Preventive effect of neutropenia on carbon tetrachloride-induced hepatotoxicity in rats

Abstract

The preventive effect of neutropenia on carbon tetrachloride (CCl4)-induced hepatotoxicity was examined in rats. In rats treated once with CCl4 (1 ml kg(-1), i.p.), the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), indices of liver cell damage, and the hepatic activity of myeloperoxidase (MPO), an index of tissue neutrophil infiltration, increased at 6 h after the intoxication and further increased at 24 h. The liver of CCl4 -treated rats showed an increase in the concentration of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation, and decreases in superoxide dismutase (SOD) activity and reduced glutathione (GSH) concentration at 6 h after the intoxication followed by a further increase in TBARS concentration and further decreases in SOD activity and GSH concentration at 24 h with increased xanthine oxidase (XO) activity at 24 h. Neutropenic treatment with anti-rat neutrophil antiserum (2 ml kg(-1), i.p.) at 0.5 h after CCl4 intoxication attenuated the increases in serum ALT and AST activities and hepatic MPO activity and TBARS concentration and the decreases in hepatic SOD activity and GSH concentration found at 6 and 24 h after CCl4 intoxication and the increase in hepatic XO activity found at 24 h after the intoxication. This neutropenia reduced the necrotic and degenerative changes with inflammatory cell infiltration in the liver cell of CCl4 -treated rats. These results indicate that neutropenia prevents CCl4 -induced hepatotoxicity in rats by attenuating the disruption of hepatic reactive oxygen species metabolism mediated by neutrophils accumulating in the liver tissue.

Antioxidant and Hepatoprotective Effect of Swertiamarin on Carbon Tetrachloride-Induced Hepatotoxicity via the Nrf2/HO-1 Pathway

“…CCl 4 exposure generates excessive levels of nitric oxide (NO) through activation of iNOS, thus contributing to damage in hepatic tissue [20]. Hepatic injury in rats treated with CCl 4 also developed with an increase in the activity of MPO, an index of hepatic neutrophil infiltration [21]. Our results revealed that STM significantly inhibited MPO and iNOS activity consistent with decreased NO level.…”

Impact of interleukin-6 classic- and trans-signaling on liver damage and regeneration

“…Also the concentration of TBARS, as a marker for lipid peroxidation, was lower in the livers of the neutrophil depleted rats. These findings showed that oxidative liver damage was, at least partly, mediated by neutrophils [90]. The impact of IL-6 trans-signaling in neutrophil depleted animals after CCl 4 liver damage still needs to be examined.…”

Neutrophils and Intravascular Immunity in the Liver during Infection and Sterile Inflammation

“…However, overexuberant or prolonged neutrophil infiltration can exacerbate tissue injury, leading to disease. Within the liver, inappropriate inflammation in response to sterile tissue injury contributes to the pathogenesis of many noninfectious diseases, including drug-or toxin-induced liver injury, ischemia-reperfusion injury, autoimmunity, alcoholic steatohepatitis, and others (Bautista 1997;Bonder et al 2004;Jaeschke and Farhood 1991;Jaeschke, Farhood, and Smith 1990;Liu et al 2006;Ohta et al 2006). Although sterile inflammation is a well-known phenomenon, the mechanisms that initiate and regulate the innate immune response to cell death have only recently begun to unfold (Chen and Nuñez 2010;Kono and Rock 2008).…”

“…As such, overexuberant neutrophil recruitment and indiscriminant release of toxic mediators contribute fundamentally to the pathogenesis of many diseases. In particular, many acute and chronic pathologies of the liver are mediated and/or exacerbated by neutrophilic inflammation, such as sepsis and endotoxemia (Jaeschke et al 1996;Molnar et al 1997) and ischemia-reperfusion injury (Jaeschke and Farhood 1991;Jaeschke, Farhood, and Smith 1990;Martinez-Mier et al 2001), as well as alcoholic (Bautista 1997), viral (Takai et al 2005), autoimmune (Bonder et al 2004), and toxin-or drug-induced hepatitis Ohta et al 2006). Despite the central role of neutrophils in a variety of liver diseases, the molecular mechanisms that allow these cells to home to the liver, and their functions therein, are not well understood.…”