Abstract
During sepsis, liver dysfunction is common, and failure of mitochondria to effectively couple oxygen consumption with energy production has been described. In addition to sepsis, pharmacological agents used to treat septic patients may contribute to mitochondrial dysfunction. This study addressed the hypothesis that remifentanil interacts with hepatic mitochondrial oxygen consumption. The human hepatoma cell line HepG2 and their isolated mitochondria were exposed to remifentanil, with or without further exposure to tumor necrosis factor-α (TNF-α). Mitochondrial oxygen consumption was measured by high-resolution respirometry, Caspase-3 protein levels by Western blotting, and cytokine levels by ELISA. Inhibitory κBα (IκBα) phosphorylation, measurement of the cellular ATP content and mitochondrial membrane potential in intact cells were analysed using commercial ELISA kits. Maximal cellular respiration increased after one hour of incubation with remifentanil, and phosphorylation of IκBα occurred, denoting stimulation of nuclear factor κB (NF-κB). The effect on cellular respiration was not present at 2, 4, 8 or 16 hours of incubation. Remifentanil increased the isolated mitochondrial respiratory control ratio of complex-I-dependent respiration without interfering with maximal respiration. Preincubation with the opioid receptor antagonist naloxone prevented a remifentanil-induced increase in cellular respiration. Remifentanil at 10× higher concentrations than therapeutic reduced mitochondrial membrane potential and ATP content without uncoupling oxygen consumption and basal respiration levels. TNF-α exposure reduced respiration of complex-I, -II and -IV, an effect which was prevented by prior remifentanil incubation. Furthermore, prior remifentanil incubation prevented TNF-α-induced IL-6 release of HepG2 cells, and attenuated fragmentation of pro-caspase-3 into cleaved active caspase 3 (an early marker of apoptosis). Our data suggest that remifentanil increases cellular respiration of human hepatocytes and prevents TNF-α-induced mitochondrial dysfunction. The results were not explained by uncoupling of mitochondrial respiration.
Highlights
Severe sepsis and septic shock are major causes of death in intensive care patients [1,2]
Cellular oxygen consumption after naloxone antagonism In order to see if the alterations in mitochondrial respiration could be prevented by the presence of an opioid receptor antagonist, we determined the effect of the antagonist naloxone (Figure 2)
The data indicate that the effect of remifentanil is prevented with naloxone: cells pretreated with naloxone before the addition of remifentanil exhibited no significant changes in complex activities in comparison with controls
Summary
Severe sepsis and septic shock are major causes of death in intensive care patients [1,2]. The causes of organ dysfunction and failure are unclear, but inadequate tissue perfusion, systemic inflammation, and direct metabolic changes at the cellular level are all likely to contribute [3,4,5]. The liver is a central organ in homeostasis, with vital metabolic and immunological functions. Liver dysfunction is common, and contributes to the high mortality observed in these patients [6,7,8]. Failure of mitochondria to effectively couple oxygen consumption with energy production has been described in sepsis [11]. Pharmacological agents used to treat septic patients may contribute to mitochondrial dysfunction [17]
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