Dual Oxidase 2 in Lung Epithelia Is Essential for Hyperoxia-Induced Acute Lung Injury in Mice

Kim, Min-Ji; Ryu, Jae Chan; Kwon, Youngho; Lee, Suhee; Bae, Yun Soo; Yoon, Joo Heon; Ryu, Ji Hwan

doi:10.1089/ars.2013.5677

Cited by 32 publications

(30 citation statements)

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“…This possibly suggests the involvement of DUOX‐2 in PAR‐2‐mediated increase in markers of apoptosis on AECs after CE allergen challenge. Kim et al have shown recently that DUOX‐2 is involved in apoptosis of AECs in response to hyperoxia. Our study also points towards the importance of DUOX‐2 signalling with respect to apoptosis in AECs.…”

Section: Discussionmentioning

confidence: 99%

“…For example, DUOX‐2 is up‐regulated in people with asthma, current smokers, and following viral infection . Moreover, hyperoxia‐induced acute lung injury is mediated by DUOX‐2‐induced H 2 O 2 , and DUOX‐A‐deficient mice that lack maturation factor for DUOX‐1/2 show decreased airway inflammation and hyper‐reactivity . Toll‐like receptors (TLRs) 2, 3, 4 and 5, which also sense the presence of pathogens on airway epithelium, have been recently identified to be involved in airway inflammation through DUOX‐2 .…”

Section: Introductionmentioning

confidence: 99%

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Proteinase activated receptor‐2‐mediated dual oxidase‐2 up‐regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma

et al. 2015

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SummaryAirway epithelial cells (AECs) express a variety of receptors, which sense danger signals from various aeroallergens/pathogens being inhaled constantly. Proteinase-activated receptor 2 (PAR-2) is one such receptor and is activated by cockroach allergens, which have intrinsic serine proteinase activity. Recently, dual oxidases (DUOX), especially DUOX-2, have been shown to be involved in airway inflammation in response to Toll-like receptor activation. However, the association between PAR-2 and DUOX-2 has not been explored in airways of allergic mice. Therefore, this study investigated the contribution of DUOX-2/reactive oxygen species (ROS) signalling in airway reactivity and inflammation after PAR-2 activation. Mice were sensitized intraperitoneally with intact cockroach allergen extract (CE) in the presence of aluminium hydroxide followed by intranasal challenge with CE. Mice were then assessed for airway reactivity, inflammation, oxidative stress (DUOX-2, ROS, inducible nitric oxide synthase, nitrite, nitrotyrosine and protein carbonyls) and apoptosis (Bax, Bcl-2, caspase-3). Challenge with CE led to up-regulation of DUOX-2 and ROS in AECs with concomitant increases in airway reactivity/inflammation and parameters of oxidative stress, and apoptosis. All of these changes were significantly inhibited by intranasal administration of ENMD-1068, a small molecule antagonist of PAR-2 in allergic mice. Administration of diphenyliodonium to allergic mice also led to improvement of allergic airway responses via inhibition of the DUOX-2/ROS pathway; however, these effects were less pronounced than PAR-2 antagonism. The current study suggests that PAR-2 activation leads to up-regulation of the DUOX-2/ROS pathway in AECs, which is involved in regulation of airway reactivity and inflammation via oxidative stress and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proteinase activated receptor‐2‐mediated dual oxidase‐2 up‐regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma

et al. 2015

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“…Conversely, minimal evidence exists to date to support a contribution of DUOX1/DUOX2 to acute lung injury or pneumonia, and studies in mouse model systems have not demonstrated a role for DUOX1/DUOX2 in LPS‐induced innate cytokine responses or neutrophilia (Chang et al ., ; Hristova et al ., ). However, one recent study indicated a role for DUOX2 in alveolar type II cells in mediating acute lung injury in response to hyperoxia (Kim et al ., ).…”

