The search for a magic bullet to fight multiple organ failure secondary to ischemia/reperfusion injury and abdominal compartment syndrome

Division of Trauma, Critical Care and Acute Care Surgery, ECMC-462 Grider Street, University at Buffalo-SUNY, Buffalo, NY.
Journal of Surgical Research (Impact Factor: 1.94). 06/2012; 184(2). DOI: 10.1016/j.jss.2012.06.024
Source: PubMed
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    ABSTRACT: Tumour necrosis factor (TNF)-α has been considered to induce ischaemia-reperfusion injury (IRI) of liver which is characterized by energy dysmetabolism. Peroxisome proliferator-activated receptor-γ co-activator (PGC)-1α and mitofusion2 (Mfn2) are reported to be involved in the regulation of mitochondrial function. However, whether PGC-1α and Mfn2 form a pathway that mediates liver IRI, and if so, what the underlying involvement is in that pathway remain unclear. In this study, L02 cells administered recombinant human TNF-α had increased TNF-α levels and resulted in down-regulation of PGC-1α and Mfn2 in a rat liver IRI model. This was associated with hepatic mitochondrial swelling, decreased adenosine triphosphate (ATP) production, and increased levels of reactive oxygen species (ROS) and alanine aminotransferase (ALT) activity as well as cell apoptosis. Inhibition of TNF-α by neutralizing antibody reversed PGC-1α and Mfn2 expression, and decreased hepatic injury and cell apoptosis both in cell culture and in animals. Treatment by rosiglitazone sustained PGC-1α and Mfn2 expression both in IR livers, and L02 cells treated with TNF-α as indicated by increased hepatic mitochondrial integrity and ATP production, reduced ROS and ALT activity as well as decreased cell apoptosis. Overexpression of Mfn2 by lentiviral-Mfn2 transfection decreased hepatic injury in IR livers and L02 cells treated with TNF-α. However, there was no up-regulation of PGC-1α. These findings suggest that PGC-1α and Mfn2 constitute a regulatory pathway, and play a critical role in TNF-α-induced hepatic IRI. Inhibition of the TNF-α or PGC-1α/Mfn2 pathways may represent novel therapeutic interventions for hepatic IRI.
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    ABSTRACT: Ischemia and reperfusion (I/R) injury is one of the main lesions after liver transplantation. This study aims to detect hypoxia-induced HIF-1α protects transplanted liver against I/R injury by promoting glucose metabolism to decrease mitochondrial injury and apoptosis on rat model. The rats were given a treatment of 90min non-lethal hypoxic preconditioning to induce and increase the HIF-1α expression. The autologous orthotopic liver transplantation model was used to imitate liver I/R injury. Hypoxic-induced HIF-1α was detected to increase in liver tissue after 90-minute hypoxic environment (HP vs. Ctrl, *P<0.001). After operation, the expression of HIF-1α in liver tissue was also stayed at a high level. At 24h after operation, several genes were promoted, such as the levels of HK-2 (HP vs. AT, 24h, *P=0.004), Lactate dehydrogenase (LDHA) (HP vs. AT, 24h, *P=0.003), pyruvate dehydrogenase kinase (PDK-1) (HP vs. AT, 24h, *P=0.007), even the NF-κB and Erk pathways. From the TUNEL assay, the apoptosis in hypoxic preconditioning liver tissue was decreased compared with non-HP operative group at 12h after operation. The expressions of cleaved-caspase 3 (HP vs. AT, *P=0.0119) and PARP (HP vs. AT, *P=0.0134) in HP group were also significantly lower than AT group. The hypoxia-induced HIF-1α could promote glucose metabolism to protect hepatocellular mitochondria from damage. It could be a useful way to protect liver against I/R injuries and inflammatory injury, and particularly promote the recovery of graft function. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    Gastroentérologie Clinique et Biologique 02/2015; 39(5). DOI:10.1016/j.clinre.2014.12.012 · 1.64 Impact Factor

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