Nilotinib protects the murine liver from ischemia/reperfusion injury.
ABSTRACT The mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), and p38, mediate liver ischemia/reperfusion (I/R) injury via cell death and inflammatory cytokine expression, respectively. Nilotinib is an orally available receptor tyrosine kinase inhibitor used for chronic myelogenous leukemia that also has in vitro activity against JNK and p38. In this study, we examine its therapeutic potential against hepatic I/R injury.
The effects of nilotinib on liver I/R injury were tested using a murine model of warm, segmental liver I/R. Serum ALT was measured and livers were analyzed by histology, RT-PCR, Western blot, and flow cytometry. The in vitro effects of nilotinib on hepatocyte and non-parenchymal cell (NPC) MAPK activation and cytokine production were also tested.
Mice receiving nilotinib had markedly lower serum ALT levels and less histologic injury and apoptosis following liver I/R. Nilotinib did not inhibit its known receptor tyrosine kinases. Nilotinib lowered intrahepatic expression of IL-1β, IL-6, MCP-1, and MIP-2 and systemic levels of IL-6, MCP-1, and TNF. Nilotinib reduced NPC activation of p38 MAPK signaling and decreased the recruitment of inflammatory monocytes and their production of TNF. Nilotinib attenuated JNK phosphorylation and hepatocellular apoptosis. In vitro, nilotinib demonstrated direct inhibition of JNK activation in isolated hepatocytes cultured under hypoxic conditions, and blocked activation of p38 MAPK and cytokine production by stimulated NPCs.
Nilotinib lowers both liver JNK activation and NPC p38 MAPK activation and may be useful for ameliorating liver I/R injury in humans.
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ABSTRACT: Ischemia-reperfusion injury is a fascinating topic which has drawn a lot of interest in the last several years. Hepatic ischemia reperfusion injury may occur in a variety of clinical situations. These include transplantation, liver resection, trauma, and vascular surgery. The purpose of this review was to outline the molecular mechanisms underlying hepatic I/R injury and present the latest approaches, both surgical and pharmacological, regarding the prevention of it. A comprehensive electronic literature search in MEDLINE/PubMed was performed to identify relative articles published within the last 2 years. The basic mechanism of hepatic ischemia - reperfusion injury is one of blood deprivation during ischemia, followed by the return of flow during reperfusion. It involves a complex series of events, such as mitochondrial deenergization, adenosine-5'-triphosphate depletion, alterations of electrolyte homeostasis, as well as Kupffer cell activation, oxidative stress changes and upregulation of proinflammatory cytokine signaling. The great number of variable pathways, with several mediators interacting with each other, leads to a high number of candidates for potential therapeutic intervention. As far as surgical approaches are concerned, the modification of existing clamping techniques and the ischemic preconditioning are the most promising techniques till recently. In the search for novel techniques of protecting against hepatic ischemia reperfusion injury, many different strategies have been used in experimental models. The biggest part of this research lies around antioxidant therapy, but other potential solutions have been explored as well. The management of hepatic trauma, in spite of the fact that it has become increasingly nonoperative, there still remains the possibility of hepatic resection in the hepatic trauma setting, especially in severe injuries. Hence, clinicians should be familiar with the concept of hepatic ischemia-reperfusion injury and respond appropriately and timely.Archives of trauma research. 08/2013; 2(2):63-70.
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ABSTRACT: Background and Aim : Ischemia/reperfusion (I/R) injury in the liver occurs after a prolonged period of ischemia followed by restoration of hepatic blood perfusion. During the surgery of abdominal aorta, I/R injury causes damage to lower extremities and many organs, especially liver. The antioxidant and tumor necrosis factor-alpha (TNF-α) suppression effects of topiramate (TPM) have been reported in several studies. We evaluated the potential protective effect of TPM on cellular damage in liver tissue during I/R injury. Materials and Methods : Thirty male Wistar albino rats were divided into three groups: Control, I/R, and I/R plus TPM (I/R + TPM) groups. Laparotomy without I/R injury was performed in the control group. After laparotomy, cross-ligation of infrarenal abdominal aorta was applied for 2 h in I/R groups that was followed by 2 h of reperfusion. TPM (100 mg/kg/day) was orally administrated to the animals in the I/R + TPM group for seven consecutive days before I/R procedure. Results : The I/R group's TNF-α and interleukin-6 (IL-6) levels were significantly higher than those of the control (P = 0.010; P = 0.002) and I/R + TPM groups (P = 0.010; P = 0.002, respectively). Asymmetric dimethyl arginine (ADMA) levels of I/R group were higher than the control (P = 0.015) and I/R + TPM groups. I/R caused serious histopathological damage to liver tissue; however, TPM led to very low histopathological changes. Conclusion : Our data demonstrated that TPM treatment prominently decreases the severity of liver I/R injury. TPM pretreatment may have preventive effects on liver injury via I/R during intra-abdominal surgery.Saudi Journal of Gastroenterology 09/2014; 20(5):297-303. · 1.22 Impact Factor
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ABSTRACT: Ischemia and reperfusion (IR) injury remains one of the major problems in liver surgery and transplantation, which determines the viability of the hepatic tissue after resection and of the grafted organ. This review aims to elucidate the mechanisms involved in IR injury of the liver in rodent experimental studies and the preventative methods and pharmacologic agents that have been applied. Many time- and percentage-related liver IR injury rodent models have been used to examine the pathophysiological mechanisms and the parameters implicated with different morbidity, mortality, and pathology findings. The most preferred experimental rodent model of liver IR is the induction of 70% IR for 45 min, which is associated with almost 100% survival. In this model, plasma levels of several parameters such as alanine transaminase, aspartate aminotransferase, gamma-glutamyltransferase, endothelin-1, malonodialdehyde, tumor necrosis factor α, interleukin 1b, inducible nitric oxide synthase, and caspases are increased. The increase of caspases is associated with the initiation of hepatic cellular apoptosis. The main injuries observed 24 h after reperfusion are nuclear pyknosis, cytoplasmic hypereosinophilia, severe necrosis, and loss of intercellular borders. Both ischemic pre- and post-conditioning preventative methods and pharmacologic agents are successfully applied to alleviate the IR injuries. The selection of the time- and percentage-related liver IR injury rodent model and the potential preventative method should be related to the clinical question being answered.Journal of Surgical Research 06/2014; · 2.12 Impact Factor