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* Department of Respiratory Medicine,
Exploratory Research for Advanced Technology (ERATO) Environmental Response Project, and
Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
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.
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