proinflammatory cytokine expression (3), and results in pulmonary endothelial and epithelial cell death (4). Given these facts, both antiinflammatory and antiapoptotic strategies have been employed to attenuate hyperoxic lung injury. Although anti-inflammatory interventions have met variable success (5-9), increasing the expression of antiapoptotic factors in transgenic murine models results in attenuated hyperoxic lung injury (10-12). These studies suggest that preventing hyperoxia-induced apoptosis can prevent lung injury, but the transcriptional mechanism mediating expression of these factors is largely unknown.Hyperoxia-induced NF-kB activation has been documented in both pulmonary epithelial and endothelial cells (13). Whether this response is protective or injurious is unclear. Some in vivo s...

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“…16 In contrast, during alveolarization, constitutive NF-kB activation was found in neonatal mouse lung endothelial cells, and its pharmacologic inhibition resulted in abnormal development. 18 Thus, NF-kB activation may have both cell typeeand developmental stageespecific effects in the premature lung. The consequences of airway epithelial NF-kB activation during different stages of lung morphogenesis have not been investigated.…”

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confidence: 99%

Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development

Benjamin

Meer

et al. 2016

The American Journal of Pathology

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The highly orchestrated interactions between the epithelium and mesenchyme required for normal lung development can be disrupted by perinatal inflammation in preterm infants, although the mechanisms are incompletely understood. We used transgenic (inhibitory kB kinase b transactivated) mice that conditionally express an activator of the NF-kB pathway in airway epithelium to investigate the impact of epithelial-derived inflammation during lung development. Epithelial NF-kB activation selectively impaired saccular stage lung development, with a phenotype comprising rapidly progressive distal airspace dilation, impaired gas exchange, and perinatal lethality. Epithelial-derived inflammation resulted in disrupted elastic fiber organization and down-regulation of elastin assembly components, including fibulins 4 and 5, lysyl oxidase likee1, and fibrillin-1. Fibulin-5 expression by saccular stage lung fibroblasts was consistently inhibited by treatment with bronchoalveolar lavage fluid from inhibitory kB kinase b transactivated mice, Escherichia coli lipopolysaccharide, or tracheal aspirates from preterm infants exposed to chorioamnionitis. Expression of a dominant NF-kB inhibitor in fibroblasts restored fibulin-5 expression after lipopolysaccharide treatment, whereas reconstitution of fibulin-5 rescued extracellular elastin assembly by saccular stage lung fibroblasts. Elastin organization was disrupted in saccular stage lungs of preterm infants exposed to systemic inflammation. Our study reveals a critical window for elastin assembly during the saccular stage that is disrupted by inflammatory signaling and could be amenable to interventions that restore elastic fiber assembly in the developing lung.

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Inhibiting NF-κB in the developing lung disrupts angiogenesis and alveolarization

Cited by 107 publications

References 78 publications

Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia

Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia

IκBβ-Mediated NF-κB Activation Confers Protection against Hyperoxic Lung Injury

Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development

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