Solutions to the discrepancies in the extent of liver damage following ischemia/reperfusion in standard mouse models

Golen, Rowan F. van; Reiniers, Megan J.; Heger, Michal; Verheij, Joanne

doi:10.1016/j.jhep.2014.12.014

Cited by 16 publications

(15 citation statements)

References 10 publications

(21 reference statements)

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“…DAMP-induced macrophage activation occurred independent of the transcription factor NF-κB, which supports the earlier notions that innate immune activation after liver I/R pro ce eds v ia a TL R4-IRF3 ax is ra ther th an th e MyD88-dependent TLR-4-NF-κB route [8,25,26], thereby preventing DAMP-mediated IL-23 transcription [27]. Because it cannot be ruled out that IL-23 is produced by a different leukocyte subset (e.g., dendritic cells) or that IL-23 is generated in a DAMP-independent manner, the IL-1β/IL-23/IL-17A signaling axis was further explored in moderate (i.e., 30-min ischemia) and severe (i.e., ≥ 60-min ischemia) mouse hepatic I/R injury models, defined on the basis of ALT and hepatocellular necrosis profiles [9]. In these models, no role for IL-23 and IL-17A was found, which corroborates the in vitro data.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, one of the proximal triggers of the axis, IL-1β, was only upregulated in the severe but not the moderate injury model, suggesting that extreme pathological conditions would be required for IL-23 and IL-17A production, which remained absent. As the severe injury model is difficult to translate to the clinical situation due to the extensive necrosis (> 75%) observed in these animals [9], results obtained in the moderate injury model might better reflect the clinical situation. The absence of IL-1β in the moderate injury model therefore adds weight to the irrelevance of the IL-1β/IL-23/IL-17A-axis in hepatic I/R injury.…”

Section: Discussionmentioning

confidence: 99%

“…All surgical and experimental details of the in vivo I/R experiments have been described in detail previously [9,16]. At the indicated time points, the animals were anesthetized and sacrificed by exsanguination using cardiac puncture.…”

Section: Mouse Model Of Hepatic Ischemia/reperfusionmentioning

confidence: 99%

“…The diverging results generated using different models of hepatic I/R currently preclude the drawing of uniform conclusions and adequate clinical translation [9]. Essentially, several scenarios could activate IL-23/IL-17A signaling during surgery-induced sterile inflammation.…”

Section: Introductionmentioning

confidence: 99%

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IL-23 and IL-17 are not involved in hepatic ischemia reperfusion injury in mouse and man

2015

J Clin Transl Res

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Background: Hepatic ischemia and reperfusion (I/R) is common in liver surgery and transplantation and compromises postoperative liver function. Hepatic I/R injury is characterized by sterile inflammation that contributes to hepatocellular necrosis. Many immune cells and cytokines have been implicated in hepatic I/R injury. However, the role and relevance of IL-23 and IL-17A remains controversial in literature. Aim: To determine whether the IL-23/IL-17A signaling axis is activated in hepatic I/R using a triple-level experimental approach (in vitro, in vivo, and clinical). Methods: IL-23 and IL-17A were assayed by ELISA in the supernatant fractions of cultured murine (RAW 264.7) macrophages that were activated by supernatant fractions of necrotic cultured mouse (AML12) hepatocytes. Similarly, levels of these cytokines were determined in plasma samples and liver tissue of mice (N = 85) subjected to partial (70%) liver I/R. Finally, IL-23 and IL-17A were assayed in plasma samples obtained from a controlled cohort of liver resection patients who were either subjected to I/R (N = 27) or not (N = 13). Results: Activated macrophages did not produce IL-23 in response to supernatant of necrotic AML12 hepatocytes. IL-23 and IL-17A were not elevated in mice subjected hepatic I/R and were not elevated in serum from patients subjected to I/R during liver resection. Conclusion: IL-23 and IL-17A are not involved in hepatic I/R injury in mouse and man. Relevance for patients: If IL-23 and IL-17A were to mediate hepatocellular injury following I/R, these cytokines would constitute potential therapeutic targets. Since this study has revealed that IL-23 and IL-17A do not play a role in hepatic I/R, other pathways and therapeutic targets should be considered when developing modalities aimed at reducing hepatic I/R injury.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mouse Model Of Hepatic Ischemia/reperfusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IL-23 and IL-17 are not involved in hepatic ischemia reperfusion injury in mouse and man

2015

J Clin Transl Res

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“…Sixty minutes of hepatic ischemia causes 75-100% hepatocellular necrosis in mice, which far exceeds the clinical hepatic I/R injury profile (31). Unfortunately, only few studies using milder injury (that is, shorter ischemia times) are currently available.…”

Section: Hypothermia and Immunomodulationmentioning

confidence: 99%

Protective Mechanisms of Hypothermia in Liver Surgery and Transplantation

Olthof

Reiniers

Dirkes

et al. 2015

Mol Med

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Hepatic ischemia/reperfusion (I/R) injury is a side effect of major liver surgery that often cannot be avoided. Prolonged periods of ischemia put a metabolic strain on hepatocytes and limit the tolerable ischemia and preservation times during liver resection and transplantation, respectively. In both surgical settings, temporarily lowering the metabolic demand of the organ by reducing organ temperature effectively counteracts the negative consequences of an ischemic insult. Despite its routine use, the application of liver cooling is predicated on an incomplete understanding of the underlying protective mechanisms, which has limited a uniform and widespread implementation of liver-cooling techniques. This review therefore addresses how hypothermia-induced hypometabolism modulates hepatocyte metabolism during ischemia and thereby reduces hepatic I/R injury. The mechanisms underlying hypothermia-mediated reduction in energy expenditure during ischemia and the attenuation of mitochondrial production of reactive oxygen species during early reperfusion are described. It is further addressed how hypothermia suppresses the sterile hepatic I/R immune response and preserves the metabolic functionality of hepatocytes. Lastly, a summary of the clinical status quo of the use of liver cooling for liver resection and transplantation is provided.

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