Abstract
BackgroundExacerbations of chronic obstructive pulmonary disease (COPD) are characterized by acute enhancement of airway neutrophilic inflammation under oxidative stress and can be involved in emphysema progression. However, pharmacotherapy against the neutrophilic inflammation and emphysema progression associated with exacerbation has not been established. Thioredoxin-1 has anti-oxidative and anti-inflammatory properties and it can ameliorate neutrophilic inflammation through anti-chemotactic effects and prevent cigarette smoke (CS)-induced emphysema. We aimed to determine whether thioredoxin-1 can suppress neutrophilic inflammation and emphysema progression in a mouse model of COPD exacerbation and if so, to reveal the underlying mechanisms.ResultsMice were exposed to CS and then challenged with polyinosine-polycytidylic acid [poly(I:C)], an agonist for virus-induced innate immunity. Airway neutrophilic inflammation, oxidative stress and lung apoptosis were enhanced in smoke-sensitive C57Bl/6, but not in smoke-resistant NZW mice. Exposure to CS and poly(I:C) challenge accelerated emphysema progression in C57Bl/6 mice. Thioredoxin-1 suppressed neutrophilic inflammation and emphysema progression. Poly(I:C) caused early neutrophilic inflammation through keratinocyte-derived chemokine and granulocyte-macrophage colony-stimulating factor (GM-CSF) release in the lung exposed to CS. Late neutrophilic inflammation was caused by persistent GM-CSF release, which thioredoxin-1 ameliorated. Thioredoxin-1 enhanced pulmonary mRNA expression of MAP kinase phosphatase 1 (MKP-1), and the suppressive effects of thioredoxin-1 on prolonged GM-CSF release and late neutrophilic inflammation disappeared by inhibiting MKP-1.ConclusionUsing a mouse model of COPD exacerbation, we demonstrated that thioredoxin-1 ameliorated neutrophilic inflammation by suppressing GM-CSF release, which prevented emphysema progression. Our findings deepen understanding of the mechanisms underlying the regulation of neutrophilic inflammation by thioredoxin-1 and indicate that thioredoxin-1 could have potential as a drug to counteract COPD exacerbation.
Highlights
Chronic obstructive pulmonary disease (COPD) is an inflammatory condition involving oxidative stress and various types of inflammatory cells such as neutrophils and macrophages [1,2]
The Lm, destructive index (DI), standard deviation (SD) and coefficient of variation (CV) in the terminal airspace sizes were significantly increased in the mice exposed to cigarette smoke (CS) and poly(I:C) (Figure 2 and Figure S1), indicating that this combination of agents contributed to airspace enlargement, the destruction of alveolar walls and increased spatial heterogeneity, which is a structural feature of progressive emphysema [38]
Poly(I:C)-induced production of neutrophilic chemokines such as keratinocyte-derived chemokine (KC) and granulocyte-macrophage colonystimulating factor (GM-CSF) promoted neutrophil migration into the lung during the early phase, and the sustained release of GM-CSF in the lung prolonged neutrophil survival [43] during the late phase, which led to persistent airway inflammation and pronounced parenchymal destruction
Summary
Chronic obstructive pulmonary disease (COPD) is an inflammatory condition involving oxidative stress and various types of inflammatory cells such as neutrophils and macrophages [1,2]. It is the fourth leading cause of death worldwide [1]. Exacerbations of chronic obstructive pulmonary disease (COPD) are characterized by acute enhancement of airway neutrophilic inflammation under oxidative stress and can be involved in emphysema progression. Thioredoxin-1 has anti-oxidative and anti-inflammatory properties and it can ameliorate neutrophilic inflammation through anti-chemotactic effects and prevent cigarette smoke (CS)-induced emphysema. We aimed to determine whether thioredoxin-1 can suppress neutrophilic inflammation and emphysema progression in a mouse model of COPD exacerbation and if so, to reveal the underlying mechanisms
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