Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema.
Emphysema is one of the major pathological abnormalities associated with chronic obstructive pulmonary disease. The protease/antiprotease imbalance and inflammation resulting from oxidative stress have been attributed to the pathogenesis of emphysema. Nrf2 is believed to protect against oxidative tissue damage through the transcriptional activation of a battery of antioxidant enzymes. In this study, we investigated the protective role of Nrf2 in the development of emphysema using elastase-induced emphysema as our model system. We found that elastase-provoked emphysema was markedly exacerbated in Nrf2-knockout (KO) mice compared with wild-type mice. The severity of emphysema in Nrf2-KO mice correlated intimately with the degree of lung inflammation in the initial stage of elastase treatment. The highly inducible expression of antioxidant and antiprotease genes observed in wild-type alveolar macrophages was significantly attenuated in the lungs of Nrf2-KO mice. Interestingly, transplantation of wild-type bone marrow cells into Nrf2-KO mice retarded the development of initial lung inflammation and subsequent emphysema, and this improvement correlated well with the appearance of macrophages expressing Nrf2-regulated antiprotease and antioxidant genes. Thus, Nrf2 appears to exert its protective effects through the transcriptional activation of antiprotease and antioxidant genes in alveolar macrophages.
Ishii
Yukio
Y
Department of Respiratory Medicine, University of Tsukuba, Japan. ishii-y@md.tsukuba.ac.jp
Itoh
Ken
K
Morishima
Yuko
Y
Kimura
Toru
T
Kiwamoto
Takumi
T
Iizuka
Takashi
T
Hegab
Ahmed E
AE
Hosoya
Tomonori
T
Nomura
Akihiro
A
Sakamoto
Tohru
T
Yamamoto
Masayuki
M
Sekizawa
Kiyohisa
K
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016026:Bone Marrow Transplantation; D004646:Emphysema / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015870:Gene Expression; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000633:toxicity; D011014:Pneumonia / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011480:Protease Inhibitors / Q000378:metabolism
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011480:Protease Inhibitors; D010196:Pancreatic Elastase