Search

Chronic lipopolysaccharide (LPS) inhalation in rodents recapitulates many classic features of chronic obstructive pulmonary disease seen in humans, including airways hyperresponsiveness, neutrophilic inflammation, cytokine production in the lung, and small airways remodeling. CD14-deficient mice (C57BL/6(CD14-/-)) have an altered response to systemic LPS, and yet the role of CD14 in the response to inhaled LPS has not been defined. We observed that C57BL/6(CD14-/-) mice demonstrate no discernable physiological or inflammatory response to a single LPS inhalation challenge. However, the physiological (airways hyperresponsiveness) and inflammatory (presence of neutrophils and TNF-alpha in whole lung lavage fluid) responsiveness to inhaled LPS in C57BL/6(CD14-/-) mice was restored by instilling soluble CD14 intratracheally. Intratracheal instillation of wild-type macrophages into C57BL/6(CD14-/-) mice restored neutrophilic inflammation only and failed to restore airways hyperresponsiveness or TNF-alpha protein in whole lung lavage. These findings demonstrate that CD14 is critical to LPS-induced airway disease and that macrophage CD14 is sufficient to initiate neutrophil recruitment into the airways but that CD14 may need to interact with other cell types as well for the development of airways hyperresponsiveness and for cytokine production.

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.