The anti-inflammatory effects of PF03715455 and roflumilast on both cellular and tissue inflammation in a mouse model of COPD

Abstract

Exposure to tobacco smoke (TS) for 11d induced lung inflammation (cellular infiltration and tissue pathology) in the mouse. The effects of the inhaled p38 MAP kinase inhibitor PF-03715455 (PF-55) and the PDE4 inhibitor Roflumilast were investigated.

Methods Mice were exposed to air or TS for 11d, the lungs lavaged and inflammatory cells counted. Lungs were inflated and fixed for histopathological assessment. PF-55 (100ug/kg) was dosed intra-nasally and Roflumilast (5mg/kg) dosed orally 1h prior to each TS-exposure.

Results TS caused cellular infiltration in the lung lavage and lung pathology with increases in peri-vascular and peri-bronchiolar inflammatory cell infiltrates. Bronchiolitis, alveolitis and pneumonitis were all evident. Lung hyper-inflation, lymphoid hyperplasia and evidence of early remodeling of the bronchiolar mucosa were also seen. PF-55 inhibited the BAL neutrophilia (67%, p<0.001) and reduced incidence/severity of TS-induced lung pathology, especially the inflammatory component. Roflumilast also impacted lung inflammation, inhibiting the neutrophils recovered in BAL fluid (56%, p<0.001). However, Roflumilast had minimal effect on the TS-induced lung pathology.

Conclusion Exposure of mice to TS induced a marked lung inflammation as evidenced by increased lavage inflammatory cell infiltrates aswell as lung pathology. PF03715455 displayed efficacy against both of these endpoints, whereas Roflumilast only inhibited the changes seen in the lavage fluid. These data suggest a dissociation of BAL and lung pathology profiles which may reflect differences in overall efficacy, or differential efficacies, upon the proximal and distal lung compartments.