Volume 10 Supplement 1

2nd Cross Company Respiratory Symposium

Open Access

Steroid-insensitive tobacco smoke-induced lung inflammation models in the mouse

  • V Russell1,
  • D Spicer1,
  • P Woodman1,
  • A Connolly1 and
  • A Young1
Journal of Inflammation201310(Suppl 1):P31

https://doi.org/10.1186/1476-9255-10-S1-P31

Published: 14 August 2013

Background

The effects of oral and inhaled steroids were investigated in murine models of lung inflammation induced by 4 or 11 days of exposure to tobacco smoke (TS). The effects were compared to other anti-inflammatory compounds.

Methods

Female mice were exposed daily to TS for 4 or 11 days. Control animals were exposed to air. Mice were killed 24hrs after the last TS-exposure, lungs lavaged and prepared for histological assessment. Steroids were given orally (dexamethasone (DEX) 300ug/kg; budesonide (BUD) 10mg/kg, 1hr prior to, and 6hrs after each TS exposure) or intra-nasally (fluticasone proprionate (FP), DEX , BUD, beclomethasone, mometasone and ciclesonide dosed at 100-500ug/kg 1hr prior to each TS-exposure). Steroid efficacy was also investigated in a mouse LPS lung inflammation model.

Results

TS-exposure induced a cellular infiltration into the lungs which was reproducible across more than 50 studies. The main cell types in the lavage were macrophages and neutrophils. Histopathological assessment showed a progressive increase in pathology from 4 days of exposure (predominantly vasculitis, alveolar congestion and epithelial hyperplasia) to 11 days of exposure (bronchiolitis, pneumonitis, bronchiolar degeneration, bronchial wall remodelling). Steroids dosed via the oral and intra-nasal routes failed to inhibit this inflammation in both models (maximal inhibition of TS-induced inflammation 14%, all p>0.05 compared to controls), although they caused body weight loss, confirming systemic availability and activity. The doses of steroids used in the TS studies all showed significant efficacy in a mouse LPS-model (all >65% inhibition, p<0.05), confirming that the TS-exposure model was refractory to steroids. The TS-induced inflammation was reduced by PDE4 inhibitors such as Roflumilast when given either i.n. (total cells 50%, neutrophils 60%, both p<0.05) or orally (total cells 50%, neutrophils 66%, both p<0.05). Inhibitors of p38 MAP kinase were effective when given orally (BIRB796: total cells 42%, neutrophils 55% inhibition, both p<0.05) or i.n. (PF03715455: total cells 50%, neutrophils 61% inhibition, both p<0.05). These inhibitory effects were confirmed in multiple studies where steroids continued to lack efficacy.

Conclusions

TS-exposure for up to 11 days induced lung inflammation. The inflammatory response was not affected by doses of steroids which were highly efficacious in a mouse LPS model. The steroid insensitive effects were robust and reproducible across multiple studies. The TS-induced inflammation was inhibited by a clinically used PDE4 inhibitor (Roflumilast) and p38 inhibitors such as PF03715455, which is currently in phase I clinical development.

Authors’ Affiliations

(1)
Argenta Discovery

Copyright

© Russell et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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