Nox2-derived ROS in PPARγ signaling and cell-cycle progression of lung alveolar epithelial cells

Tickner, Jennifer; Fan, Lampson M.; Du, Junjie; Meijles, Daniel N.; Li, Jian-Mei

doi:10.1016/j.freeradbiomed.2011.05.027

Cited by 31 publications

(24 citation statements)

References 26 publications

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“…2A). Middle-aged mice were chosen because their tissues are terminally differentiated (32), mirroring the early stages of age-related complications in humans (33). Immunoblotting revealed a significant increase in PCNA abundance in TSP1 −/− mice compared to age-matched wild-type controls.…”

Section: Resultsmentioning

confidence: 99%

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The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1

et al. 2017

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Senescent cells withdraw from the cell cycle and do not proliferate. The prevalence of senescent compared to normally functioning parenchymal cells increases with age, impairing tissue and organ homeostasis. A contentious principle governing this process has been the redox theory of aging. We linked matricellular protein thrombospondin 1 (TSP1) and its receptor CD47 to the activation of NADPH oxidase 1 (Nox1), but not of the other closely related Nox isoforms, and associated oxidative stress, and to senescence in human cells and aged tissue. In human endothelial cells, TSP1 promoted senescence and attenuated cell cycle progression and proliferation. At the molecular level, TSP1 increased Nox1-dependent generation of reactive oxygen species (ROS), leading to the increased abundance of the transcription factor p53. p53 mediated a DNA damage response that led to senescence through Rb and p21cip, both of which inhibit cell cycle progression. Nox1 inhibition blocked the ability of TSP1 to increase p53 nuclear localization and p21cip abundance and its ability to promote senescence. Mice lacking TSP1 showed decreases in ROS production, p21cip expression, p53 activity, and aging-induced senescence. Conversely, lung tissue from aging humans displayed increases in the abundance of vascular TSP1, Nox1, p53, and p21cip. Finally, genetic ablation or pharmacological blockade of Nox1 in human endothelial cells attenuated TSP1-mediated ROS generation, restored cell cycle progression, and protected against senescence. Together, our results provide insights into the functional interplay between TSP1 and Nox1 in the regulation of endothelial senescence and suggest potential targets for controlling the aging process at the molecular level.

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Section: Resultsmentioning

confidence: 99%

“…Members of the Nox family of isozymes, namely, Nox1, Nox2, and Nox4, have roles in proliferation and vessel remodeling (33, 72, 73). Thus, we did not expect Nox enzymes to play a role in aging-associated senescence.…”

Section: Discussionmentioning

confidence: 99%

The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1

et al. 2017

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“…1). The key Nox isoform expressed in macrophages and neutrophils is the NOX2 oxidase, whereas airway and alveolar epithelial cells express NOX1 (Carnesecchi et al, 2009), NOX2 (Fink et al, 2008;Soucy-Faulkner et al, 2010;Takemura et al, 2010;Tickner et al, 2011), and DUOX1 and 2. In vascular endothelial cells, there is a high abundance of both NOX2 and NOX4 oxidases, and in vascular smooth muscle, there is a strong expression of NOX4 (Peshavariya et al, , 2009aSelemidis et al, 2007;Selemidis, 2008;Drummond et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

NADPH Oxidases as Novel Pharmacologic Targets against Influenza A Virus Infection

Vlahos¹,

Selemidis²

2014

Mol Pharmacol

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Influenza A viruses represent a major global health care challenge, with imminent pandemics, emerging antiviral resistance, and long lag times for vaccine development, raising a pressing need for novel pharmacologic strategies that ideally target the pathology irrespective of the infecting strain. Reactive oxygen species (ROS) pervade all facets of cell biology with both detrimental and protective properties. Indeed, there is compelling evidence that activation of the NADPH oxidase 2 (NOX2) isoform of the NADPH oxidase family of ROS-producing enzymes promotes lung oxidative stress, inflammation, injury, and dysfunction resulting from influenza A viruses of low to high pathogenicity, as well as impeding virus clearance. By contrast, the dual oxidase isoforms produce ROS that provide vital protective antiviral effects for the host. In this review, we propose that inhibitors of NOX2 are better alternatives than broad-spectrum antioxidant approaches for treatment of influenza pathologies, for which clinical efficacy may have been limited owing to poor bioavailability and inadvertent removal of beneficial ROS. Finally, we briefly describe the current suite of NADPH oxidase inhibitors and the molecular features of the NADPH oxidase enzymes that could be exploited by drug discovery for development of more specific and novel inhibitors to prevent or treat disease caused by influenza.

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“…1D). This result suggests that both cell types (endothelial and type 2 epithelial) are activated to generate ROS after treatment with LPS, and the presence of NOX2 has been demonstrated in both cell types (18,29,41,48). However, it also is possible that only one of the cell types was responsible for generating H 2 O 2 that then diffused to the other type of cells.…”

Section: Resultsmentioning

confidence: 81%

Protection against LPS-induced acute lung injury by a mechanism-based inhibitor of NADPH oxidase (type 2)

Lee

Dodia

Chatterjee

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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The phospholipase A2 activity of peroxiredoxin 6 is inhibited by the transition state analog, 1-hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol (MJ33). This activity is required for the activation of NADPH oxidase, type 2. The present study evaluated the effect of MJ33 on manifestations of acute lung injury. Mice were injected intratracheally (IT) with LPS from Escherichia coli 0111:B4 (LPS, 1 or 5 mg/kg), either concurrently with LPS or 2 h later, and evaluated for lung injury 24 h later. MJ33 inhibited reactive oxygen species (ROS) generation by lungs when measured at 24 h after LPS. LPS at either a low or high dose significantly increased lung infiltration with inflammatory cells, secretion of proinflammatory cytokines (IL-6, TNF-α, and the chemokine macrophage inflammatory protein-2), expression of lung vascular cell adhesion molecule, lung permeability (protein in bronchoalveolar lavage fluid, leakage of FITC-dextran, lung wet-to-dry weight ratio), tissue lipid peroxidation (thiobarbituric acid reactive substances, 8-isoprostanes), tissue protein oxidation (protein carbonyls), and activation of NF-κB. MJ33, given either concurrently or 2 h subsequent to LPS, significantly reduced all of these measured parameters. Previous studies of toxicity showed a high margin of safety for MJ33 in the intact mouse. Thus we have identified MJ33 as a potent, nontoxic, and specific mechanism-based inhibitor of NADPH oxidase type 2-mediated ROS generation that protects mice against lung injury associated with inflammation.

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Nox2-derived ROS in PPARγ signaling and cell-cycle progression of lung alveolar epithelial cells

Cited by 31 publications

References 26 publications

The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1

The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1

NADPH Oxidases as Novel Pharmacologic Targets against Influenza A Virus Infection

Protection against LPS-induced acute lung injury by a mechanism-based inhibitor of NADPH oxidase (type 2)

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