NADPH oxidase subunit NOXO1 is a target for emphysema treatment in COPD

Seimetz, Michael; Sommer, Natascha; Bednorz, Mariola; Pak, Oleg; Veith, Christine; Hadžić, Stefan; Gredic, Marija; Parajuli, Nirmal; Kojonazarov, Baktybek; Kraut, Simone; Wilhelm, Jochen; Knoepp, Fenja; Henneke, Ingrid; Pichl, Alexandra; Kanbagli, Zeki Ilker; Scheibe, Susan; Fysikopoulos, Athanasios; Wu, Chengyu; Klepetko, Walter; Jaksch, Péter; Eichstaedt, Christina A.; Grünig, Ekkehard; Hinderhofer, Katrin; Geiszt, Miklós; Müller, Niklas; Rezende, Flávia; Buchmann, Giulia; Wittig, Ilka; Hecker, Matthias; Hecker, Andreas; Padberg, Winfried; Dorfmüller, Peter; Gattenlöhner, Stefan; Vogelmeier, Claus; Günther, Andreas; Karnati, Srikanth; Baumgart-Vogt, Eveline; Schermuly, Ralph T.; Ghofrani, Hossein Ardeschir; Seeger, Werner; Schröder, Katrin; Grimminger, Friedrich; Brandes, Ralf P.; Weißmann, Norbert

doi:10.1038/s42255-020-0215-8

Cited by 27 publications

(42 citation statements)

References 48 publications

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“…Oxidative stress is often implicated in the pathogenesis of COPD, but findings on the involvement of NADPH oxidases (NOX) in experimental models of COPD are variable and sometimes even contradicting (17,(19)(20)(21). Our present findings extend intriguing previous observations that the primary epithelial NOX isoform DUOX1 is in fact downregulated within the airways of subjects with COPD (22,23), and demonstrate a gradual loss of small airway DUOX1 protein expression in COPD patients in correlation with lung function decline and extracellular matrix remodeling and emphysema.…”

Section: Discussionsupporting

confidence: 80%

“…Several reports indicate that NOX4 is upregulated in airway smooth muscle of COPD patients and correlates with disease severity (17,18). NOX2, primarily expressed in cells of the innate immune system, also appears to be increased in COPD, and some studies suggest that NOX2 contributes to experimental emphysema, although contrasting findings were reported as well and NOX2-deficiency may even promote spontaneous emphysema (19)(20)(21). Recently, a crucial role was reported for the NOX organizer protein NOXO1, which regulates the function of several isoforms, in CS-induced emphysema (21).…”

Section: Introductionmentioning

confidence: 99%

“…NOX2, primarily expressed in cells of the innate immune system, also appears to be increased in COPD, and some studies suggest that NOX2 contributes to experimental emphysema, although contrasting findings were reported as well and NOX2-deficiency may even promote spontaneous emphysema (19)(20)(21). Recently, a crucial role was reported for the NOX organizer protein NOXO1, which regulates the function of several isoforms, in CS-induced emphysema (21). In contrast to the general concept of increased involvement of NOX enzymes COPD pathology, recent studies indicate that the dual oxidases DUOX1, and to a lesser extent DUOX2, are downregulated within the bronchial epithelia of healthy smokers and patients with COPD (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a crucial role was reported for the NOX organizer protein NOXO1, which regulates the function of several isoforms, in CS-induced emphysema (21). In contrast to the general concept of increased involvement of NOX enzymes COPD pathology, recent studies indicate that the dual oxidases DUOX1, and to a lesser extent DUOX2, are downregulated within the bronchial epithelia of healthy smokers and patients with COPD (21)(22)(23). Both DUOX1 and DUOX2 are primarily expressed in airway and alveolar epithelia, with a proposed critical function in innate antimicrobial and antiviral host defense, with DUOX1 being particularly critical in innate airway epithelial wound responses to diverse non-microbial triggers (24,25).…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of epithelial DUOX1 in chronic obstructive pulmonary disease

Schiffers¹,

Wetering²,

Bauer³

et al. 2021

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Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by small airway remodeling and alveolar emphysema due to environmental stresses such as cigarette smoking (CS). Oxidative stress is commonly implicated in COPD pathology, but recent findings suggest that one oxidant-producing NADPH oxidase homolog, dual oxidase 1 (DUOX1), is downregulated in the airways of patients with COPD. We evaluated lung tissue sections from patients with COPD for small airway epithelial DUOX1 protein expression, in association with measures of lung function and small airway and alveolar remodeling. We also addressed the impact of DUOX1 for lung tissue remodeling in mouse models of COPD. Small airway DUOX1 levels were decreased in advanced COPD and correlated with loss of lung function and markers of emphysema and remodeling. Similarly, DUOX1 downregulation in correlation with extracellular matrix remodeling was observed in a genetic model of COPD, transgenic SPC-TNF-α mice. Finally, development of subepithelial airway fibrosis in mice due to exposure to the CS-component acrolein, or alveolar emphysema induced by administration of elastase, were in both cases exacerbated in Duox1 -deficient mice. Collectively, our studies highlight that downregulation of DUOX1 may be a contributing feature of COPD pathogenesis, likely related to impaired DUOX1-mediated innate injury responses involved in epithelial homeostasis.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Downregulation of epithelial DUOX1 in chronic obstructive pulmonary disease

Schiffers¹,

Wetering²,

Bauer³

et al. 2021

JCI Insight

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“…This appears possible as a global knockout mouse was used in the present study, of which we know that the lifespan is expanded [ 53 ] and that inflammatory burden is reduced [ 11 ]. Moreover, it has been shown that NoxO1, potentially through Nox1, promotes peroxynitrite formation, which contributes to the development of degenerative diseases like COPD [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Deletion of NoxO1 limits atherosclerosis development in female mice

et al. 2020

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Objective Oxidative stress is a risk factor for atherosclerosis. NADPH oxidases of the Nox family produce ROS but their contribution to atherosclerosis development is less clear. Nox2 promotes and Nox4 rather limits atherosclerosis. Although Nox1 with its cytosolic co-factors are largely expressed in epithelial cells, a role for Nox1 for atherosclerosis development was suggested. To further define the role of this homologue, the role of its essential cytosolic cofactor, NoxO1, was determined for atherosclerosis development with the aid of knockout mice. Methods and results Wildtype (WT) and NoxO1 knockout mice were treated with high fat diet and adeno-associated virus (AAV) overexpressing pro-protein convertase subtilisin/kexin type 9 (PCSK9) to induce hepatic low-density lipoprotein (LDL) receptor loss. As a result, massive hypercholesterolemia was induced and spontaneous atherosclerosis developed within three month. Deletion of NoxO1 reduced atherosclerosis formation in brachiocephalic artery and aortic arch in female but not male NoxO1−/− mice as compared to WT littermates. This was associated with a reduced pro-inflammatory cytokine signature in the plasma of female but not male NoxO1−/− mice. MACE-RNAseq of the vessel did not reveal this signature and the expression of the Nox1/NoxO1 system was low to not detectable. Conclusions The scaffolding protein NoxO1 plays some role in atherosclerosis development in female mice probably by attenuating the global inflammatory burden.

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