Airway smooth muscle NOX4 is upregulated and modulates ROS generation in COPD

Abstract

The burden of oxidative stress is increased in chronic obstructive pulmonary disease (COPD). However, whether the intra-cellular mechanisms controlling the oxidant/anti-oxidant balance in structural airway cells such as airway smooth muscle in COPD is altered is unclear. We sought to determine whether the expression of the NADPH oxidase (NOX)-4 is increased in airway smooth muscle in COPD both in vivo and primary cells in vitro and its role in hydrogen peroxide-induced reactive oxygen species generation. We found that in vivo NOX4 expression was up-regulated in the airway smooth muscle bundle in COPD (n = 9) and healthy controls with >20 pack year history (n = 4) compared to control subjects without a significant smoking history (n = 6). In vitro NOX4 expression was increased in airway smooth muscle cells from subjects with COPD (n = 5) compared to asthma (n = 7) and upregulated following TNF-α stimulation. Hydrogen peroxide-induced reactive oxygen species generation by airway smooth muscle cells in COPD (n = 5) was comparable to healthy controls (n = 9) but lower than asthma (n = 5); and was markedly attenuated by NOX4 inhibition. Our findings demonstrate that NOX4 expression is increased in vivo and in vitro in COPD and although we did not observe an intrinsic increase in oxidant-induced reactive oxygen species generation in COPD, it was reduced markedly by NOX4 inhibition supporting a potential therapeutic role for NOX4 in COPD.

Cysteine redox state regulates human β2-adrenergic receptor binding and function

“…The upregulation of NOX isoforms and resulting progressive increases in ROS generation in asthma, COPD, and other inflammatory pulmonary conditions produce a highly oxidative state 2,4 . Additionally, our laboratory as well as others, have shown that agonism of the β2AR elicits ROS generation 5,6,[8][9][10][11][12]50,51 , and together, these data suggest that chronic use of β2AR agonists in these pulmonary diseases can lead to a significantly higher oxidative load.…”

“…Inhaled β2-adrenergic receptor (β2AR) agonists are efficacious bronchodilators that are used clinically in patients with pulmonary disorders such as asthma or chronic obstructive pulmonary disease (COPD), the hypercontractility of which is linked to pulmonary inflammation and a highly oxidative environment. In these disease states, the pulmonary epithelia and underlying smooth muscle contain elevated concentrations of reactive oxygen species (ROS), and the membrane-bound ROS generating enzyme NADPH oxidase (NOX) is known to be upregulated [1][2][3] . Of note, NOX4 is overexpressed in the lungs of asthmatic patients compared to healthy controls, while NOX2, NOX4 and the related DUOX2 oxidases are upregulated in airway epithelia of COPD patients, increasing the total burden of oxidative stress in both diseases 2,4 .…”

“…In these disease states, the pulmonary epithelia and underlying smooth muscle contain elevated concentrations of reactive oxygen species (ROS), and the membrane-bound ROS generating enzyme NADPH oxidase (NOX) is known to be upregulated [1][2][3] . Of note, NOX4 is overexpressed in the lungs of asthmatic patients compared to healthy controls, while NOX2, NOX4 and the related DUOX2 oxidases are upregulated in airway epithelia of COPD patients, increasing the total burden of oxidative stress in both diseases 2,4 . Moreover, agonism of β2AR activates NOX isoforms and induces ROS generation, an effect that has been shown to occur in a myriad of cell lines and tissues including cardiomyocytes [5][6][7] , neuroglial cells 8 , aortic tissue 9 , and the COS-7 6 and HEK293 [10][11][12] clonal cell lines, suggesting that clinical treatment with inhaled β2AR agonists may contribute to the oxidizing pulmonary environment.…”

Mitochondrial alterations during oxidative stress in chronic obstructive pulmonary disease

“…An increasing number of researches have revealed that an increased expression of NOX4 was observed in pulmonary diseases 28–31. Recently, Hollins et al found that the expression of NOX4 was increased in ASM in COPD both in vivo and in primary cells in vitro 32. Liu et al also showed NOX4 protein was increased in the ASM, and its expression correlated positively with disease severity and inversely correlated with the pulmonary functions in COPD patients 33.…”

Down-regulation of NOX4 expression in dorsal root ganglion of spinal cord could alleviate cancer induced bone pain in rats by reducing oxidative stress response

“…during oxidative phosphorylation [6,7]. NOX4 was the rst kidney-speci c NOX to be discovered, and has since been detected in nerve cells and vascular smooth muscle cells, and in organelles including mitochondria, nuclei and endoplasmic reticulum.…”