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Free Radic Biol Med. 2018 Oct;126:350-357. doi: 10.1016/j.freeradbiomed.2018.08.014. Epub 2018 Aug 15.

Role of GPx3 in PPARγ-induced protection against COPD-associated oxidative stress.

Author information

1
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
2
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
3
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA. Electronic address: reddyrc@upmc.edu.

Abstract

Cigarette smoke, a source of numerous oxidants, produces oxidative stress and exaggerated inflammatory responses that lead to irreversible lung tissue damage. It is the single, most significant risk factor for chronic obstructive pulmonary disease (COPD). Although an intrinsic defense system that includes both enzymatic and non-enzymatic modulators exists to protect lung tissues against oxidative stress, impairment of these protective mechanisms has been demonstrated in smokers and COPD patients. The antioxidant enzyme GSH peroxidase (GPx) is an important part of this intrinsic defense system. Although cigarette smoke has been shown to downregulate its expression and activity, the underlying mechanism is not known. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear hormone receptor with antioxidant effects. PPARγ activation has demonstrated protective effects against cigarette smoke-induced oxidative stress and inflammation. Molecular mechanisms for PPARγ's antioxidant function likewise remain to be elucidated. This study explored the link between PPARγ and GPx3 and found a positive association in cigarette smoke extract (CSE)-exposed human bronchial epithelial cells. Moreover, we provide evidence that identifies GPx3 as a PPARγ transcriptional target. Attenuation of antioxidant effects in the absence of GPx3 highlights the antioxidant's prominent role in mediating PPARγ's function. We also demonstrate that ligand-mediated PPARγ activation blocks CSE-induced reactive oxygen species and hydrogen peroxide production via upregulation of GPx3. In summary, our findings describing the molecular mechanisms involving GPx3 and PPARγ in CSE-induced oxidative stress and inflammation may provide valuable information for the development of more effective therapeutics for COPD.

KEYWORDS:

Antioxidant; Cigarette smoke; GSH peroxidases; Glutathione (GSH); Human bronchial epithelial cells; Hydrogen peroxide (H(2)O(2)); Inflammation; NF-κB; Nuclear hormone receptor; Oxidative stress; PPAR response element (PPRE); Reactive oxygen species (ROS)

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