Endogenous and exogenous glucocorticoids have different roles in modulating endotoxin lethality in D-galactosamine-sensitized mice.
Endotoxin sensitivity and dexamethasone protection have been assessed in mice that were adrenalectomized and also treated with D-galactosamine at the time of endotoxin challenge. Our data establish that adrenalectomy did not detectably alter the magnitude of the increased sensitivity induced by D-galactosamine alone. Furthermore, protection provided by acute exogenous glucocorticoid treatment was still demonstrable in these mice and was not influenced by chronic experimentally induced glucocorticoid deficiency. Our data confirm that the adrenalectomized mouse model of endotoxin lethality is characterized by increased sensitivity to endotoxin and establish that the magnitude of this sensitizing effect is more than 100-fold. We also show for the first time that adrenalectomy causes an appreciable kinetic shift in the endotoxic crisis and that dexamethasone, given at the time of endotoxin challenge, will significantly reverse the increased sensitivity to lethality. Our results indicate that the protective effects of corticosteroids may involve important chronic as well as acute responses. In particular, we conclude that endogenous glucocorticoid need not always increase host resistance to endotoxin, nor does such a circumstance eliminate the possibility for exogenous glucocorticoid-mediated protective effects.
Gonzalez
J C
JC
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City 66103.
Johnson
D C
DC
Morrison
D C
DC
Freudenberg
M A
MA
Galanos
C
C
Silverstein
R
R
D000315:Adrenalectomy; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000633:toxicity*; D005260:Female; D005688:Galactosamine / Q000494:pharmacology*; D005938:Glucocorticoids / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D013997:Time Factors
D004731:Endotoxins; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D005688:Galactosamine; D003907:Dexamethasone