EDITORIALS Enhancing organ pool by statins: Is this the future? Jorge Gracia-Sancho Hepatic Hemodynamic Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona and CIBERehd, Barcelona, Spain See article in J. Gastroenterol. Hepatol. 2012; 27: 1353–1361. In the 1970s, the search for the holy grail compound able to lower cholesterol levels led to the development of the first statin, mevastatin, by Akira Endo. During subsequent years, changes in the original formulation resulted in a variety of drugs with high effectiveness in its original purpose, but also with strong cardio- protective effects. In fact, statins are now considered drugs with pleiotropic benefits that prevent and improve various cardiovascu- lar diseases such as myocardial infarction, stroke and thrombosis. In addition, recent studies suggest that statins may also ameliorate liver pathologies. Although one would expect that the vasoprotec- tive properties of statin might derive from its cholesterol-lowering action, different studies have shown that much of the positive effects are independent from it. 1 Probably the most known example is the JUPITER trial, which showed prevention of car- diovascular events in a broad spectrum of healthy individuals without hyperlipidemia. 2 In the field of hepatology, almost a decade ago Zafra and col- leagues were the first to show beneficial effects of simvastatin for the treatment of the most common complication of liver cirrhosis, portal hypertension, without modification in cholesterol levels. 3 Following studies have unraveled the molecular basis of the statin- derived liver protection demonstrating that statins regulate the expression of different genes and proteins that globally protect the unhealthy liver. 4,5 Particularly, statins activate the transcription factor Kruppel-like factor 2 (KLF2) that precisely orchestrates a variety of vasoprotective pathways. 6,7 It is important to denote that not all statins confer the same hepatic vasoprotection; indeed sim- vastatin and mevastatin are the most effective (Marrone and Gracia-Sancho, unpubl. data, 2012). In the field of experimental ischemia and reperfusion (I/R) injury, simvastatin was proposed as prophylactic treatment for donors to prevent hepatocellular damage resulting from warm I/R in 2008. 8 More recently, and focusing on expanded criteria donors, Llacuna and colleagues elegantly demonstrated that 1-week pre- treatment with atorvastatin confers hepatoprotection against warm I/R injury in animals with hypercholesterolemia and stetatosis. 9 The study from Ajamieh and colleagues published this month in the Journal of Gastroenterology and Hepatology provides new and important concepts regarding the use of statins as prophylactic agents to prevent warm I/R injury in the liver. 10 This study, con- ducted in experimental models of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), demonstrated that oral administration of atorvastatin for 10 days prior to warm I/R injury markedly prevented hepatocellular damage. Although readers might now think that the herein published study represents a reit- eration of the Llacuna study, it is not. Ajamieh et al. used models of hepatic steatosis similar to the human pathology (with obesity and insulin resistance but without accumulation of cholesterol), and thoroughly investigated the molecular mechanisms partly responsible for the statin-derived liver protection. Authors showed that animals pretreated with atorvastatin exhibited lower levels of the I/R injury mediator TLR4, and of the chemokines derived from this toll-like receptor. Since the TLR4 dependent pathways play an important role in the pro-inflammatory response during I/R injury, blockade of its activation represents an important advance in understanding the molecular mechanisms of statins hepatoprotec- tive effects. Moreover, these results add new information to pre- vious reports demonstrating that inflammation contention during I/R injury significantly reduces liver damage and graft dysfunc- tion. 11 Previous studies have shown that during ischemia and reperfusion the endothelium undergoes significant phenotypic changes involving loss of vasodilator capacity and increment in cell activation and cell death. 12,13 The present study further con- firms these data but more importantly demonstrates that the del- eterious effects of warm I/R injury are avoided pre-treating the animals with atorvastatin. At this point, it would be interesting to investigate if these endothelial phenotypic derangements are asso- ciated with deterioration in liver microcirculation, which has been described as the primary deleterious event leading to early graft failure, and whether statin can prevent it. In fact, it may be possible that activation of the KLF2-derived vasoprotective pathways by atorvastatin would play a role in the endothelial improvement described in this study, which paracrinally may improve hepato- cyte viability. From a practical point of view, administering statin to a poten- tial donor for 7 days before a non-programmed liver donation is unfeasible. For this reason, Ajamieh and colleagues also investi- gated the effects of a single dose of atorvastatin intravenously administered 24 h before warm I/R injury. These experiments evi- denced that semi-acute statin treatment also confers hepatic pro- tection in front of a warm I/R episode, and is associated with an improvement in the previously described pro-inflammatory and vasoactive pathways. Since a 24-h treatment would not affect cholesterol levels, authors argue that this experimental setting dis- cards a possible cholesterol-lowering dependency on hepatic pro- tection. Future experiments evaluating the protective effects of statins on hepatic I/R injury should include an acute administration of the drug, i.e. 30 or 60 min before ischemia, which would be sufficient to activate statin-derived protective mechanisms and will probably have higher translational applicability. Although warm I/R injury contributes to the pathophysiology of liver transplantation, cold ischemia represents the most challeng- ing and detrimental stage during the transplant procedure. 14 Thus, the possible benefits of treating extended criteria donors with statin on hepatic I/R injury should be investigated in the context of graft cold storage followed by warm reperfusion. In that regard, recent Accepted for publication 13 April 2012. Correspondence Dr Jorge Gracia-Sancho, Hepatic Hemodynamic Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149, Room 4.5, 08036 Barcelona, Spain. Email: jgracia@clinic.ub.es Financial support: Funded by the Instituto de Salud Carlos III, Ministe- rio de Economía y Competitividad (FIS PI11/00235) and co-funded by FEDER (Fondo Europeo de Desarrollo Regional, Unión Europea). J.G.-S. is a recipient of a contract from the Programa Ramón y Cajal, Ministerio de Economía y Competitividad, Spain. CIBERehd is funded by Instituto de Salud Carlos III. doi:10.1111/j.1440-1746.2012.07160.x 1259 Journal of Gastroenterology and Hepatology 27 (2012) 1259–1265 © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd