| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | ADVANCED SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Respiratory Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan
2 ERATO Environmental Response Project, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan
3 Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan
4 Central Laboratories for Key Technology, Kirin Brewery Co. Ltd., 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Inflammation, protease/anti-protease imbalance and oxidative stress play important roles in the pathogenesis of emphysema. Nrf2 counteracts oxidative tissue damage and inflammation through transcriptional activation via the anti-oxidant responsive element (ARE). To clarify the protective role of Nrf2 in the development of emphysema, the susceptibility of Nrf2-knockout mice to cigarette smoke (CS)-induced emphysema was examined. In Nrf2-knockout mice, emphysema was first observed at 8 weeks and exacerbated by 16 weeks following CS-exposure, whereas no pathological abnormalities were observed in wild-type mice. Neutrophilic lung inflammation and permeability lung damage were significantly enhanced in Nrf2-knockout mice 8 weeks after CS-exposure. Importantly, neutrophil elastase activity in bronchoalveolar lavage fluids was markedly higher in Nrf2-knockout mice preceding the pronounced neutrophil accumulation. The expression of secretory leukoprotease inhibitor, a potent inhibitor of neutrophil elastase, was inducible in wild-type, but not in Nrf2-knockout mice. This protease/anti-protease imbalance, together with the lack of inducible expression of ARE-regulated anti-oxidant/anti-inflammatory genes, may explain the predisposition of Nrf2-knockout mice to neutrophilic inflammation. Indeed, specific activators of Nrf2 induced the expression of the SLPI gene in macrophages. These results indicate that Nrf2 protects against the development of emphysema by regulating not only the oxidant/anti-oxidant balance, but also inflammation and the protease/anti-protease balance.
* Correspondence: E-mail: ishii-y{at}md.tsukuba.ac.jp
This article has been cited by other articles:
|
|
 |
|
  T. R. Richens, D. J. Linderman, S. A. Horstmann, C. Lambert, Y.-Q. Xiao, R. L. Keith, D. M. Boe, K. Morimoto, R. P. Bowler, B. J. Day, et al. Cigarette Smoke Impairs Clearance of Apoptotic Cells through Oxidant-dependent Activation of RhoA Am. J. Respir. Crit. Care Med., June 1, 2009; 179(11): 1011 - 1021. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. McGrath-Morrow, T. Lauer, M. Yee, E. Neptune, M. Podowski, R. K. Thimmulappa, M. O'Reilly, and S. Biswal Nrf2 increases survival and attenuates alveolar growth inhibition in neonatal mice exposed to hyperoxia Am J Physiol Lung Cell Mol Physiol, April 1, 2009; 296(4): L565 - L573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Suzuki, T. Betsuyaku, Y. Ito, K. Nagai, N. Odajima, C. Moriyama, Y. Nasuhara, and M. Nishimura Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice Am J Physiol Lung Cell Mol Physiol, April 1, 2009; 296(4): L614 - L623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-Y. Cho, F. Imani, L. Miller-DeGraff, D. Walters, G. A. Melendi, M. Yamamoto, F. P. Polack, and S. R. Kleeberger Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease Am. J. Respir. Crit. Care Med., January 15, 2009; 179(2): 138 - 150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. E. Sussan, T. Rangasamy, D. J. Blake, D. Malhotra, H. El-Haddad, D. Bedja, M. S. Yates, P. Kombairaju, M. Yamamoto, K. T. Liby, et al. From the Cover: Targeting Nrf2 with the triterpenoid CDDO- imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice PNAS, January 6, 2009; 106(1): 250 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Rahman Review: Antioxidant therapeutic advances in COPD Therapeutic Advances in Respiratory Disease, December 1, 2008; 2(6): 351 - 374. [Abstract] [PDF]
|
|
|
|
 |
|
 P. J. Barnes Future Treatments for Chronic Obstructive Pulmonary Disease and Its Comorbidities Proceedings of the ATS, December 1, 2008; 5(8): 857 - 864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Suzuki, T. Betsuyaku, Y. Ito, K. Nagai, Y. Nasuhara, K. Kaga, S. Kondo, and M. Nishimura Down-Regulated NF-E2-Related Factor 2 in Pulmonary Macrophages of Aged Smokers and Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Cell Mol. Biol., December 1, 2008; 39(6): 673 - 682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Adair-Kirk, J. J. Atkinson, G. L. Griffin, M. A. Watson, D. G. Kelley, D. DeMello, R. M. Senior, and T. Betsuyaku Distal Airways in Mice Exposed to Cigarette Smoke: Nrf2-Regulated Genes Are Increased in Clara Cells Am. J. Respir. Cell Mol. Biol., October 1, 2008; 39(4): 400 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Baglole, P. J. Sime, and R. P. Phipps Cigarette smoke-induced expression of heme oxygenase-1 in human lung fibroblasts is regulated by intracellular glutathione Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L624 - L636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Barnes Defective Antioxidant Gene Regulation in COPD: A Case for Broccoli Am. J. Respir. Crit. Care Med., September 15, 2008; 178(6): 552 - 554. [Full Text] [PDF]
|
|
|
|
 |
|
 X.-J. Wang, Z. Sun, N. F. Villeneuve, S. Zhang, F. Zhao, Y. Li, W. Chen, X. Yi, W. Zheng, G. T. Wondrak, et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2 Carcinogenesis, June 1, 2008; 29(6): 1235 - 1243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Kelsen, X. Duan, R. Ji, O. Perez, C. Liu, and S. Merali Cigarette Smoke Induces an Unfolded Protein Response in the Human Lung: A Proteomic Approach Am. J. Respir. Cell Mol. Biol., May 1, 2008; 38(5): 541 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Churg, M. Cosio, and J. L. Wright Mechanisms of cigarette smoke-induced COPD: insights from animal models Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L612 - L631. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Sun, S. Zhang, J. Y. Chan, and D. D. Zhang Keap1 Controls Postinduction Repression of the Nrf2-Mediated Antioxidant Response by Escorting Nuclear Export of Nrf2 Mol. Cell. Biol., September 15, 2007; 27(18): 6334 - 6349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yoshida and R. M. Tuder Pathobiology of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease Physiol Rev, July 1, 2007; 87(3): 1047 - 1082. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | ADVANCED SEARCH | TABLE OF CONTENTS |
