Abstract
Corticosteroid insensitive inflammation is one of the important hallmarks of chronic obstructive pulmonary disease (COPD). Tobacco smoke (TS) and poly(I:C) reduce corticosteroid responsiveness by down-regulation of histone deacetylase 2 (HDAC2). Previous in vitro study suggests that TNF-α also reduces corticosteroid responsiveness. Therefore, we examined the effects of the combination of TNF-α neutralization and dexamethasone (DEX) treatment on corticosteroid insensitive inflammation.
Mice were exposed to TS for 11 days, followed by administration of poly(I:C) and DEX for 3 days, and also treated with anti-TNF-α antibody for 14 days once every other day. Mice were sacrificed 24 hours after the latest poly(I:C) and DEX administration, and bronchoalveolar lavage fluid (BALF) and lungs were collected. Inflammatory cells in BALF were measured by flow cytometry. The mRNA expression levels in lungs were measured by real-time PCR method.
TS and poly(I:C) induced marked accumulation of neutrophils in BALF and enhancement of TNF-α mRNA expression in lungs. Furthermore, TS and poly(I:C) also decreased in HDAC2 mRNA levels in lungs. The combination of anti-TNF-α antibody and DEX treatment suppressed the increases in neutrophils and TNF-α mRNA levels, even though anti-TNF-α antibody alone had no effects on these increases. In addition, the combination of anti-TNF-α antibody and DEX treatment also restored HDAC2 mRNA levels.
These results suggest that TNF-α will contribute to the decrease of corticosteroid responsiveness and the combination of TNF-α neutralization and corticosteroid treatment will provide a new therapeutic approach of COPD.
- Copyright ©the authors 2016
