Abstract

Epidemiological evidence suggests that APAP may play a role in the pathogenesis of asthma, likely through pro-oxidant mechanisms. However, no studies have investigated the direct effects of APAP on the development of allergic inflammation. To determine the likelihood of a causal relationship between APAP and asthma pathogenesis, we explored the effects of APAP on inflammatory responses in a murine house dust mite (HDM) model of allergic airway disease. We hypothesized that APAP would enhance the development of HDM induced allergic inflammation. The HDM model consisted of once daily intranasal instillations for up to two weeks with APAP or vehicle administration 1 hour prior to HDM during either week 1 or 2. Primary assessment of inflammation included bronchoalveolar lavage (BAL), cytokine expression in lung tissue, and histopathology. Contrary to our hypothesis, the effects of HDM treatment were substantially diminished in APAP treated groups compared to controls. APAP treated groups had markedly reduced airway inflammation: including decreased inflammatory cells in the BAL fluid, lower cytokine expression in lung tissue, and less perivascular and peribronchiolar immune cell infiltration. The anti-inflammatory effect of APAP was not abrogated by an inhibitor of cytochrome P450 metabolism, suggesting that the effect was due to the parent compound or a non-CYP450 generated metabolite. Taken together, our studies do not support the biological plausibility of the "APAP hypothesis" that APAP use may contribute to the causation of asthma. Importantly, they suggest the mechanism by which APAP modulates airway inflammation may provide novel therapeutic targets for asthma.