Effect of Theophylline on Endotoxin and Tumor Necrosis Factor Induced Airway Changes in an in vivo Animal Model

We have previously reported that exposure to aerosolized endotoxin causes bronchial hyperresponsiveness in rats. This is at least partly due to secondary release of tumor necrosis factor (TNF). In this study, we evaluated the effect of pretreatment with aminophylline on these lipopolysaccharide-induced airway changes. Compared to placebo-pretreated animals aminophylline (20 mg/kg i.p.) significantly inhibited the lipopolysaccharide-induced increase in responsiveness without influencing neutrophil counts or TNF levels in bronchoalveolar lavage fluid. In a second part of the study, aminophylline- or placebo-pretreated rats were exposed to aerosolized recombinant human TNF. Compared to saline-exposed animals, TNF caused a significant increase in 5-hydroxytryptamine responsiveness which was inhibited by pretreatment with aminophylline. We conclude that the attenuating effect of aminophylline on lipopolysaccharide-induced airway hyperresponsiveness is not due to inhibition of TNF release, but could be explained by its inhibitory effect on TNF-induced hyperresponsiveness.