vels of protein carbonyl in BALF and the numbers of cleaved caspase 3- and ssDNA-positive cells in 24211709 the lungs were also significantly increased, whereas MMP-9 and MMP-12 mRNA induction was not affected. Poly combined with CS did not increase protein carbonyl levels or total cell, neutrophil, and macrophage counts in BALF, or apoptotic cell markers in the lungs of NZW mice that are resistant to developing emphysema Regadenoson supplier induced by CS . Therefore, we considered that these components were exacerbation-related, rather than general non-specific changes caused by viral infections and that they could feasibly be used to evaluate responses to therapy in this model. Effects of TRX and Systemic Corticosteroids on Polyinduced Changes in C57Bl/6 Mice Exposed to CS Thioredoxin-1 and Emphysema Progression Effects of TRX and Systemic Corticosteroids on Lung Morphometry in C57Bl/6 mice Exposed to CS and Poly We administered poly seven times along with TRX, DEX or saline in mice exposed to CS to determine lung morphometry. Duration of CS exposure and time course of poly challenges was shown in days after the challenge. Moreover, the significantly increased mRNA level of GM-CSF at 3 days after poly challenge in lung homogenates of mice exposed to CS was ameliorated by TRX. The neutrophil count in BALF in mice exposed to CS at 3 days after poly challenge was significantly and similarly decreased by aspirated anti-GM-CSF antibody and TRX. Transcriptional Regulation by TRX in Mice Exposed to CS and Poly To identify a candidate molecule involved in anti-inflammatory effects of TRX, the expression profiles of pulmonary mRNA in mice exposed to CS and poly and then treated or not with TRX were examined using microarrays. Among possible genes that were up- or down- regulated by TRX, dualspecificity phosphatase 1, also called MAP kinase phosphatase 1 was further investigated because TRX inhibits P38 MAP kinase 
in neutrophils and MKP-1 negatively regulates inflammatory responses both in vitro and in vivo. The results of real-time PCR showed that MKP-1 mRNA levels significantly increased in the lungs of mice exposed to CS at 3 days, but not at 6 h, after the poly challenge and treatment with TRX compared with saline. Anti-inflammatory Effect of TRX We investigated how TRX regulates airway neutrophilic inflammation by measuring levels of inflammatory cytokines in BALF. Many cytokines, including neutrophil chemokines such as keratinocyte-derived chemokine and GM-CSF, were significantly increased at 6 h after poly challenge. Notably, the increase in GM-CSF was still detectable after 3 days, whereas that in KC spontaneously resolved. TRX ameliorated the sustained increase in GM-CSF 3 6 Thioredoxin-1 and Emphysema Progression We investigated whether MKP-1 up-regulation is associated with the suppressive effect of TRX on airway neutrophil inflammation and GM-CSF production by inhibiting MKP-1 using NSC 95397, which inhibits both MKP-1 and MKP-3. Unlike MKP-1, the extent of MKP-3 induction at both 6 h and 3 days after the poly challenge in mice exposed to CS did not differ between TRX and saline treatment. TRX reduced BALF neutrophil counts and GM-CSF 10408253 levels at 3 days after the poly challenge in mice exposed to CS, but not in those treated with NSC95397. Discussion The present study showed that TRX has potential to counteract neutrophilic inflammation and emphysema progression in a mouse model of COPD exacerbation. Recombinant TRX suppressed the accelerated progression of emphy
