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This Article Full Text Full Text (PDF) All Versions of this Article: 289/2/L329    most recent 00014.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Savov, J. D. Articles by Schwartz, D. A. Search for Related Content PubMed PubMed Citation Articles by Savov, J. D. Articles by Schwartz, D. A.

Toll-like receptor 4 antagonist (E5564) prevents the chronic airway response to inhaled lipopolysaccharide

¹Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, and ²Veterans Affairs Medical Center, Durham, North Carolina

Submitted 11 January 2005 ; accepted in final form 11 April 2005

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 µg 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 µg of E5564 intratracheally did not cause any measurable toxicity. Therefore, in a chronic experiment, mice were treated with either E5564 (50 µg) or vehicle three times weekly for 5 wk and simultaneously daily exposed to either LPS (4.65 ± 0.30 µg/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.

endotoxin; asthma; airway inflammation; airway remodeling; airway pressure-time index; lipid A

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