Lipid A-induced tolerance and hyperreactivity to hypothermia in mice

Abstract

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.

Inverse relationship between the susceptibility of lipopolysaccharide (lipid A)-pretreated mice to the hypothermic and lethal effect of lipopolysaccharide

“…Thus, tolerance to LPS lethality induced by 13 daily LPS injections was also due to lipid A. DISCUSSION In a recent report (20) it was found that hypothermic tolerance (early and late) and hyperreactivity to LPS in mice, induced by LPS pretreatment, was due to the lipid A component. The results of the present investigations, therefore, complement these previous findings by demonstrating a lipid A-inducible tolerance and hyperreactivity to LPS lethality in mice.…”

“…Induction oftolerance to Re LPS lethality with Re LPS and free lipid A (day 14). In a previous paper (20) we reported a lipid A-induced late tolerance to S. minnesota Re LPS hypothermia occurring on day 12 after daily injections of LPS or free lipid A (MHD = 1,000 Ag in both cases compared to 10 Mug on day 0).…”

“…DAY 0 £ 500 pg (10) o 100 pg (20) a 10 pg 20,0.2ml PBS (30) o 0.1 pg 10 Induction of hyperreactivity to S. minnesota Re LPS lethality in S. minnesota Re LPS-pretreated mice. Groups of 10 to 30 NMRI mice were pretreated on day 0 with PBS or graded doses of S. minnesota Re LPS.…”

“…Recently (20), we described a model in mice where changes in reactivity to lipopolysaccharide (LPS) hypothermia were induced after single or multiple injections of LPS or free lipid A. Although mice responded to LPS on day 0 with hypothermia, they showed early hypothermic tolerance when challenged on day 1, hypothermic hyperreactivity when challenged on day 4, and a late hypothermic tolerance when challenged on day 8 after daily LPS injections. Reciprocal cross-tests with smooth (S)-and rough (R)-form LPS, as well as with free lipid A, showed that both phases of tolerance, as well as hyperreactivity, were due to the lipid A component (20).…”

Biochemistry and cell biology of bacterial endotoxins

“…production of cytokines or septic symptoms, whereas the second exposure to LPS only leads to a minimal or no response. This phenomenon is observed in vitro as well as ex vivo [199,200] and is well reviewed recently [201]. Several terms are used for this phenomenon: desensitization, refractoriness, hyporesponsiveness, adaption and tolerance.…”