Attenuation of cadmium-induced liver injury in senescent male fischer 344 rats: role of Kupffer cells and inflammatory cytokines.
In the previous study we showed that senescent male Fischer 344 rats were resistant to Cd-induced hepatotoxicity compared with young-adult rats. In the present study we investigated the role of Kupffer cells and inflammatory cytokines in this effect of aging. The phagocytic activity of Kupffer cells, determined as the removal of carbon from blood, was stimulated by the administration of a hepatotoxic dose of Cd (3 mg/kg sc) in young-adult (5 months) rats but not in old (28 months) rats. Hepatic concentrations of interleukin (IL)-1beta and cytokine-induced neutrophil chemoattractant (CINC), but not of tumor necrosis factor-alpha or IL-6, were elevated in young rats treated with Cd. In old rats, however, the increase in IL-1beta produced by Cd was not statistically significant and the increase in CINC was much lower than in young-adult rats. Pretreatment with gadolinium chloride or cyclosporin A inhibited the elevations in hepatic cytokines and attenuated Cd-induced liver damage, assessed on the basis of serum alanine aminotransferase and sorbitol dehydrogenase activities. Cd-induced hepatotoxicity in the different treatment groups correlated well with hepatic levels of CINC (r = 0.98, p < 0.001) but not with those of IL-1beta. The results suggest that (1) Kupffer cell activation is essential for inflammatory liver damage from Cd, (2) IL-1beta and CINC are important mediators of the inflammatory response induced by Cd, and (3) the attenuation of Cd-induced liver injury in senescent rats is caused by an impairment in Kupffer cell activation, leading to a lower production of CINC and less inflammatory liver injury.
Yamano
T
T
Osaka City Institute of Public Health and Environmental Sciences, Osaka, Japan.
DeCicco
L A
LA
Rikans
L E
LE
D000367:Age Factors; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D002244:Carbon / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D002633:Chemotaxis / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005682:Gadolinium / Q000494:pharmacology; D018836:Inflammation Mediators / Q000502:physiology*; D007375:Interleukin-1 / Q000378:metabolism; D007728:Kupffer Cells / Q000502:physiology*; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D002104:Cadmium; D002244:Carbon; D016572:Cyclosporine; D005682:Gadolinium; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; C038958:gadolinium chloride