h neutrophilic buy Debio1347 inflammation including KC, IL-6, RANTES, and TNF alpha were increased at 6 h after poly challenge but spontaneously resolved at 3 days after the challenge. These results indicate that early phase of CS and poly-induced neutrophilic inflammation could be prompted by many cytokines, but the enhanced inflammation could be sustained exclusively by prolonged GM-CSF release. TRX ameliorated enhanced GM-CSF mRNA expression and protein production at 3 days after poly challenge. The airway neutrophil inflammation at 3 days after the challenge was reduced as much by anti-GM-CSF antibody as by TRX in mice exposed to CS. These suggest that TRX regulates late phase of neutrophilic inflammation by suppressing prolonged GM-CSF release. The suppressive effects of TRX against the early increases in inflammatory cytokines such as IL-6, TNF alpha, and RANTES were also found, and this might have affected the reduction of GM-CSF and resolution of neutrophilic inflammation during the late phase. To elucidate the signaling pathway associated with the suppression of GM-CSF release and regulation of neutrophilic inflammation by treatment with TRX, we focused on MKP-1 in the lung of mice treated with TRX based on the findings of an investigation into the suppressive effect of TRX on P38 MAP 12411425 kinase in neutrophils. Inflammatory cytokine release is regulated by MKP-1 in innate immune responses. Pulmonary mRNA of MKP-1 was up-regulated at 6 h after poly challenge in both mice exposed to CS and then treated with TRX or saline, but the extent of MKP-1 induction did not differ between the two groups. In contrast, 3 days after the challenge, more MKP-1 was expressed in the group treated with TRX than with saline. TRX reduced neutrophil counts and GMCSF levels in BALF at 3 days after poly challenge in mice exposed to CS, but this effect disappeared in mice exposed to 
CS and treated with the MKP-1 and MKP-3 inhibitor NSC95397. These findings suggest that MKP-1 might be involved in the suppression of GM-CSF release and late phase of neutrophilic inflammation by TRX. In 15658870 addition to mRNA expression, we examined MKP-1 protein levels in the lungs at 3 days after poly challenge using Western blotting. However, MKP-1 protein levels did not significantly differ between mice treated with or without TRX. This is a major limitation of the present study. Nevertheless, our findings are quite important, because they show for the first time an association between TRX, MKP-1, and inflammation. The findings also provide a hypothesis that MKP-1 induction by TRX is essential for suppressing persistent GM-CSF release and neutrophilic inflammation. This should be verified in future studies. Thioredoxin-1 and Emphysema Progression Effects of systemic corticosteroids on “exacerbation-related changes”such as airway neutrophilic inflammation and emphysema progression were also evaluated. In human, 3040 mg/body of prednisolone has been recommended for treatment of COPD exacerbations. Given that 0.75 mg/kg of DEX is equivalent in anti-inflammatory activity to 5 mg/kg of prednisolone, 0.1 mg/kg of DEX in the present model could be relevant to the clinical dose currently applied to manage COPD exacerbation. Notably, airway neutrophilic inflammation and emphysema progression could be suppressed only when the dose of DEX was increased up to 1.0 mg/kg, which may reflect approximately 10 times of the standard dose in practice. These suggest that the current regimen of systemic corticostero