Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema.
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.
Iizuka
Takashi
T
Department of Respiratory Medicine, University of Tsukuba, Japan.
Ishii
Yukio
Y
Itoh
Ken
K
Kiwamoto
Takumi
T
Kimura
Toru
T
Matsuno
Yosuke
Y
Morishima
Yuko
Y
Hegab
Ahmed E
AE
Homma
Shinsuke
S
Nomura
Akihiro
A
Sakamoto
Tohru
T
Shimura
Masako
M
Yoshida
Aruto
A
Yamamoto
Masayuki
M
Sekizawa
Kiyohisa
K
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D020022:Genetic Predisposition to Disease; D019272:Leukocyte Elastase / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000502:physiology; D009504:Neutrophils / Q000378:metabolism; D010587:Phagocytosis; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D053481:Secretory Leukocyte Peptidase Inhibitor; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; D014028:Tobacco Smoke Pollution; D019272:Leukocyte Elastase