TUMOR-NECROSIS-FACTOR CAUSES BRONCHIAL HYPERRESPONSIVENESS IN RATS

We have previously reported that exposure of rats to aerosolized endotoxin (LPS) causes a transient, dose-dependent increase in bronchial responsiveness (BR) to 5 hydroxytryptamine (5HT), 90 min after exposure. In the present study we examined whether LPS induces the release of tumor necrosis factor (TNF) in the airways and whether TNF contributes to the increase in BR. After 90 min following exposure to aerosolized LPS, at a concentration of 1 or 10-mu-g/ml, TNF concentrations in bronchoalveolar lavage (BAL) fluid were 17.9 +/- 6.9 and 80.5 +/- 7.8 U/ml, respectively. No TNF was detected in BAL fluid of saline-exposed animals. At 90 min after exposure to aerosolized recombinant human TNF (rhTNF) (1-mu-g/ml) an increase in BR was observed: the provocative concentration of 5HT causing a 50% increase in lung resistance (PC50R(L) 5HT) was 2.7 +/- 0.4 versus 4.4 +/- 0.3-mu-g/kg in saline-exposed animals (p < 0.01). Pretreatment with anti-TNF antibodies 30 min before LPS exposure significantly diminished the increase in BR: PC50R(L) 5HT was 2.3 +/- 0.4 versus 1.2 +/- 0.5-mu-g/kg in control pretreated LPS-exposed rats (p < 0.01). Exposure to aerosolized TNF also induced a significant influx of neutrophils in BAL fluid (12.1 +/- 3.7 versus 1.7 +/- 0.4% in saline-exposed animals) (p < 0.01). The LPS-induced neutrophil influx in BAL fluid was partly inhibited by pretreatment with anti-TNF antibodies (55.2 +/- 5.1 versus 76.0 +/- 3.9%) (p < 0.01). We conclude that TNF causes bronchial hyperresponsiveness and airway inflammation. Exposure to aerosolized LPS induces local release of TNF, which accounts at least partly for the LPS-induced hyperresponsiveness and airway inflammation.