Lipid A-induced tolerance and hyperreactivity to hypothermia in mice.
Mice responded to lipopolysaccharide (LPS) with a dose-dependent, monophasic hypothermia reaching a maximum at 2 h postinjection. Degraded polysaccharide was not active; free lipid A, however, induced a similar pattern of hypothermia, indicating that the hypothermic principle of LPS was embedded within the lipid A component. The hypothermic response of mice to LPS was modified by prior exposure of the host to LPS. This altered reactivity was manifested by refractory periods (early and late tolerance), in which animals no longer responded with hypothermia, or a hyperreactive phase (hypersensitivity), in which hypothermic responses were greatly augmented upon LPS challenge. Thus, tolerance observed 24 h after a single injection of LPS (early tolerance) was followed, on further LPS challenge, by an enhanced hypothermic responses reaching a maximum on day 4. Further daily exposure of the animals to LPS eliminated hyperreactivity and led to the establishment of a late tolerance maximally expressed on day 8. Hyperreactivity could also be evoked on day 4 after a single injection of LPS. Mice pretreated with Salmonella S- and R-form LPS or free lipid A (Salmonella) demonstrated tolerance and hyperreactivity to both homologous and heterologous challenge. In addition, complete cross-tolerance was observed with S-form LPS derived from Shigella. It was concluded that the differential effects of LPS on host responses (tolerance and hyperreactivity) were due to lipid A.
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000209:etiology; D004361:Drug Tolerance; D005260:Female; D007035:Hypothermia / Q000139:chemically induced*; D008050:Lipid A / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011135:Polysaccharides, Bacterial / Q000494:pharmacology; D012475:Salmonella; D013045:Species Specificity
D008050:Lipid A; D008070:Lipopolysaccharides; D011135:Polysaccharides, Bacterial