title: Toll-like receptor 4 blocker as potential therapy for acetaminophen-induced organ failure in mice.
abstract: Acetaminophen (APAP, 4-hydroxyacetanilide) is the most common cause of acute liver failure in the United States. In addition to exhibiting hepatotoxicity, APAP exerts a nephrotoxic effect may be independent of the induced liver damage. Toll-like receptors (TLRs) have been suggested as a potential class of novel therapeutic targets. The aim of the present study was to investigate the potential of the TLR-4 blocker TAK-242 in the prevention of APAP-induced hepato-renal failure. Four groups of C57BL mice were studied: Vehicle-treated/control (VEH), APAP-treated (APAP), N-acetyl cysteine (NAC)-pretreated plus APAP (APAP + NAC) and TAK-242-pretreated plus APAP (APAP + TAK) groups. Mice were clinically assessed then perfused 4 h later. Liver and kidney tissues were collected and examined histologically using basic hematoxylin and eosin staining to detect signs of necrosis and inflammation. Plasma samples were collected to measure the levels of alanine transaminase, aspartate transaminase and serum creatinine. In addition, liver and kidney tissues were assayed to determine the levels of reduced glutathione. The results of the present study indicate the potential role of TLR-4 in APAP-induced organ toxicity. In the APAP + TAK and APAP + NAC groups, histopathological examination indicated that pretreatment with TAK-242 or NAC afforded protection against APAP-induced injury. However, this protective effect was more clinically evident in the APAP + TAK group compared with the APAP + NAC group. The various biochemical parameters (serum enzymes and reduced glutathione) revealed no significant protection in either of the pretreated groups. Therefore, the present study indicated that the TLR-4 blocker had protective effects against acute APAP toxicity in liver and kidney tissues. These effects were identified clinically, histologically and biochemically. Furthermore, the TLR-4 blocker TAK-242 exhibited antioxidant properties in addition to anti-inflammatory effects.
authors.affiliation: Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt ; Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Salama
authors.affiliation: Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elgamal
authors.affiliation: Mansoura-Manchester Programme, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Azza
authors.initials: A
authors.lastname: Abdelaziz
authors.affiliation: Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Moataz
authors.initials: M
authors.lastname: Ellithy
authors.affiliation: Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Dina
authors.initials: D
authors.lastname: Magdy
authors.affiliation: Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Lina
authors.initials: L
authors.lastname: Ali
authors.affiliation: Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Emad
authors.initials: E
authors.lastname: Fekry
authors.affiliation: Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Zinab
authors.initials: Z
authors.lastname: Mohsen
authors.affiliation: Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Mariam
authors.initials: M
authors.lastname: Mostafa
authors.affiliation: Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Hoda
authors.initials: H
authors.lastname: Elgamal
authors.affiliation: Urology and Nephrology Center, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Hussein
authors.initials: H
authors.lastname: Sheashaa
authors.affiliation: Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt ; Urology and Nephrology Center, Faculty of Medicine, Mansoura University, Mansoura 36511, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Sobh
keywords: acetaminophen; hepatotoxicity; nephrotoxicity; toll-like receptor 4