title: Exacerbation of acetaminophen-induced disturbances of liver sinusoidal endothelial cells in the absence of Kupffer cells in mice.
abstract: Although there has been considerable research in terms of liver sinusoidal endothelial cells (LSECs) and hepatic resident macrophages (Kupffer cells, KCs) during the overall pathogenesis of acetaminophen (APAP)-induced liver injury, little is known about their potential interaction and relationship. In the present study, employing the use of liposome/clodronate to deplete KCs, we were able to confirm the previously demonstrated hepato-protective role for KCs. Such a protective role may be mediated, in part, via regulation of LSEC homeostasis and integrity. The further aggravation of APAP-induced LSEC disturbance upon depletion of KCs correlated with increased hepatic vascular permeability and red blood cell accumulation. The depletion of KCs prior to APAP challenge also resulted in the increased expression of cellular adhesion molecules on LSECs. Such increased disturbance in the hepatic endothelial may represent a contributing factor in the exacerbation of APAP-induced liver injury in the absence of KCs. However, these disturbances may also be a result of the increased hepatic damage, and as such, does not rule out the potential for additional mechanisms of KC-mediated hepato-protection during the pathogenesis of APAP-induced hepatotoxicity.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Denver, CO, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Holt
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ju
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007728:Kupffer Cells / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000082:Acetaminophen