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

Inhal Toxicol. 2000 Mar;12(3):225-43. doi: 10.1080/08958370050165085.


Lipopolysaccharide (LPS) is a component of the gram-negative bacterial cell wall that is known to activate inflammatory cells and enhance the production of inflammatory mediators in the lung. As it is a ubiquitous compound, inhalation 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 development 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 Fisher 344 rats and C57Bl/6J mice. Animals were exposed to low-dose (predicted lung deposition approximately 20 ng in rats and approximately 5 ng in mice) LPS aerosols for 10 min on 3 consecutive days; on day 4, a high dose (rats approximately 200 ng; mice approximately 25 ng) was delivered. Another group of animals received only the high LPS dose on day 4, whereas controls were unexposed. Twenty-four hours after the last exposure, cellular and inflammatory parameters in bronchoalveolar lavage (BAL) were determined. An adaptive response was found in both rats and mice. Adapted animals showed significantly fewer BAL neutrophils compared to nonadapted ones; there was also a significantly lower release of oxidants from phorbol methyl ester-stimulated BAL cells from adapted compared to nonadapted animals, which, in turn, showed a greater response than controls. Furthermore, studies in old animals (21 mo of age) showed that adaptation also occurs in this age group. The adaptive response is clear in old mice; in rats, there is greater variability in the response, but an adaptive trend is apparent. Therefore, we have demonstrated that inhaled low-dose LPS can induce adaptation to subsequent higher doses, much as has been shown for other toxicants that induce oxidative lung injury.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Inhalation
  • Aging / physiology*
  • Animals
  • Bronchoalveolar Lavage Fluid / cytology
  • Cell Count
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Immune Tolerance / drug effects*
  • Immune Tolerance / immunology
  • Lipopolysaccharides / administration & dosage
  • Lipopolysaccharides / toxicity*
  • Lung / drug effects
  • Lung / metabolism
  • Male
  • Metallothionein / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Pseudomonas aeruginosa*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred F344
  • Respiratory Burst / drug effects
  • Specific Pathogen-Free Organisms
  • Tetradecanoylphorbol Acetate / pharmacology


  • Cytokines
  • Lipopolysaccharides
  • RNA, Messenger
  • Metallothionein
  • Tetradecanoylphorbol Acetate