Effect of Pretreatment with FTY720 and Cyclosporin on Ischaemia-Reperfusion Injury of the Liver in Rats

Abstract

The effect of pretreatment with FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride) or cyclosporin, or both, on neutrophil-mediated injury has been examined by use of a rat model of transient clamping of hepatic flow. Pretreatment with FTY720 alone or with cyclosporin induced a marked reduction of circulatory lymphocytes, whereas the use of these drugs in combination was very effective at suppressing the elevation of the number of peripheral polymorphonuclear neutrophils (PMN) after reperfusion. Pretreatment with cyclosporin, with or without FTY720, significantly reduced hepatic damage, whereas FTY720 alone tended to prolong hepatic damage. Pretreatment of cyclosporin alone, but not in combination with FTY720, significantly reduced the accumulation of PMN and led to lower myeloperoxidase levels in the damaged liver. In conclusion, pretreatment with cyclosporin, with or without FTY720, reduced hepatic damage after warm ischaemia-reperfusion, whereas pretreatment with FTY720 alone tended to prolong this damage.

Mitochondrial Ca2+ and regulation of the permeability transition pore

“…Indeed, inhibiting the mPTP in the heart can prevent up to 50% of the final infarct size, (Yellon and Hausenloy 2007). The mPTP’s role in I/R is also evident in the brain, liver, intestine, and kidney (Shiga et al 1992; Konukoglu et al 1998; Soda et al 1999; Mizuta et al 1999; Saxton et al 2002; Feldkamp et al 2009; Park et al 2011; Gill et al 2012; Cho et al 2013). An abundance of evidence indicates that the mPTP plays a critical role in I/R injury, which can be prevented using pharmacological means, or by pre- and post-conditioning (periods of brief ischemia that prevents Ca 2+ overload through transient mPTP opening and reperfusion that desensitizes the mPTP of the ischemic tissue (Javadov et al 2003; Hausenloy et al 2004; Feng et al 2005; Clarke et al 2008; Gomez et al 2008; Inserte et al 2009).…”

Cyclophilin D as a Drug Target

“…A considerable number of studies report protection by CsA against ischemia/reperfusion damage in the liver, as evaluated by a variety of parameters in rats [82][83][84][85][86], including prevention of parenchymal apoptosis [87], and dogs [88]. In one study in isolated perfused rat liver, a role for MPT inhibition in the protective effect of CsA is considered [89].…”

Effect of ONO-4057 and tacrolimus on ischemia-reperfusioninjury of the liver

“…We investigated the effect of the LTB4 receptor antagonist, ONO-4057, on hepatic ischemia-reperfusion injury to determine whether they affect neutrophil infiltration into the liver and attenuate neutrophil-induced postischemic injury. Recent reports have also shown that some immunosuppressive drugs protect or attenuate the neutrophil-mediated ischemia-reperfusion injury in various organs (liver, small intestine, kidney, and heart) [5,14,15] . As tacrolimus has variable effects [16] , we tested the effect of a combination of ONO-4057 with tacrolimus.…”

“…These cells are markedly activated when the ischemically damaged liver is transplanted. Experimental efforts have focused on understanding the etiology of ischemic injury and protecting the liver by pharmacological intervention [4][5][6][7] . Pretreatment with certain immunosuppressive drugs has been shown to protect against neutrophil-mediated reperfusion injury [4,5] .…”

“…Experimental efforts have focused on understanding the etiology of ischemic injury and protecting the liver by pharmacological intervention [4][5][6][7] . Pretreatment with certain immunosuppressive drugs has been shown to protect against neutrophil-mediated reperfusion injury [4,5] . Calcineurin inhibiters are thought to suppress both proinflammatory cytokine production and expression of adhesive molecules of neutrophils [8] .…”