Administered N-acetylcysteine reduces the viscosity and purulence of phlegm in COPD patients. CuZn superoxide dismutase is known to be a strong antioxidant, and Tg mice overproducing human CuZn superoxide dismutase do not develop pulmonary inflammation in models of pulmonary emphysema induced by cigarette smoke or elastase. In addition, the antioxidant thioredoxin 1 inhibits elastase-induced emphysema in mice. In the present study, we showed that expression of antioxidant genes such as GST, SOD1, and SOD3 was decreased in the lungs of IL-18 Tg mice. These results suggest that decreased antioxidant activities in the lungs may contribute to pulmonary inflammation and emphysema in the COPD mouse model. Expression of cathepsin S is induced by IFN-c in several cell types, including smooth muscle cells. Increased levels of cathepsin L have been observed in BALF of patients with emphysema, and alveolar macrophages from COPD patient Tubacin 537049-40-4 secrete more cysteine protease than macrophages from smokers without disease, or those from non-smokers. Overexpression of IFN-c in the lungs induces emphysema in mice with increased expression of cathepsins B, D, H, L and S. In the present study, we found that cathepsins S, D, B, Z, L and C were strongly expressed in the lungs of IL-18 Tg mice, and that this was associated with severe emphysematous changes. These results suggest that in Tg mice, overexpression of IL-18 may increase the levels of cathepsins, which may in turn induce the development of emphysematous changes in the lungs. In the present study we found that the levels of mRNA and/or protein for the chitinase-related genes Chi3l1, Chi3l3, and AMCase were strongly increased in the lungs of IL-18 Tg mice, relative to Tg negative littermate mice, suggesting that IL-18 induces the expression of chitinase-related genes in vivo. Previous studies have demonstrated that IL-13 directly induces the expression of Chi3l1 in vivo and Chi3l1 induction by cigarette smoke was found to be partly dependent on the IL-18 pathway. In contrast, IL-18 induction was not significantly modulated in the absence of the Chi3l1 gene, suggesting that Chi3l1 operates downstream of IL-18. A previous study reported that AMCase was greatly induced in lung-specific IL-13 transgenic mice over-expressing mouse IL-13 proteins in the lungs. In contrast, AMCase was not up-regulated relative to WT mice in the IL-13 mouse asthma model. These results suggest that Chi3l3 and AMCase are IL-13-driven chitinase-like proteins. We have reported that IL-18 induces both Th1 and Th2 cytokines, including IL-13 and IFN-c in vivo and in vitro. Moreover, disruption of the IL-13 gene but not the IFN-c gene prevented emphysema and pulmonary inflammation in SPC-IL-18 Tg mice. Therefore, we hypothesized that the expression of Chi3l1 induced by IL-18 is at least partly dependent on the IL-13 pathway in vivo. We established IL-13 SPC-IL-18 Tg mice by backcrossing B6 SPC-IL-18 Tg mice with B6 IL-13 mice. However, IL-13 gene deletion did not significantly reduce the protein level of Chi3l1 in the lungs of IL-18 transgenic mice, suggesting that IL-18 drives the expression of Chi3l1 independently of the IL-13 pathway.