bims-noxint 2022-06-12 papers

Issue of 2022‒06‒12
four papers selected by
Laia Caja Puigsubira
Uppsala University

Front Pharmacol. 2022 ;13 880878

NOX4 Mediates Epithelial Cell Death in Hyperoxic Acute Lung Injury Through Mitochondrial Reactive Oxygen Species.

Anantha Harijith, Prathima Basa, Alison Ha, Jaya Thomas, Anjum Jafri, Panfeng Fu, Peter M MacFarlane, Thomas M Raffay, Viswanathan Natarajan, Tara Sudhadevi.

Management of acute respiratory distress involves O2 supplementation, which is lifesaving, but causes severe hyperoxic acute lung injury (HALI). NADPH oxidase (NOX) could be a major source of reactive oxygen species (ROS) in hyperoxia (HO). Epithelial cell death is a crucial step in the development of many lung diseases. Alveolar type II (AT2) cells are the metabolically active epithelial cells of alveoli that serve as a source of AT1 cells following lung injury. The aim of this study was to determine the possible role of AT2 epithelial cell NOX4 in epithelial cell death from HALI. Wild type (WT), Nox4 fl/fl (control), and Nox4 -/- Spc-Cre mice were exposed to room air (NO) or 95% O2 (HO) to investigate the structural and functional changes in the lung. C57BL/6J WT animals subjected to HO showed increased expression of lung NOX4 compared to NO. Significant HALI, increased bronchoalveolar lavage cell counts, increased protein levels, elevated proinflammatory cytokines and increased AT2 cell death seen in hyperoxic Nox4 fl/fl control mice were attenuated in HO-exposed Nox4 -/- Spc-Cre mice. HO-induced expression of NOX4 in MLE cells resulted in increased mitochondrial (mt) superoxide production and cell apoptosis, which was reduced in NOX4 siRNA silenced cells. This study demonstrates a novel role for epithelial cell NOX4 in accelerating lung epithelial cell apoptosis from HALI. Deletion of the Nox4 gene in AT2 cells or silencing NOX4 in lung epithelial cells protected the lungs from severe HALI with reduced apoptosis and decreased mt ROS production in HO. These results suggest NOX4 as a potential target for the treatment of HALI.

Keywords: NADPH oxidase 4; alveolar type 2 epithelial cell; apoptosis; hyperoxic acute lung injury; mitochondrial ROS

DOI: https://doi.org/10.3389/fphar.2022.880878

FASEB J. 2022 Jul;36(7): e22381

NADPH and xanthine oxidases control induction of inflammatory mediator expression by organic dust in the lung.

Velmurugan Meganathan, Cory E Hamilton, Kartiga Natarajan, Shiva Keshava, Vijay Boggaram.

Exposure to organic dust in animal and agricultural farms and the ensuing lung inflammation are linked to the development of respiratory diseases. We found previously that elevated production of reactive oxygen species (ROS) by aqueous poultry organic dust extract (hereafter referred to as dust extract) mediates induction of proinflammatory mediators in airway epithelial cells. In the present study, we investigated whether ROS generated by NADPH oxidases (NOX) and xanthine oxidase (XO) controls induction of inflammatory mediators by dust extract and the underlying mechanisms in bronchial epithelial cells. Using chemical inhibitors and siRNA targeted knockdown, we found that NOX1, NOX2, NOX4, and XO-derived ROS regulates induction of proinflammatory mediator levels. Like airway epithelial cells in vitro, NOX inhibitor VAS2870 reduced keratinocyte chemoattractant (KC), IL-6, and TNF-α production and 4-hydroxynonenal (4-HNE) staining induced by dust extract in mouse lungs. VAS2870 inhibition of proinflammatory mediators was associated with reduced NFκB and Stat3 activation indicating that NOX generated ROS activates NFκB and Stat3 to induce proinflammatory gene expression. Dust extract increased the membrane association of p47phox in airway epithelial cells indicating NOX2 activation but had no effect on NOX2 protein levels. In summary, our studies have shown that NOX and XO generated ROS control organic dust induction of proinflammatory mediators in airway epithelial cells via NFκB and Stat3 activation.

