Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice
Tirumalai Rangasamy, … , Rubin M. Tuder, Shyam Biswal
Tirumalai Rangasamy, … , Rubin M. Tuder, Shyam Biswal
Published November 1, 2004
Citation Information: J Clin Invest. 2004;114(9):1248-1259. https://doi.org/10.1172/JCI21146.
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Article Genetics

Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice

Abstract

Although inflammation and protease/antiprotease imbalance have been postulated to be critical in cigarette smoke–induced (CS-induced) emphysema, oxidative stress has been suspected to play an important role in chronic obstructive pulmonary diseases. Susceptibility of the lung to oxidative injury, such as that originating from inhalation of CS, depends largely on its upregulation of antioxidant systems. Nuclear factor, erythroid-derived 2, like 2 (Nrf2) is a redox-sensitive basic leucine zipper protein transcription factor that is involved in the regulation of many detoxification and antioxidant genes. Disruption of the Nrf2 gene in mice led to earlier-onset and more extensive CS-induced emphysema than was found in wild-type littermates. Emphysema in Nrf2-deficient mice exposed to CS for 6 months was associated with more pronounced bronchoalveolar inflammation; with enhanced alveolar expression of 8-oxo-7,8-dihydro-2′-deoxyguanosine, a marker of oxidative stress; and with an increased number of apoptotic alveolar septal cells — predominantly endothelial and type II epithelial cells — as compared with wild-type mice. Microarray analysis identified the expression of nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lung that may work in concert to counteract CS-induced oxidative stress and inflammation. The responsiveness of the Nrf2 pathway may act as a major determinant of susceptibility to tobacco smoke–induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis.

Authors

Tirumalai Rangasamy, Chung Y. Cho, Rajesh K. Thimmulappa, Lijie Zhen, Sorachai S. Srisuma, Thomas W. Kensler, Masayuki Yamamoto, Irina Petrache, Rubin M. Tuder, Shyam Biswal

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Figure 4

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Increased sensitivity of Nrf2–/– mice to oxidative stress after CS expos...
Increased sensitivity of Nrf2–/– mice to oxidative stress after CS exposure. (A) Immunohistochemical staining for 8-oxo-dG in lung sections from the mice exposed to CS (6 months) (n = 5 per group). Lung sections from the CS-exposed Nrf2–/– mice show increased staining for 8-oxo-dG (indicated by arrows) when compared with lung sections from CS-exposed Nrf2+/+ mice and the respective air-exposed control mice. Magnification, ×40. (B) Quantification of 8-oxo-dG–positive alveolar septal cells in lungs after 6 months of CS exposure. The number of cells that reacted with anti–8-oxo-dG antibody was significantly higher in the lung tissues of the CS-exposed Nrf2–/– mice than in the lung tissues of the CS-exposed Nrf2+/+ mice and air-exposed control mice. Values (positive cells/mm alveolar length) represent mean ± SEM. *P – 0.05 vs. CS-exposed Nrf2+/+ mice. (C) Immunohistochemical staining with normal mouse-IgG1 antibody in lung sections from air- or CS-exposed Nrf2+/+ and Nrf2–/– mice. Magnification, ×40. Scale bars: 25 μm.