Induction of adaptation to inhaled lipopolysaccharide in young and old rats and mice

Lipopolysaccharide (LPS) is a component of the gram-negative bacterial cell wall that is known to activate inflammatory cells and enhance the producti on of inflammatory mediators in the lung. As it is a ubiquitous compound, i nhalation exposure is highly likely in the human environment. Adaptation is a phenomenon by which a previous exposure results in improved survival or reduced injury as compared to a single exposure alone. We hypothesized that the basic proinflammatory effects of LPS in the lung could result in the d evelopment of adaptation in animals. Based on evidence of age- and species- related differences in lung injury, we used an acute lung injury model with inhaled LPS to compare the development of adaptation in young and old Fish er 344 rats and C57B1/61 mice; Animals were exposed to low-dose (predicted lung deposition similar to 20 ng in rats and similar to 5 ng in mice) LPS a erosols For 10 min on 3 consecutive days; on day 4, a high dose (rate simil ar to 200 ng; mice similar to 25 ng) was delivered. Another group of animal s received only the high LPS dose on day 4, whereas controls were unexposed Twenty-four hours after the last exposure, cellular and inflammatory param eters in bronchoalveolar lavage (BAL) were determined. An adaptive response was found in both rats and mice. Adapted animals showed significantly fewe r BAL neutrophils compared to nonadapted ones; there was also a significant ly lower release of oxidants from phorbol methyl ester-stimulated BAL cells from adapted compared to nonadapted animals, which, in turn, showed a grea ter response than controls. Furthermore, studies in old animals (21 mo of a ge) showed that adaptation also occurs in this age group. The adaptive resp onse is clear in old mice: in rats, there is greater variability in the res ponse, but an adaptive trend ir apparent. Therefore, we have demonstrated t hat inhaled low-dose LPS can induce adaptation to subsequent higher doses, much as has been shown for other toxicants that induce oxidative lung injur y.