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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 3

Aging and JunD deficiency lead to lung cellular senescence and structural alterations that can be prevented by chronic NAC treatment.

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Aging and JunD deficiency lead to lung cellular senescence and structura...
Measurements were performed in mouse lungs from young and aged control and JunD–/– mice treated with NAC or its vehicle. (A) Quantification of lung double-stranded DNA breaks by Western blot determination of γH2.AX proteins. Results are individual values and means. Representative gels for γH2.AX and β‑actin. (B and C) Quantification of p16- and p21-stained cells in mouse lungs. Individual values and means of percentages of positive cells per field are reported. Photomicrographs of representative images are shown below. Positive p16- or p21-stained cells are indicated by red arrows. (D) Quantification of lung emphysema by measurement of the mean linear intercept (Lm) length per animal, expressed in μm. Results are individual values and means for 8 animals per group. P values were calculated using 2-way ANOVA with Bonferroni’s post hoc test. ***P < 0.001; **P < 0.01; *P < 0.05.

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