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  • HMGB could theoretically also derive from


    HMGB1 could theoretically also derive from other Meropenem or organs after liver I/R, such as the intestines [39]. It is however most plausible that hepatocytes are the source of HMGB1, for several reasons. First, the postoperative rise in HMGB1 is not seen in hepatocyte-specific HMGB1 knockout mice subjected to liver I/R [40]. Similar results have been obtained with mice deficient in hepatocyte TLR-4, an innate immune receptor that mediates HMGB1 release after I/R [24,41]. Second, HMGB1 levels were more prominent in caval than in portal blood after liver transplantation [32], whereas no differences were noted between systemic and portal HMGB1 concentrations. The latter excludes the bowel as a source of HMGB1 after liver transplantation. Last, in vitro studies have shown that hepatocytes rendered hypoxic or exposed to the oxidant hydrogen peroxide release HMGB1 into the culture supernatant [24]. An unanswered question is which HMGB1 isoform is released after liver I/R, as the biological effects of HMGB1 depend on the oxidation status of the protein [28]. In addition, it should be elucidated how HMGB1 is inactivated and/or regulated at sites of inflammation. This is imperative given the transient nature of postoperative HMGB1 surges noted both after liver transplantation [32] and in the current study (Fig. 2). The finding that mtDNA levels were unaffected by liver I/R is unexpected, given that mtDNA release was seen in mice and patients with acetaminophen (APAP) hepatotoxicity, which pathophysiologically resembles I/R in terms of oxidative injury to hepatocyte mitochondria [12,42,43]. The discrepancy may relate to several differences between I/R injury and APAP overdose. First, the mechanistic pathways culminating in mitochondrial damage are different. In case of APAP, cytoplasmic glutathione stores are depleted, leading to the accumulation of the toxic NAPQI that associates with mitochondrial proteins and leads to mitochondrial permeability transition (MPT) and necrotic cell death [43]. Accordingly, APAP causes cytoplasmic redox stress that subsequently migrates to the mitochondria. In case of I/R, the depletion and subsequent repletion of the terminal substrate of the electron transport chain (ETC) - molecular oxygen - leads to an oxidative burst and ROS production that perturbs ETC proteins by redox modification and causes MPT and mainly necrotic cell death [44]. Mitochondrial damage by I/R therefore has a mitochondrial origin, which could translate to differential mtDNA kinetics versus APAP-triggered mtDNA kinetics. Corroboratively, mtDNA release seems to be a tightly regulated process rather than a mere consequence of necrosis inasmuch as rendering livers necrotic with furosemide instead of APAP did not trigger mtDNA release [12]. Second, hepatocellular injury in patients with APAP toxicity was considerably more severe than in our I/R cohort based on ALT levels [12]. The proposition that mtDNA is released mainly in severe liver injury is also in line with a later report showing that mtDNA release is more pronounced in patients with poor outcome after APAP overdose [11]. One could further argue that ischemia by itself is the factor that differentiates APAP toxicity from I/R injury. Indeed, mtDNA release has been predominantly reported in patients with non-ischemic causes of sterile injury, which in addition tot APAP hepatotoxicity includes inflammatory bowel disease [45] and trauma [46]. This line of reasoning, however, does not align with the fact that we also did not find mtDNA release in patients who underwent a major hepatectomy without intraoperative VIO use (i.e., non-ischemic sterile liver injury). The current data also highlight that mitochondrial oxidative stress may be an even more proximal target for intervention [47], as this may limit DAMP release. The finding that MitoQ was able to suppress HMGB1 release fits the earlier notion that the glutathione precursor n-acetyl-cysteine (NAC) reduced HMGB1 release after in vitro hepatocyte anoxia/reoxygenation [24]. Antioxidants, including NAC, lack efficacy in various clinical scenarios, including hepatic I/R injury [48]. MitoQ differs from these compounds in that RuBP is designed to target the site of oxidant production after I/R (i.e., mitochondria) and also detoxifies the most relevant oxidant (i.e., superoxide) [5]. MitoQ has been used previously in mice to successfully treat hepatic I/R injury [27]. In the latter report, MitoQ efficacy was assessed using surrogate markers for oxidative injury such as mitochondrial protein carbonylation and hepatic 3-nitrotyrosine content [27]. Using a direct intravital fluorescence-based method [25] it was confirmed that MitoQ reduces hepatocyte oxidative stress early after I/R. In addition, MitoQ has already been employed in phase II studies where it lowered transaminase levels in patients with hepatitis C [49], which is an encouraging follow-up to the preclinical notion that MitoQ is generally well-tolerated and not toxic [50]. The clinical investigation and implementation of mitochondria-targeted antioxidants such as MitoQ therefore seems a realistic objective.