Keywords: cytokines; gene regulation; occupational lung diseases; oxidative stress

DOI: https://doi.org/10.1096/fj.202100732R

Biochem Biophys Res Commun. 2022 May 02. pii: S0006-291X(22)00692-1. [Epub ahead of print]617(Pt 1): 1-7

Inhibition of NADPH oxidase 2 (NOX2) reverses cognitive deficits by modulating excitability and excitatory transmission in the hippocampus after traumatic brain injury.

Weijie Wang, Xiaotian Zhang, Lihui Lin, Jiangbin Ren, Ruixing He, Kun Sun.

Traumatic brain injury (TBI) is a closed or open head injury caused by external mechanical forces that induce brain damage, resulting in a wide range of postinjury dysfunctions of emotions, learning and memory, adversely affecting the quality of life of patients. In this study, we aimed to explore the possible mechanisms of NOX2 on cognitive deficits in a TBI mouse model. Behavioral tests were applied to evaluate learning and memory ability, and electrophysiological experiments were performed to measure synaptic transmission and intrinsic excitability of the CA1 pyramidal cells (PCs) and long-term potentiation (LTP) in the TBI hippocampus. We found that inhibitors of nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2; NOX2) (GSK2795039 and apocynin) attenuate neurological deficits, facilitate long-term potentiation (LTP) and decrease spontaneous synaptic transmission and intrinsic excitability of CA1 pyramidal cells (PCs) in traumatic brain injury (TBI) mice. NOX2-/- mice display reduced learning and memory impairment, enhanced LTP and reduced spontaneous synaptic transmission and intrinsic excitability of PCs after TBI. Our study demonstrates that NOX2 is a potential target for learning and memory by modulating excitability and excitatory transmission in the hippocampus after TBI.

Keywords: Cognitive deficits; Excitatory transmission; Long-term potentiation (LTP); NADPH Oxidase 2 (NOX2); Traumatic brain injury (TBI)

DOI: https://doi.org/10.1016/j.bbrc.2022.05.002

Int J Gen Med. 2022 ;15 5307-5317

Serum NOX4 as a Promising Prognostic Biomarker in Association with 90-Day Outcome of Severe Traumatic Brain Injury.

Feng Jiang, Zhicheng Chen, Jiemiao Hu, Qianzhi Liu.

Purpose: Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is related to brain oxidative stress. We attempted to examine the association between serum NOX4 levels, severity and prognosis of severe traumatic brain injury (sTBI).Methods: We measured serum NOX4 levels in 105 patients with sTBI. Trauma severity was assessed using Glasgow coma scale (GCS) and Rotterdam computed tomography (CT) classification. Study outcome data on death and worst outcome (Glasgow outcome scale score of 1-3) were collected at 90 days after trauma. Multivariate analyses were performed to determine independent factors for overall survival and worst outcome. Area under receiver operating characteristic curve (AUC) was estimated to assess prognostic predictive ability.
Results: Serum NOX4 levels were tightly correlated with GCS score (t=-5.843, P < 0.001) and Rotterdam CT score (t = 4.231, P < 0.001). During 90 days of follow-up, 50 participants (47.6%) experienced a worse outcome, 28 (26.7%) died and the mean overall survival time was 71.9 days (95% confidence interval (CI), 65.7-78.1 days). Serum NOX4 was independently associated with an increased risk of short overall survival (hazard ratio, 1.129; 95% CI, 1.039-1.228) or worse outcome (odds ratio, 1.053; 95% CI, 1.014-1.095). Serum NOX4 levels had a certain predictive value for the patient's risk of mortality (AUC, 0.803; 95% CI, 0.714-0.874) or worse outcome (AUC, 0.780; 95% CI, 0.689-0.855). Moreover, its AUC was in the range of GCS score and Rotterdam CT score (both P > 0.05) and it significantly improved their AUCs (both P < 0.05).
Conclusion: Serum NOX4 levels in the acute phase of sTBI were associated with trauma severity, an increased risk of mortality and worse outcome, suggesting that serum NOX4 could be an important prognostic factor for sTBI.

Keywords: NOX4; biomarker; prognosis; severity; traumatic brain injury

DOI: https://doi.org/10.2147/IJGM.S366170