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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 Article has an altmetric score of 11

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

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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 5

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Increased inflammation in the lungs of CS-exposed Nrf2–/– mice. (A) Lava...
Increased inflammation in the lungs of CS-exposed Nrf2–/– mice. (A) Lavaged inflammatory cells from control and CS-exposed mice. The number of macrophages in BAL fluid collected from the CS-exposed (both 1.5 months and 6 months) Nrf2–/– mice was significantly higher than in the BAL fluid from CS-exposed Nrf2+/+ mice and the respective age-matched control mice. Values represent mean ± SEM (n = 8). PMNs, polymorphonuclear leukocytes. *P – 0.05 vs. control of the same genotype; P – 0.05 across the genotypes in CS-exposed group. (B) Immunohistochemical detection of macrophages (arrows) in lungs of Nrf2+/+ and Nrf2–/– mice exposed to CS for 6 months. Magnification, ×40. Scale bars: 25 μm. (C) Quantification of macrophages in lungs after 6 months of CS exposure. The lung sections from the CS-exposed Nrf2–/– mice showed significantly more macrophages than did those from wild-type counterparts exposed to CS (**P – 0.025). However, there was no significant difference in the number of alveolar macrophages between the air-exposed Nrf2+/+ and Nrf2–/– mice (P > 0.9).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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