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The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in mice
Marielle Breau, … , Fatima Mechta-Grigoriou, Serge Adnot
Marielle Breau, … , Fatima Mechta-Grigoriou, Serge Adnot
Published October 3, 2019
Citation Information: JCI Insight. 2019;4(19):e127647. https://doi.org/10.1172/jci.insight.127647.
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Research Article Oncology Pulmonology

The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in mice

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Abstract

Oxidative stress is a major contributor to chronic lung diseases. Antioxidants such as N-acetylcysteine (NAC) are broadly viewed as protective molecules that prevent the mutagenic effects of reactive oxygen species. Antioxidants may, however, increase the risk of some forms of cancer and accelerate lung cancer progression in murine models. Here, we investigated chronic NAC treatment in aging mice displaying lung oxidative stress and cell senescence due to inactivation of the transcription factor JunD, which is downregulated in diseased human lungs. NAC treatment decreased lung oxidative damage and cell senescence and protected from lung emphysema but concomitantly induced the development of lung adenocarcinoma in 50% of JunD-deficient mice and 10% of aged control mice. This finding constitutes the first evidence to our knowledge of a carcinogenic effect of antioxidant therapy in the lungs of aged mice with chronic lung oxidative stress and warrants the utmost caution when considering the therapeutic use of antioxidants.

Authors

Marielle Breau, Amal Houssaini, Larissa Lipskaia, Shariq Abid, Emmanuelle Born, Elisabeth Marcos, Gabor Czibik, Aya Attwe, Delphine Beaulieu, Alberta Palazzo, Jean-Michel Flaman, Brigitte Bourachot, Guillaume Collin, Jeanne Tran Van Nhieu, David Bernard, Fatima Mechta-Grigoriou, Serge Adnot

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Figure 1

Oxidative stress and decreased JunD and Nrf2 levels in lungs from patients with lung disease.

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Oxidative stress and decreased JunD and Nrf2 levels in lungs from patien...
(A) JunD protein levels measured in the lungs relative to β-actin, using Western blotting, in patients with COPD and controls and JunD and Nrf2 mRNA levels measured in cultured pulmonary artery smooth muscle cells from patients with COPD and controls. (B) Levels of manganese superoxide dismutase (mnSOD), NAD(P)H quinone dehydrogenase 1 (NQO1), and heme oxygenase (Hmox) mRNA measured in cultured pulmonary artery smooth muscle cells from patients with COPD and controls. (C) Representative micrographs of lungs from patients with COPD and controls stained for 4-hydroxynonenal (4-HNE) as a marker of lipid peroxidation and (D) for 8-oxoguanine (8oxoG), as a marker of DNA oxidation. Individual values and means are represented on the right. (E) p16 and γH2.AX protein levels measured by Western blotting in lung samples from patients with COPD and controls. Data are individual values and mean. n = 8 in each group. P values were calculated using the Mann-Whitney test. ***P < 0.001; **P < 0.01; *P < 0.05. (F) Representative images of JunD and p16 protein immunostaining in lung tissue from a patient with COPD. In the top panels, JunD and p16 are merged with elastin and nuclei.

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