Simvastatin protects against cholestasis‐induced liver injury

Abstract

Background: Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. The aim of this study was to evaluate the effect of simvastatin on cholestasis-induced liver inflammation and tissue damage. Experimental approach: C57BL/6 mice were treated with simvastatin (0.02 and 0.2 mg·kg -1 ) and vehicle before and after undergoing bile duct ligation (BDL) for 12 h. Leukocyte recruitment and microvascular perfusion in the liver were analysed using intravital fluorescence microscopy. CXC chemokines in the liver were determined by enzyme-linked immunosorbent assay. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of myeloperoxidase (MPO) were also determined. Key results: Administration of 0.2 mg·kg -1 simvastatin decreased ALT and AST by 87% and 83%, respectively, in BDL mice. This dose of simvastatin reduced hepatic formation of CXC chemokines by 37-82% and restored sinusoidal perfusion in cholestatic animals. Moreover, BDL-induced leukocyte adhesion in sinusoids and postsinusoidal venules, as well as MPO levels in the liver, was significantly reduced by simvastatin. Notably, administration of 0.2 mg·kg -1 simvastatin 2 h after BDL induction also decreased cholestatic liver injury and inflammation. Conclusions and implications:These findings show that simvastatin protects against BDL-induced liver injury. The hepatoprotective effect of simvastatin is mediated, at least in part, by reduced formation of CXC chemokines and leukocyte recruitment. Thus, our novel data suggest that the use of statins may be an effective strategy to protect against the hepatic injury associated with obstructive jaundice.

Effect of rosuvastatin on cholestasis‐induced hepatic injury in rat livers

“…These inflammatory signs were improved by the administration of RO. Our results are in accordance with previous findings concerning other statins such as fluvastatin and simvastatin where it was proved that these statins, respectively, decreased expression of the transcription nuclear factor kappa beta (activated by inflammation) and reduced hepatic formation of CXC chemokines induced by the BDL model [39,40].…”

Multidrug donor preconditioning prevents cold liver preservation and reperfusion injury

“…Statins have been shown to suppress inflammation and proliferation in vascular endothelial and smooth muscle cells [8,39] and to reduce I/R injury in the liver [8] and the kidney [40]. Of interest, the pleiotropic actions of statins are not related to its lipid-lowering mechanism but rather caused by their anti-oxidative properties [17,41], their inhibitory action on leukocyte adhesion [42,43], and their modulatory function on the microcirculation [42,44]. These statin actions may have contributed to the prevention of I/R injury observed in the present study after MDDP application.…”

Deteriorating effect of fluvastatin on the cholestatic liver injury induced by bile duct ligation in rats

“…Statins are widely used for lowering hypercholesterolemia, but increase in the evidence of their anti-inflammatory effects could extend the spectrum of their therapeutic usage. The sporadic studies have documented statins to reduce the development of cholestatic liver injury (Demirbilek et al 2007;Dold et al 2009;Awad and Kamel 2010). Contrary to these findings statins have a potential for adverse effects that could be mediated by induction of mitochondrial dysfunction (Velho et al 2006;Nadanaciva et al 2007;Hattori et al 2009;Lee et al 2010).…”

“…Protective effects of fluvastatin (Demirbilek et al 2007), simvastatin (Dold et al 2009) and rosuvastatin (Awad and Kamel 2010) have been described. The effect of simvastatin was studied in mice ligated for 12 hours, rosuvastatin and fluvastatin were administered to Sprague-Dawley rats starting three days after BDL.…”