title: Role of galectin-3 in acetaminophen-induced hepatotoxicity and inflammatory mediator production.
abstract: Galectin-3 (Gal-3) is a β-galactoside-binding lectin implicated in the regulation of macrophage activation and inflammatory mediator production. In the present studies, we analyzed the role of Gal-3 in liver inflammation and injury induced by acetaminophen (APAP). Treatment of wild-type (WT) mice with APAP (300 mg/kg, ip) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was associated with increased hepatic expression of Gal-3 messenger RNA and protein. Immunohistochemical analysis showed that Gal-3 was predominantly expressed by mononuclear cells infiltrating into necrotic areas. APAP-induced hepatotoxicity was reduced in Gal-3-deficient mice. This was most pronounced at 48-72 h post-APAP and correlated with decreases in APAP-induced expression of 24p3, a marker of inflammation and oxidative stress. These effects were not due to alterations in APAP metabolism or hepatic glutathione levels. The proinflammatory proteins, inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, macrophage inflammatory protein (MIP)-2, matrix metalloproteinase (MMP)-9, and MIP-3α, as well as the Gal-3 receptor (CD98), were upregulated in livers of WT mice after APAP intoxication. Loss of Gal-3 resulted in a significant reduction in expression of iNOS, MMP-9, MIP-3α, and CD98, with no effects on IL-1β. Whereas APAP-induced increases in MIP-2 were augmented at 6 h in Gal-3(-/-) mice when compared with WT mice, at 48 and 72 h, they were suppressed. Tumor necrosis factor receptor-1 (TNFR1) was also upregulated after APAP, a response dependent on Gal-3. Moreover, exaggerated APAP hepatotoxicity in mice lacking TNFR1 was associated with increased Gal-3 expression. These data demonstrate that Gal-3 is important in promoting inflammation and injury in the liver following APAP intoxication.
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Ana-Cristina
authors.initials: AC
authors.lastname: Dragomir
authors.forename: Richard
authors.initials: R
authors.lastname: Sun
authors.forename: Vladimir
authors.initials: V
authors.lastname: Mishin
authors.forename: LeRoy B
authors.initials: LB
authors.lastname: Hall
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D037502:Galectin 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D013997:Time Factors
chemical_list: D018712:Analgesics, Non-Narcotic; D037502:Galectin 3; D018836:Inflammation Mediators; C485095:Lgals3 protein, mouse; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione