Thioredoxin-1 protects against neutrophilic inflammation and emphysema progression in a mouse model of chronic obstructive pulmonary disease exacerbation.
BACKGROUND
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. 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.


RESULTS
Mice 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.


CONCLUSIONS
Using 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.
Departments of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Naoya
N
Tanabe
Yuma
Y
Hoshino
Satoshi
S
Marumo
Hirofumi
H
Kiyokawa
Susumu
S
Sato
Daisuke
D
Kinose
Kazuko
K
Uno
Shigeo
S
Muro
Toyohiro
T
Hirai
Junji
J
Yodoi
Michiaki
M
Mishima
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007369:Interferon Inducers / Q000494:pharmacology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011070:Poly I-C / Q000494:pharmacology; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012907:Smoking / Q000009:adverse effects*; D013879:Thioredoxins / Q000494:pharmacology*
D007369:Interferon Inducers; C515559:Txn1 protein, mouse; D013879:Thioredoxins; D011070:Poly I-C