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 challenge. In preliminary studies, we found that these LPS antagonists did not act as agonists in vitro (THP-1 cells) or in vivo (after intratracheal instillation of 10 μg) and that these compounds (at least 1 μg/ml) effectively antagonized the release of tumor necrosis factor-α by LPS-stimulated THP-1 cells. Pretreatment of mice with 10 μg of either 1044 or 1287 resulted in a decrease in the LPS-induced airway hyperreactivity. Moreover, pretreatment of mice with 10 μg of 975, 1044, or 1287 resulted in significant reductions in LPS-induced lung lavage fluid concentrations of total cells, neutrophils, and specific proinflammatory cytokines compared with mice pretreated with sterile saline. Using residual oil fly ash to induce airway inflammation, we found that the action of the LPS antagonists was specific to LPS-induced airway disease. These results suggest that LPS antagonists may be an effective and potentially safe treatment for endotoxin-induced airway disease.