sema in smoke-sensitive mice exposed to CS and repeatedly challenged with poly. Our findings deepen understanding of the mechanism underlying the regulation of neutrophilic inflammation by TRX. Exaggerated airway neutrophilic inflammation was central to the accelerated progression of CS and poly-Debio-1347 web induced emphysema, and neutrophilic inflammation comprised two phases. Poly-induced production of neutrophilic chemokines such as KC and GM-CSF promoted neutrophil migration into the lung during the early phase, and then the sustained release of GM-CSF in the lung prolonged neutrophil survival during the late phase, which led to 
persistent airway inflammation and pronounced parenchymal destruction. TRX can suppress neutrophilic inflammation, perhaps through directly inhibiting neutrophil infiltration into sites of inflammation. Notably, we discovered that TRX suppresses prolonged GM-CSF release, indicating that 7 Thioredoxin-1 and Emphysema Progression recombinant TRX regulates neutrophilic inflammation via a dual mechanism. We used the animal model established by Kang et al. with slight modification. It has been shown that in this model, airway inflammation is greater and emphysema develops more rapidly than conventional mouse model of emphysema induced by CS exposure alone. This model is appropriate for exploring enhanced airway inflammation and accelerated emphysema progression, which are the main immunopathological changes in human COPD exacerbation. Although the time course of poly challenge and duration of smoke exposure slightly differed in the present, from the original study, similar inflammatory responses and progressive emphysema were detected. To identify “exacerbation-related changes”, we compared smoke-sensitive C57Bl/6 mice and smoke-resistant NZW mice assuming that changes induced by poly in NZW mice were not related to exacerbation. Consequently, exposure 1685439 to CS and poly enhanced airway neutrophilic and macrophage inflammation and induced oxidative stress and lung apoptosis in smoke-sensitive, but not in smokeresistant, mice. We considered that these findings were exacerbation-related changes that should be targeted with therapeutic interventions. It should be also noted that although various types of inflammatory cells such as neutrophil, macrophage, and T cells are associated with the pathogenesis of murine emphysema induced by CS alone, neutrophil and macrophage play an 14522929 important role in amplifying airway inflammation in the present COPD exacerbation model. TRX suppressed airway neutrophilic inflammation, lung apoptosis and the further progression of emphysema in mice exposed to CS and poly. Although TRX has anti-oxidant properties, these were not considered central in the present model because TRX did not improve the increase in oxidative stress assessed by carbonyl protein in BALF. This finding was consistent with previous reports concerning the limited anti-oxidant properties of exogenous TRX. To reinforce this conclusion, other markers of oxidative stress such as F2-isoprostanes should be measured. GM-CSF is a direct neutrophil chemotactic factor that increases neutrophil survival in the respiratory tract, and can be involved in CS-induced airway neutrophilic inflammation. The present study showed that in mice exposed to CS and poly, the airway level of GM-CSF was increased at 6 h after poly challenge and sustained until 3 days after the challenge, while the levels of other inflammatory cytokines especially associated wit