Trolox contributes to Nrf2-mediated protection of human and murine primary alveolar type II cells from injury by cigarette smoke

Cigarette smoke (CS) is a main risk factor for chronic obstructive pulmonary disease (COPD). Oxidative stress induced by CS causes DNA and lung damage. Oxidant/antioxidant imbalance occurs in the distal air spaces of smokers and in patients with COPD. We studied the effect of oxidative stress genera...

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Published in:	Cell death & disease Vol. 4; no. 4; p. e573
Main Authors:	Messier, E M, Bahmed, K, Tuder, R M, Chu, H W, Bowler, R P, Kosmider, B
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-04-2013 Springer Nature B.V Nature Publishing Group
Subjects:	631/45/612/822 631/92/609 692/699/1785 Aldehydes - metabolism Alveolar Epithelial Cells - cytology Alveolar Epithelial Cells - drug effects Alveolar Epithelial Cells - metabolism Animals Antibodies Antioxidants - pharmacology Biochemistry Biomedical and Life Sciences Cell Biology Cell Culture Chromans - pharmacology Gene Expression Regulation - drug effects Heme Oxygenase-1 - genetics Heme Oxygenase-1 - metabolism Humans Immunology Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Life Sciences Mice Mice, Knockout NF-E2-Related Factor 2 - agonists NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism Nicotiana - toxicity Original original-article Oxidative Stress Pulmonary Alveoli - cytology Pulmonary Alveoli - drug effects Pulmonary Alveoli - metabolism Reactive Oxygen Species - antagonists & inhibitors Reactive Oxygen Species - metabolism Signal Transduction - drug effects Smoke - adverse effects Smoking - adverse effects Tumor Suppressor p53-Binding Protein 1 Tumor Suppressor Protein p53 - agonists Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism lung trolox cigarette smoke Nrf2 alveolar type II cells
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Summary:	Cigarette smoke (CS) is a main risk factor for chronic obstructive pulmonary disease (COPD). Oxidative stress induced by CS causes DNA and lung damage. Oxidant/antioxidant imbalance occurs in the distal air spaces of smokers and in patients with COPD. We studied the effect of oxidative stress generated by CS both in vivo and in vitro on murine primary alveolar type II (ATII) cells isolated from nuclear erythroid 2-related factor-2 (Nrf2) −/− mice. We determined human primary ATII cell injury by CS in vitro and analyzed ATII cells isolated from smoker and non-smoker lung donors ex vivo . We also studied whether trolox (water-soluble derivative of vitamin E) could protect murine and human ATII cells against CS-induced DNA damage and/or decrease injury. We analyzed oxidative stress by 4-hydroxynonenal expression, reactive oxygen species (ROS) generation by Amplex Red Hydrogen Peroxide Assay, Nrf2, heme oxygenase 1, p53 and P53-binding protein 1 (53BP1) expression by immonoblotting, Nrf2 nuclear translocation, Nrf2 and p53 DNA-binding activities, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and cytokine production by ELISA. We found that ATII cells isolated from Nrf2 −/− mice are more susceptible to CS-induced oxidative DNA damage mediated by p53/53BP1 both in vivo and in vitro compared with wild-type mice. Therefore, Nrf2 activation is a key factor to protect ATII cells against injury by CS. Moreover, trolox abolished human ATII cell injury and decreased DNA damage induced by CS in vitro . Furthermore, we found higher inflammation and p53 mRNA expression by RT-PCR in ATII cells isolated from smoker lung donors in comparison with non-smokers ex vivo . Our results indicate that the Nrf2 and p53 cross talk in ATII cells affect the susceptibility of these cells to injury by CS. Trolox can protect against oxidative stress, genotoxicity and inflammation induced by CS through ROS scavenging mechanism, and serve as a potential antioxidant prevention strategy against oxidative injury of ATII cells in CS-related lung diseases.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-4889 2041-4889
DOI:	10.1038/cddis.2013.96