Abstract
Exposure to tobacco smoke (TS) for 4d induced a steroid-insensitive lung inflammation in mice which was exaggerated by the addition of the viral mimetic poly IC (pIC). The effects of an inhaled steroid and an inhaled p38 inhibitor on the exaggerated inflammation were examined.
Methods Mice were exposed to air or TS for 4d. Saline or pIC was administered intra-nasally and mice killed 24h after the last exposure, the lungs lavaged and cells counted. Single intra-nasal doses of vehicle, Fluticasone proprionate (FP, 0.3mg/kg) or the p38 inhibitor PF-03715455 (PF-55, 0.1mg/kg) were dosed 2h after the final challenge.
Results TS-exposure caused a significant cellular infiltration into the lung, which was not inhibited by single doses of either PF-55 or FP. In non-TS exposed mice, pIC induced an inflammation which was also not inhibited by either PF-55 or FP. Administration of pIC in addition to TS-exposure induced an exaggerated inflammatory response which was greater than the additive effect of the two stimuli, with large increases in neutrophil numbers in particular (TS ∼0.07 million, PIC ∼0.2 million, TS+PIC ∼0.6 million). The inflammation at 24h after exposure was significantly inhibited by both PF-55 (54%, p<0.0001) and FP (44%, p<0.001), in contrast to the lack of efficacy of either compound in the TS or PIC groups. However, the level of inflammation never fell below the TS-alone baseline.
Conclusions TS exposure for 4d induced a lung inflammation which was insensitive to steroid. Addition of PIC elicited a markedly enhanced inflammatory response that was sensitive to intra-nasal administration of PF-03715455 and also to FP, thus mimicking features of human COPD.
- © 2013 ERS
