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Lipooligosaccharide Inhalation Produces Dose- and Time-Dependant Lung Inflammation and Cytokine Release In Mice

Rationale: Endotoxin is a potent inflammatory agent capable of triggering asthma episodes as well as inducing organic dust toxic syndrome. Our goal was to test the inflammatory potency of one form of endotoxin (lipooligosaccharide or LOS) to establish the dose-response curve, the time course and histopathological changes in the lungs for future studies of MD-2 and TLR4 signalling. Methods: Endotoxin-responsive 6-wk old BALB/c mice were exposed to selected doses of LOS from N. meningitidis (0, 5, 10, 30, 300 and 3000 EU/mouse) by nasal aspiration. Concentrations of total and differential cells and cytokines (TNF-α , MIP-1α , IL-1β , IL-6, G-CSF, IL-17) were measured at 1, 4, 8, 16, 24 and 48 hr in bronchoalveolar lavage fluid (BAL). Results: BAL neutrophils, proinflammatory cytokines, especially TNF-α , MIP-1α , IL-1β , IL-6 and histopathological changes in the lungs clearly showed a dose-response relationship with increasing doses producing increased inflammation and cytokine concentrations. Time-course studies demonstrated maximal neutrophilia in BAL at 24 hours followed by histopathological changes in the lungs. Assay of BAL supernatant for TNF-α and MIP-1α concentration showed significant increases compared to controls 4 hr after LOS exposure. After 8 hr, their concentration began to decline toward baseline. Conclusions: We characterized the early inflammatory events associated with nasal aspiration of LOS. A similar pattern of cytokine release was shown after aspiration of 30 and 300 EU/mouse. The dose response and time course of LOS response now make possible more detailed studies of the mechanism of proinflammatory cytokine signaling and neutrophil recruitment in the lungs. Funded By: NIH P30 ES05605-15

endotoxin; N. meningitidis; proinflammatory cytokines; lung

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