NADPH Oxidases in Lung Health and Disease

Bernard, Karen; Hecker, Louise; Luckhardt, Tracy; Cheng, Guangjie; Thannickal, Victor J.

doi:10.1089/ars.2013.5608

Cited by 97 publications

(91 citation statements)

References 188 publications

(243 reference statements)

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“…An acute increase in lung cytokine levels and neutrophil influx have been reported in infants or adults with sepsisinduced acute lung injury (10,18,32). In our neonatal model of sepsis induced by intraperitoneal LPS, we observed an acute increase in lung expression of cytokines TNF-a, KC (equivalent to human IL-8), IL-1b, and ICAM-1, similar to studies of sepsis-induced lung injury in adult rodent models.…”

Section: Discussionsupporting

confidence: 87%

“…Some NOX isoforms, such as NOX4, are constitutively active, whereas others are activated by cellular stress, hormones, cytokines, and bacterial ligands. NOX-derived ROS play a key role in homeostatic cellular signaling when compartmentalized and regulated (16,18). However, pathological activation of NOX has been implicated in various disease processes such as ischemiareperfusion, inflammation, hypertension, and cancer (14,18).…”

mentioning

confidence: 99%

“…NOX-derived ROS play a key role in homeostatic cellular signaling when compartmentalized and regulated (16,18). However, pathological activation of NOX has been implicated in various disease processes such as ischemiareperfusion, inflammation, hypertension, and cancer (14,18). In the lung, NOX isoforms show cell-type-specific distribution and function and are found in endothelial cells, epithelial cells, fibroblasts, macrophages, and smooth muscle cells (18).…”

mentioning

confidence: 99%

“…However, pathological activation of NOX has been implicated in various disease processes such as ischemiareperfusion, inflammation, hypertension, and cancer (14,18). In the lung, NOX isoforms show cell-type-specific distribution and function and are found in endothelial cells, epithelial cells, fibroblasts, macrophages, and smooth muscle cells (18). Prior work in our laboratory demonstrated that nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) regulates LPS (TLR4 agonist)-mediated superoxide production and cytokine expression in fetal lung endothelial cells (15).…”

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confidence: 99%

See 3 more Smart Citations

Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Buonfiglio

Bagegni

Borcherding

et al. 2016

Am J Respir Cell Mol Biol

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In premature infants, sepsis is associated with alveolar simplification manifesting as bronchopulmonary dysplasia. The redox-dependent mechanisms underlying sepsis-induced inflammation and alveolar remodeling in the immature lung remain unclear. We developed a neonatal mouse model of sepsisinduced lung injury to investigate whether nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) regulates Toll-like receptor (TLR)-mediated inflammation and alveolar remodeling. Six-day-old NOX2 1/1 and NOX2 2/2 mice were injected with intraperitoneal LPS to induce sepsis. Lung inflammation and canonical TLR signaling were assessed 24 hours after LPS. Alveolar development was examined in 15-day-old mice after LPS on Day 6. The in vivo efficacy of a NOX2 inhibitor (NOX2-I) on NOX2 complex assembly and sepsis-induced lung inflammation were examined. Lung cytokine expression and neutrophil influx induced with sepsis in NOX2 1/1 mice was decreased by .50% in NOX2 2/2 mice. LPS-induced TLR4 signaling evident by inhibitor of NF-kB kinase-b and mitogen-activated protein kinase phosphorylation, and nuclear factor-kB/AP-1 translocation were attenuated in NOX2 2/2 mice. LPS increased matrix metalloproteinase 9 while decreasing elastin and keratinocyte growth factor levels in NOX21/1 mice. An LPS-induced increase in matrix metalloproteinase 9 and decrease in fibroblast growth factor 7 and elastin were not evident in NOX22/2 mice. An LPS-induced reduction in radial alveolar counts and increased mean linear intercepts were attenuated in NOX2 2/2 mice. LPS-induced NOX2 assembly evident by p67phox/gp91phox coimmunoprecipitation was disrupted with NOX2-I. NOX2-I also mitigated LPS-induced cytokine expression, TLR pathway signaling, and alveolar simplification. In a mouse model of neonatal sepsis, NOX2 regulates proinflammatory TLR signaling and alveolar remodeling induced by a single dose of LPS. Our results provide mechanistic insight into the regulation of sepsis-induced alveolar remodeling in the developing lung.Keywords: nicotinamide adenine dinucleotide phosphate oxidase; sepsis; Toll-like receptor signaling; neonatal lung injury; bronchopulmonary dysplasia Postnatal inflammation and tissue injury in the developing lung contribute to the disrupted alveolar development observed in premature infants with bronchopulmonary dysplasia (BPD) (1, 2). Risk factors associated with BPD, such as hyperoxia, barotrauma, and sepsis, trigger the production of reactive oxygen species (ROS) in the premature lung, which contributes to lung inflammation and matrix degradation (3-5). Multiple investigators have shown that markers of oxidant-mediated lung injury, such as 8-Oxo-29-deoxyguanosine, oxidized surfactant phospholipids, F2-isoprostanes, and nitrotyrosine, are elevated in the bronchoalveolar lavage, serum, or urine of premature infants who subsequently develop BPD (4-7). Therapies to mitigate oxidant stress, such as recombinant superoxide dismutase and vitamin A, have been used in premature infants to decrease BPD, with limited succes...

