title: Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema.
abstract: 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.
authors.affiliation: Department of Respiratory Medicine, University of Tsukuba, Japan. ishii-y@md.tsukuba.ac.jp
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ishii
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Yuko
authors.initials: Y
authors.lastname: Morishima
authors.forename: Toru
authors.initials: T
authors.lastname: Kimura
authors.forename: Takumi
authors.initials: T
authors.lastname: Kiwamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Iizuka
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Hegab
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hosoya
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nomura
authors.forename: Tohru
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Kiyohisa
authors.initials: K
authors.lastname: Sekizawa
mesh_terms: 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
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011480:Protease Inhibitors; D010196:Pancreatic Elastase