Cigarette Smoke Impairs A2A Adenosine Receptor Mediated Wound Repair through Up-regulation of Duox-1 Expression

Abstract

Cigarette smoke (CS) exposure and intrinsic factors such as the NADPH oxidases produce high levels of reactive oxygen species (ROS), ensuing inflammatory tissue injury. We previously demonstrated that CS-generated ROS, particularly hydrogen peroxide (H2O2), impaired adenosine stimulated wound repair. We hypothesized that CS exposure modulates expression of Dual oxidase 1 (Duox-1), a NADPH oxidases known to generate H2O2. To test this hypothesis, we used human bronchial epithelial cell line Nuli-1 and C57BL/6 mice. Cells were treated with 5% CS extract (CSE) for various periods of time, and mice were exposed to whole body CS for six weeks. Both CSE and CS treatment induced increased expression of Duox-1, and silencing of Doux-1 improved the rate of cell wound repair induced by CSE treatment. Nuli-1 cells pretreated with thapsigargin but not calcium ionophore exhibited increased Duox-1 mRNA expression. CSE treatment stimulated PKCα activation, which was effectively blocked by pretreatment with diphenylene iodonium, a NADPH oxidase inhibitor. Compared to control, lungs from CS-exposed mice showed a significant increase in PKCα activity and Duox-1 expression. Collectively, the data demonstrated that CS exposure upregulates expression of Duox-1 protein. This further leads to H2O2 production and PKCα activation, inhibiting A2AAR-stimulated wound repair.

Histone hypo-acetylation of Sox9 mediates nicotine-induced weak cartilage repair by suppressing BMSC chondrogenic differentiation

“…Nicotine is a high-risk factor for many diseases and has negative effects on soft and bony tissue healing [ 11 , 12 ], which can also influence the repair of cartilage defects and suppress the chondrogenic differentiation of BMSCs [ 13 , 17 ]. However, the mechanism of nicotine’s adverse effect is still unclear.…”

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Redox regulation of motile cilia in airway disease

“…While the precise mechanism of PKCε activation by cigarette smoke is not fully understood, it has recently been reported that smoke increases Duox1 and H 2 O 2 and IL-8 release in an immortalized bronchial epithelial cell-line and in smoke-exposed mice. Inhibition of Duox1 with a non-specific Nox inhibitor DPI blocked IL-8 release [120]. In a separate bovine bronchial epithelial cell model, exogenous IL-8 caused cilia dysfunction [121].…”

Dimethylarginine dimethylaminohydrolase (DDAH) overexpression enhances wound repair in airway epithelial cells exposed to agricultural organic dust

“…The rate of wound repair was measured as a function of cell monolayer resistance using the Electric Cell-substrate Impedance Sensing (ECIS) device (Applied BioPhysics, Troy, NY) (Tian et al 2017). Mouse tracheal epithelial cells were cultured to confluence onto ECIS electrode slides (8W1E; Applied Biophysics) and baseline impedance values recorded for the purpose of calculating both resistance and capacitance.…”