Section: Duox In Disease Pathologymentioning

confidence: 97%

Dual oxidase: a novel therapeutic target in allergic disease

Vliet

Danyal

Heppner

2018

British J Pharmacology

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NADPH oxidases (NOXs) represent a family of enzymes that mediate regulated cellular production of reactive oxygen species (ROS) and play various functional roles in physiology. Among the NOX family, the dual oxidases DUOX1 and DUOX2 are prominently expressed in epithelial cell types at mucosal surfaces and have therefore been considered to have important roles in innate host defence pathways. Recent studies have revealed important insights into the host defence mechanisms of DUOX enzymes, which control innate immune response pathways in response to either microbial or allergic triggers. In this review, we discuss the current level of understanding with respect to the biological role(s) of DUOX enzymes and the unique role of DUOX1 in mediating innate immune responses to epithelial injury and allergens and in the development of allergic disease. These novel findings highlight DUOX1 as an attractive therapeutic target, and opportunities for the development of selective inhibitor strategies will be discussed. AbbreviationsCPZ, chlorpromazine; DPI, diphenylene iodonium; DUOX, dual oxidase; DUOXA, dual oxidase maturation factor; EGFR, EGF receptor; ER, endoplasmic reticulum; HDM, house dust mite; ILC2, type 2 innate lymphoid cell; LPO, lactoperoxidase; MPO, myeloperoxidase; NOX, NADPH oxidase; NOXA, NOX activator; PDB, protein database; PHD, peroxidase homology domain; ROS, reactive oxygen species; TK, tyrosine kinase; TLR, toll-like receptor; TPO, thyroperoxidase; TRX, thioredoxin IntroductionThe concept of oxidative stress has been widely embraced as a major factor in disease pathology and has fuelled a billion dollar industry based on antioxidant dietary supplements. However, clinical studies using antioxidant supplementation strategies have generally been unsuccessful in attenuating disease risk or progression, and antioxidant supplementation was in some cases found to even worsen pathological outcomes (Ghezzi et al., 2017). This lack of success likely relates to the flawed concept of oxidative stress as a pharmacological target. First, oxidative stress can be brought about by a range of ROS (the commonly used acronym to define this group of reactive metabolites), which can originate from external sources (e.g. environmental pollution and metabolism of xenobiotics) or be generated endogenously by various enzymatic systems, in some cases in a regulated and deliberate fashion to serve important biological functions [e.g. by activation of NADPH oxidases (NOXs)]. Therefore, generic non-selective approaches that indiscriminately suppress ROS may not have the desired outcome. A second flaw with such generic antioxidant approaches is the fact that ROS represent a diverse group of reactive metabolites that each have unique (bio)chemical properties, and it is often unclear to what extent antioxidant supplements counter the action of individual ROS species. To clarify this, it is helpful to distinguish primary from secondary ROS, with primary ROS representing the initial products of (enzymatic) O 2 reduction [i.e. superoxi...

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“…DUOX1 has been reported to mediate allergic asthma [121], prolong ROS generation after irradiation [122], and play a role in cancer development [123]. DUOX2 has been reported to mediate keratinocyte inflammation [124], cochlear injury [103], and lung injury [125]. Furthermore, both DUOX enzymes have been implicated to be important in ROS-dependent immunity [126].…”

Section: Introductionmentioning

confidence: 99%

NADPH oxidase in brain injury and neurodegenerative disorders

Merry

Wang

Zhang

et al. 2017

Mol Neurodegeneration

341

309

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Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic.

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Dual Oxidase 2 in Lung Epithelia Is Essential for Hyperoxia-Induced Acute Lung Injury in Mice

Cited by 32 publications

References 51 publications

Proteinase activated receptor‐2‐mediated dual oxidase‐2 up‐regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma

Proteinase activated receptor‐2‐mediated dual oxidase‐2 up‐regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma

Dual oxidase: a novel therapeutic target in allergic disease

NADPH oxidase in brain injury and neurodegenerative disorders

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