Glucocorticoid and/or glucocorticoid antagonist effects in inflammatory disease-susceptible Lewis rats and inflammatory disease-resistant Fischer rats.
Lewis (LEW/N) and Fischer (F344) rats are inbred strains that respond antithetically to administration of several inflammatory stimuli. Thus, in response to streptococcal cell wall-derived peptidoglycan/polysaccharide, 6-week-old female Lewis rats develop acute and chronic polyarthritis, whereas age- and sex-matched Fischer rats are arthritis-resistant. The susceptibility of Lewis rats to development of chronic severe inflammatory disease has been attributed to their inability to appropriately activate their hypothalamic-pituitary-adrenal axis in response to inflammatory stimuli, leading to a functional glucocorticoid deficiency. To investigate whether the acute neurogenic inflammatory response was also different in the two strains, we studied the air-pouch model of carrageenin-induced neurogenic inflammation in adult male Lewis and Fischer rats. Both the volume and the leukocyte concentration of the inflammatory exudate were significantly higher in Lewis than in Fischer rats, suggesting that the known differences in the handling of chronic inflammation between the two strains pertain to the acute neurogenic type of inflammation as well. To confirm that glucocorticoids play a major role in the differential response of the two strains to this inflammatory stimulus, we administered graded doses of the glucocorticoid agonist dexamethasone or antagonist RU 486 to both strains and examined their responses to concomitantly administered carrageenin. RU 486 increased, whereas dexamethasone decreased, the inflammatory response of Fischer and Lewis rats, respectively, to approach the magnitude of each other's natural response, suggesting that glucocorticoids are involved in this phenomenon as well. To rule out any differences in end-organ sensitivity to glucocorticoids between the two strains, we evaluated dose-response relations of whole body, thymus, spleen, and adrenal weights after 1 week daily administration of graded doses of dexamethasone. We found similar ED50 for both Lewis and Fischer rats. We conclude that the differences in the susceptibility to acute, carrageenin-induced, neurogenic inflammation between the LEW/N and F344 rat strains are similar to those of chronic inflammatory responses in these strains and likewise glucocorticoid-dependent. No apparent major differences exist in the sensitivity of target tissues to exogenous glucocorticoids between Lewis and Fischer rats.
Karalis
K
K
Developmental Endocrinology Branch, National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Crofford
L
L
Wilder
R L
RL
Chrousos
G P
GP
D000311:Adrenal Glands / Q000033:anatomy & histology; D000818:Animals; D001168:Arthritis / Q000139:chemically induced; D002351:Carrageenan; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D004198:Disease Susceptibility; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000209:etiology*; D008297:Male; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D010457:Peptidoglycan; D011135:Polysaccharides, Bacterial; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013154:Spleen / Q000033:anatomy & histology; D013291:Streptococcus / Q000737:chemistry; D013950:Thymus Gland / Q000033:anatomy & histology
D010457:Peptidoglycan; D011135:Polysaccharides, Bacterial; D015735:Mifepristone; D003907:Dexamethasone; D002351:Carrageenan