Abstract
Remote ischemic preconditioning (RIPC) is known to have a protective effect against hepatic ischemia-reperfusion (IR) injury in animal models. However, the underlying mechanism of action is not clearly understood. This study examined the effectiveness of RIPC in a mouse model of hepatic IR and aimed to clarify the mechanism and relationship of the ATP-sensitive potassium channel (KATP) and HMGB1-induced TLR4/MyD88/NF-κB signaling. C57BL/6 male mice were separated into six groups: (i) sham-operated control, (ii) IR, (iii) RIPC+IR, (iv) RIPC+IR+glyburide (KATP blocker), (v) RIPC+IR+diazoxide (KATP opener), and (vi) RIPC+IR+diazoxide+glyburide groups. Histological changes, including hepatic ischemia injury, were assessed. The levels of circulating liver enzymes and inflammatory cytokines were measured. Levels of apoptotic proteins, proinflammatory factors (TLR4, HMGB1, MyD88, and NF-κB), and IκBα were measured by Western blot and mRNA levels of proinflammatory cytokine factors were determined by RT-PCR. RIPC significantly decreased hepatic ischemic injury, inflammatory cytokine levels, and liver enzymes compared to the corresponding values observed in the IR mouse model. The KATP opener diazoxide + RIPC significantly reduced hepatic IR injury demonstrating an additive effect on protection against hepatic IR injury. The protective effect appeared to be related to the opening of KATP, which inhibited HMGB1-induced TRL4/MyD88/NF-kB signaling.
Highlights
The induction of ischemia by clamping blood vessels of the target organ is frequently applied during surgical procedures to prevent blood loss and to secure an adequate surgical field
To confirm the disruption of Toll-like receptor 4 (TLR4) signaling by remote ischemic preconditioning (RIPC), the protein levels of TLR4, high mobility group box 1 (HMGB1), myeloid differentiation primary response 88 (MyD88), and NF-κB were measured; all were downregulated in RIPC-treated IR mice (TLR4, 4.3 ± 1.2; HMGB1, 1.3 ± 1.0; MyD88, 4.7 ± 0.8; NF-κB, 1.0 ± 0.6) compared to levels in IR mice (TLR4, 10.6 ± 2.3; HMGB1, 7.0 ± 1.2; MyD88, 7.9 ± 0.7; NF-κB, 9.8 ± 2.8; p < 0.05; Figure 1I,J)
This anti-hepatic ischemia effect was achieved via activating mitochondrial KATP and inhibiting HMGB1-induced TLR4/MyD88/NF-κB signaling, and the combination of diazoxide and RIPC had an additive protective effect in this mouse model of IR
Summary
The induction of ischemia by clamping blood vessels of the target organ is frequently applied during surgical procedures to prevent blood loss and to secure an adequate surgical field. Hepatic ischemia-reperfusion (IR) injury can be caused by direct interventions to organs, including surgery, or by hypoxic damage to the liver [3,4]. This may result in hepatocyte and sinusoidal cell injury and perhaps necrosis or apoptosis, which can eventually lead to hepatic failure [1,5]. Several preconditioning strategies that have been proposed to reduce IR injury include direct transient clamping of the blood vessel of the target organ before ischemia [6,7] and remote ischemic preconditioning (RIPC) of distal limbs [8,9]. The protective effect of RIPC has been studied in several animal models, especially for heart and vascular surgeries [10,11,12]
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