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Am J Physiol Lung Cell Mol Physiol (June 6, 2003). doi:10.1152/ajplung.00001.2003
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Submitted on January 6, 2003
Accepted on May 27, 2003

Subchronic endotoxin inhalation causes persistent airway disease

David M. Brass1, Jordan D. Savov1, Stephen H. Gavett2, Najwa Haykal-Coates2, and David A. Schwartz3*

1 Department of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC, USA
2 National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA
3 Department of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC, USA; Department of Veteran's Affairs, , Durham, NC, USA

* To whom correspondence should be addressed. E-mail: david.schwartz{at}duke.edu.

The endotoxin component of organic dusts causes acute reversible airflow obstruction and airway inflammation. To test the hypothesis that endotoxin alone causes airway remodeling, we have compared the response of two inbred mouse strains to subchronic endotoxin exposure. Physiological and biological parameters were evaluated after 1 day, 5 days, or 8 weeks of exposure to endotoxin {lipopolysaccharide (LPS)} in endotoxin-sensitive (C3HeB/FeJ) and endotoxin-resistant (C3H/HeJ) mice. After 5 days or 8 weeks of LPS exposure, only C3HeB/FeJ had elevated airway hyperreactivity to inhaled methacholine. Only the C3HeB/FeJ mice had significant inflammation of the lower respiratory tract after 1 day, 5 days, or 8 weeks of LPS exposure. Stereological measurements of small, medium and large airways indicate that an 8-week exposure to LPS resulted in expansion of the submucosal area only in the C3HeB/FeJ mice. Cell proliferation as measured by BrdU incorporation contributed to the expansion of the submucosa and was only significantly elevated in C3HeB/FeJ mice actively exposed to LPS. C3HeB/FeJ mice had significantly elevated levels of interleukin 1{beta} protein in whole lung lavage after 1 day and 5 days of LPS exposure and significantly elevated protein levels of total and active transforming growth factor {beta}1 in whole lung lavage fluid after five days of LPS exposure. Our findings demonstrate that subchronic inhalation of LPS results in the development of persistent airway disease in endotoxin responsive mice.




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