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Section: Discussionsupporting

confidence: 87%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Buonfiglio

Bagegni

Borcherding

et al. 2016

Am J Respir Cell Mol Biol

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“…T h e N A D P H -o x i d a s e ( N o x ) e n z y m e s a r e a n evolutionarily conserved gene family that that is most consistently linked to host defense mechanisms, including lung fibrosis (20,31). Among the seven members of the Nox family, Nox4 has been implicated in a variety of fibrotic diseases, including the liver (32-34), skin (35), kidney (36,37), heart (38,39), and lung (15,40,41).…”

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confidence: 99%

Getting to the core of fibrosis: targeting redox imbalance in aging

Hecker

Thannickal

2016

Ann. Transl. Med.

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Expression of nicotinamide adenine dinucleotide phosphate oxidase in chronic rhinosinusitis with nasal polyps

Zheng

Hao

Xiao

et al. 2020

Int Forum Allergy Rhinol

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BackgroundNicotinamide adenine dinucleotide phosphate (NADPH) oxidase produces reactive oxygen species (ROS) involved in oxidative stress and signal transduction. Recent studies have suggested that NADPH oxidase is associated with the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). The aim of this study was to detect the expression of NADPH oxidase subunits and 4‐hydroxynonenal (4‐HNE) in nasal polyp tissue and normal nasal mucosa, in order to explore the possible role played by NADPH oxidase in the pathogenesis of CRSwNP.MethodsThirteen patients with CRSwNP and 9 normal control subjects were selected to participate in this study, in which we evaluated the expression of different NADPH oxidase subunits (gp91phox, p67phox, p47phox, and p22phox) in nasal polyp (NP) tissue and control mucosa by Western blotting and real‐time polymerase chain reaction (PCR). Immunohistochemistry and immunofluorescence staining were used to detect expression of the p67phox subunit and 4‐HNE in NP tissue and normal nasal mucosa.ResultsWestern blot and real‐time PCR results showed that p67phox expression was significantly increased in NP tissue when compared with its expression in control mucosa (p = 0.004). p67phox was expressed in the eosinophils and neutrophils found in NP tissue, but not in the macrophages. Additionally, the levels of 4‐HNE expression were also significantly increased in NP tissue when compared with control mucosa (p = 0.001).ConclusionThe levels of p67phox messenger RNA (mRNA) and protein as well as 4‐HNE were both upregulated in NP tissue, suggesting that p67phox and oxidative stress play roles in the pathogenesis of CRSwNP.

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NADPH Oxidases in Lung Health and Disease

Abstract: Here, we review evolving functions of Nox enzymes in normal lung physiology and emerging pathophysiologic roles in lung disease.

Cited by 97 publications

References 188 publications

Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Getting to the core of fibrosis: targeting redox imbalance in aging

Expression of nicotinamide adenine dinucleotide phosphate oxidase in chronic rhinosinusitis with nasal polyps

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