Although chronic inhalation of
endotoxin or
lipopolysaccharide (LPS) causes all of the classic features of
asthma, including airway hyperreactivity, airway
inflammation, and
airway remodeling, the mechanisms involved in this process are not clearly understood. The objective of this study was to determine whether intratracheal treatment with LPS antagonist (
E5564, a
lipid A analog) prevented the development of chronic
endotoxin-induced airway disease in a mouse model of environmental airway disease. Pretreatment with 10 and 100 microg of
E5564 was found to inhibit the airway response (hyperreactivity and
inflammation) for up to 48 h after the administration of the compound. Repeated dosing with 50 microg of
E5564 intratracheally did not cause any measurable toxicity. Therefore, in a chronic experiment, mice were treated with either
E5564 (50 microg) or vehicle three times weekly for 5 wk and simultaneously daily exposed to either LPS (4.65 +/- 0.30 microg/m3) or saline
aerosol.
E5564 was effective in decreasing the airway hyperreactivity to
methacholine, the air space neutrophilia, the
interleukin-6 in the lung lavage fluid, and the neutrophil infiltration of the airways 36 h after 5 wk of LPS inhalation. Less
collagen deposition was observed in the airways of E5564-treated mice compared with vehicle-treated mice after a 4-wk recovery period. Our results indicate that
E5564, a
Toll-like receptor 4 antagonist, minimizes the physiological and
biological effects of chronic LPS inhalation, suggesting a therapeutic role for competitive LPS antagonists in preventing or reducing
endotoxin-induced environmental airway disease.