Acta pharmacologica Sinica · 2012
The dual role of osteopontin in acetaminophen hepatotoxicity.
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He Chun-yan, Liang Bei-bei, Fan Xiao-yu, Cao Lei, Chen Rui, Guo Ya-jun, Zhao Jian
Аннотация
AIM: Osteopontin (OPN), a multifunctional protein, has been reported to be protoxicant in acetaminophen hepatotoxicity. In this study, the mechanisms underlying the detrimental role of OPN in acetaminophen toxicity were explored.
METHODS: Male C57BL/6 (wild-type, WT) and OPN(-/-) mice were administered with acetaminophen (500 mg/kg, ip). After the treatment, serum transaminase (ALT), as well as OPN expression, histology changes, oxidative stress and inflammation response in liver tissue were studied. Freshly isolated hepatocytes of WT and OPN(-/-) mice were prepared.
RESULTS: Acetaminophen administration significantly increased OPN protein level in livers of WT mice. OPN expression was mainly localized in hepatic macrophages 6 h after the administration. In OPN(-/-) mice, acetaminophen-induced serum ALT release was reduced, but the centrilobular hepatic necrosis was increased. In OPN(-/-) mice, the expression of CYP2E1 and CYP1A2 in livers was significantly increased; GSH depletion and lipid peroxidation in livers were enhanced. On the other hand, OPN(-/-) mice exhibited less macrophage and neutrophil infiltration and reduced expression of proinflammatory cytokines TNF-α and IL-1α in livers. An anti-OPN neutralizing antibody significantly reduced acetaminophen-induced serum ALT level and inflammatory infiltration in livers of WT mice.
CONCLUSION: OPN plays a dual role in acetaminophen toxicity: OPN in hepatocytes inhibits acetaminophen metabolism, while OPN in macrophages enhances acetaminophen toxicity via recruitment of inflammatory cells and production of proinflammatory cytokines.
METHODS: Male C57BL/6 (wild-type, WT) and OPN(-/-) mice were administered with acetaminophen (500 mg/kg, ip). After the treatment, serum transaminase (ALT), as well as OPN expression, histology changes, oxidative stress and inflammation response in liver tissue were studied. Freshly isolated hepatocytes of WT and OPN(-/-) mice were prepared.
RESULTS: Acetaminophen administration significantly increased OPN protein level in livers of WT mice. OPN expression was mainly localized in hepatic macrophages 6 h after the administration. In OPN(-/-) mice, acetaminophen-induced serum ALT release was reduced, but the centrilobular hepatic necrosis was increased. In OPN(-/-) mice, the expression of CYP2E1 and CYP1A2 in livers was significantly increased; GSH depletion and lipid peroxidation in livers were enhanced. On the other hand, OPN(-/-) mice exhibited less macrophage and neutrophil infiltration and reduced expression of proinflammatory cytokines TNF-α and IL-1α in livers. An anti-OPN neutralizing antibody significantly reduced acetaminophen-induced serum ALT level and inflammatory infiltration in livers of WT mice.
CONCLUSION: OPN plays a dual role in acetaminophen toxicity: OPN in hepatocytes inhibits acetaminophen metabolism, while OPN in macrophages enhances acetaminophen toxicity via recruitment of inflammatory cells and production of proinflammatory cytokines.