Department of Diving Medicine, Second Military Medical University, Shanghai, China.
Department of Medical Genetics, Second Military Medical University, Shanghai, China.
J Hepatol. 2014 Nov;61(5):1048-55. doi: 10.1016/j.jhep.2014.06.020. Epub 2014 Jun 24.
BACKGROUND & AIMS: Hepatic ischemia and reperfusion (I/R) injury is a major complication of liver transplantation, hepatic resection and trauma. Helium preconditioning (HPC) exerts protection against ischemic stress. We investigated potential beneficial effects of HPC on I/R-induced liver injury and investigated mechanisms underlying HPC-induced protection.
We employed a model of segmental warm hepatic I/R on BALB/c mice. Serum ALT was measured and livers were analysed by histology, RT-PCR and western blot. HPC was induced by inhalation of a 70% helium/30% oxygen mixture for three 5-min periods, interspersed with three 5-min washout periods by room air. We tested which component of HPC (the helium/air mixture inhalation, the air room gap, or the interaction between these two factors) is protective.
We found that HPC caused a significant increase in Akt phosphorylation in hepatocytes. The HPC-induced Akt phosphorylation resulted in decreased hepatocellular injury and improved survival rate of the treated animals. PI3K inhibitors abolished HPC induced effects. HPC-induced Akt phosphorylation affected expression of its downstream molecules. The effects of HPC on the PI3K/Akt pathway were attenuated by adenosine A2A receptor blockade, but could be re-established by PTEN inhibition. We demonstrated that the interaction of helium/air breathing and air gaps is responsible for the observed effects of HPC.
HPC may be a promising strategy leading to a decrease in I/R induced liver injury in clinical settings. Additionally, the PI3K/Akt pathway plays an essential role in the protective effects of HPC in hepatic I/R injury.
肝脏缺血再灌注（I/R）损伤是肝移植、肝切除和创伤的主要并发症。氦预处理（HPC）可对抗缺血应激。我们研究了 HPC 对 I/R 诱导的肝损伤的潜在有益作用，并研究了 HPC 诱导保护作用的机制。
我们采用 BALB/c 小鼠肝段热缺血再灌注模型。检测血清 ALT，通过组织学、RT-PCR 和 Western blot 分析肝脏。HPC 通过吸入 70%氦气/30%氧气混合气进行 3 次，每次 5 分钟，中间用室内空气进行 3 次 5 分钟的洗脱期。我们测试了 HPC 的哪个组成部分（氦气/空气混合物吸入、空气室间隔或这两个因素之间的相互作用）具有保护作用。
我们发现 HPC 导致肝细胞中 Akt 磷酸化显著增加。HPC 诱导的 Akt 磷酸化导致肝细胞损伤减少和治疗动物存活率提高。PI3K 抑制剂消除了 HPC 诱导的作用。HPC 诱导的 Akt 磷酸化影响其下游分子的表达。腺苷 A2A 受体阻断削弱了 HPC 对 PI3K/Akt 通路的作用，但可以通过 PTEN 抑制重新建立。我们证明了氦气/空气呼吸和空气间隙的相互作用是 HPC 观察到的作用的原因。
HPC 可能是一种有前途的策略，可以减少临床环境中 I/R 诱导的肝损伤。此外，PI3K/Akt 通路在 HPC 对肝 I/R 损伤的保护作用中起重要作用。
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