Inhibition of LPS-induced airway hyperresponsiveness and airway inflammation by LPS antagonists

To determine whether the inflammatory effects of inhaled endotoxin could be prevented, we pretreated mice with synthetic competitive antagonists (975, 1044, and 1287) for lipopolysaccharide (LPS) before a LPS inhalation chall enge. In preliminary studies, we found that these LPS antagonists did not a ct as agonists in vitro (THP-1 cells) or in vivo (after intratracheal insti llation of 10 mug) and that these compounds (at least 1 mug/ml) effectively antagonized the release of tumor necrosis factor-alpha by LPS-stimulated T HP-1 cells. Pretreatment of mice with 10 mg of either 1044 or 1287 resulted in a decrease in the LPS-induced airway hyperreactivity. Moreover, pretrea tment of mice with 10 mg of 975, 1044, or 1287 resulted in significant redu ctions in LPS-induced lung lavage fluid concentrations of total cells, neut rophils, and specific proinflammatory cytokines compared with mice pretreat ed with sterile saline. Using residual oil fly ash to induce airway inflamm ation, we found that the action of the LPS antagonists was specific to LPS- induced airway disease. These results suggest that LPS antagonists may be a n effective and potentially safe treatment for endotoxin-induced airway dis ease.