Subchronic endotoxin inhalation causes persistent airway disease.
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 wk of exposure to endotoxin [lipopolysaccharide (LPS)] in endotoxin-sensitive (C3HeB/FeJ) and endotoxin-resistant (C3H/HeJ) mice. After 5 days or 8 wk 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 wk of LPS exposure. Stereological measurements of small, medium, and large airways indicated that an 8-wk exposure to LPS resulted in expansion of the submucosal area only in the C3HeB/FeJ mice. Cell proliferation as measured by bromodeoxyuridine 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-1beta 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-beta1 in whole lung lavage fluid after 5 days of LPS exposure. Our findings demonstrate that subchronic inhalation of LPS results in the development of persistent airway disease in endotoxin-responsive mice.
Brass
D M
DM
Pulmonary and Critical Care Medicine, Duke Univ. Medical Center, Research Dr., Rm. 277 MSRB, DUMC Box 2629, Durham, NC 27710-0001, USA.
Savov
J D
JD
Gavett
S H
SH
Haykal-Coates
N
N
Schwartz
D A
DA
D000280:Administration, Inhalation; D000818:Animals; D002455:Cell Division / Q000276:immunology; D002908:Chronic Disease; D004797:Enzyme-Linked Immunosorbent Assay; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D007375:Interleukin-1; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta