Role of platelets in systemic tissue protection after remote ischemic preconditioning

O wing to the potential of cancer cure by hepatectomy, the surgical limits of liver resection were pushed forward in recent years. Major liver surgery frequently requires the occlusion of hepatic inflow (Pringle maneuver) to diminish intraoperative blood loss. Reinducing blood flow after tissue ischemia leads to ischemia reperfusion injury (IRI), which may substantially compromise patient outcome. Especially as hepatotoxic preoperative chemotherapy is increasingly used to improve oncological outcome, the reduction of further harm to the liver is of major importance to allow adequate postoperative liver regeneration. Furthermore, IRI is a major concern in liver transplantation, as the donor organ shortage has prompted the inclusion of “marginal” organs, which are more likely to suffer from increased IRI. Several potential treatment strategies have been developed to reduce IRI. Ischemic preconditioning (IP), which is defined as the repetitive occlusion of blood flow to the target organ for short time periods prior to surgery, has been shown to be effective in reducing IRI. While one could assume that the effects of IP are caused by local tissue adaptation, remote ischemic preconditioning (RIPC) induced by repeated brief periods of limb ischemia distinct from the target organ, is also able to induce protection. While several findings have been implicated to account for the beneficial effects of RIPC in the target organ, the exact mechanisms remain poorly understood. In this issue of HEPATOLOGY, Oberkofler et al. address the role of platelet-derived serotonin in the process of RIPC. They were able to demonstrate that the reduction of IRI by RIPC was associated with increased platelet activation and the protective effect of RIPC was lost in platelet-depleted mice. They further focused on serotonin as a potential effector of platelets in protecting against IRI, as it has been implicated in tissue repair after ischemia. Platelets, which are incapable of synthesizing serotonin themselves, absorb serotonin efficiently from the plasma pool and store it in their dense granules. Upon platelet activation dense granules are released first, followed by a-granules. Indeed, the authors found that after RIPC, serotonin was released by platelets and serotonin-deficient mice did not benefit from RIPC prior to IRI. The authors further aimed to identify the downstream effector(s) of serotonin in RIPC. In accordance with the previously reported effects of serotonin on vascular endothelial growth factor (VEGF), they were able to demonstrate that serotonin induced expression of VEGF in cultured endothelial cells (ECs). Importantly, they were also able to show that inhibition of VEGF abolished the effects of RIPC. Of note, as platelet a-granules contain high levels of VEGF, the increase in circulating VEGF after RIPC is presumably derived from both ECs and platelets. Indeed, Oberkofler et al. used P-selectin to document platelet activation after RIPC, which is in fact a protein stored in agranules such as VEGF, suggesting a relevant contribution of a-granule release after RIPC. Using gene expression analysis the authors were further able to document that two specific target gene products mediated RIPC effects. In particular, matrix metalloproteinase-8 (Mmp-8) and interleukin-10 (IL10) were found to be up-regulated in the target organ and the specific inhibition of both molecules eliminated the protective effect of RIPC. Importantly, Oberkofler et al. confirmed that the RIPC induced platelet-serotonin-VEGF-IL-10/Mmp-8 axis is also crucial to protect against renal IRI and demonstrated specific induction of protective gene expression in several organs (liver, kidney, lung, heart, intestine) after RIPC, rendering their observation from an organspecific phenomenon to a presumably “general principal. ” Indeed, the authors also observed a reduced expression of inflammatory genes in RIPC-treated mice Abbreviations: ECs, endothelial cells; HMG-B1, high mobility group-box 1; IL-10, interleukin 10; IP, ischemic preconditioning; IRI, ischemia reperfusion injury; Mmp-8, metalloproteinase-8; RIPC, remote ischemic preconditioning; TNF-a, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor. Address reprint requests to: Prof. Thomas Gruenberger, M.D., Ph.D., Department of Surgery, Medical University of Vienna, General Hospital, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail: thomas.gruenberger@ meduniwien.ac. at; fax: 143-1-25330331881. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27146 Potential conflict of interest: Nothing to report.