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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 3

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CS treatment leads to activation of caspase-3 in Nrf2–/– lungs. (A) Acti...
CS treatment leads to activation of caspase-3 in Nrf2–/– lungs. (A) Active caspase-3 expression in lung sections from CS-exposed (6 months) Nrf2+/+ and Nrf2–/– mice. CS-exposed Nrf2 –/– mice show increased numbers of caspase-3–positive cells in the alveolar septa (n = 5 per group). Magnification, ×40. (B) Number of caspase-3–positive cells in the lungs of air- and CS-exposed mice. Caspase-3–positive cells were significantly higher in the lungs of CS-exposed Nrf2–/– mice. (C) Increased expression of the 18-kDa active form of caspase-3 in lungs of CS-exposed (6 months) Nrf2–/– mice (Western blot; lanes 1 and 3: air- and CS-exposed Nrf2+/+ mice, respectively; lanes 2 and 4: air- and CS-exposed Nrf2–/– mice, respectively). (D) Quantification of procaspase-3 and active caspase-3 obtained in Western blots of air- or CS-exposed Nrf2+/+ and Nrf2–/– lungs. Values are represented as mean ± SEM. (E) Caspase-3 activity in the lungs of air- or CS-exposed (6 months) Nrf2+/+ and Nrf2–/– mice. Caspase-3 activity was significantly higher in the lungs of CS-exposed Nrf2–/– mice than in the lungs of their wild-type counterparts (n = 3 per group). Values (relative fluorescence units [RFU]) are represented as mean ± SEM. *P – 0.05 vs. CS-exposed Nrf2+/+ mice.

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

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