Center for Advanced Biomedical Science and Swine Research, Division of Organ Replacement and Xenotransplantation Surgery M, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima City, Kagoshima, 890-8520, Japan.
Columbia Center for Translational Immunology, Department of Surgery, Columbia University Medical Center, New York, USA.
J Gastrointest Surg. 2020 May;24(5):974-982. doi: 10.1007/s11605-019-04283-0. Epub 2019 Jun 26.
The development of treatment strategies to protect against ischemia-reperfusion injury (IRI) to livers is important not only for liver surgeries but also in regard to increasing the utilization of livers from marginal donors. In this study, we examined whether inhalational carbon monoxide (CO) therapy reduced IRI after a 45-min (min) warm ischemia (WI) in a miniature swine model.
Six CLAWN miniature swine underwent a 45-min hepatic WI induced by clamping the portal vein and proper hepatic artery. Three animals were subjected to control conditions while the remaining three were treated with CO inhalation for a total of 345-min, including 120-min after reperfusion to maintain a concentration of CO-Hb under 15% (CO-treated group). IRI of the livers was evaluated by liver function tests, serum pro-inflammatory cytokines, and liver biopsies.
All controls had statistically significant increased levels of liver enzymes compared to the CO-treated group (p < 0.05). In controls, liver biopsies at 2 h after reperfusion showed marked histological changes including diffuse hemorrhage, congestion, necrosis, vacuolization, and neutrophil infiltration with apoptosis. In contrast, the CO-treated group showed less obvious or only minimal histological changes. Furthermore, increases in high-mobility group box 1, TNF-α, and IL-6 in sera that were induced by IRI in controls were markedly inhibited by the CO treatment.
We demonstrated that low-dose CO inhalation reduces hepatic warm IRI, potentially through downregulation of pro-inflammatory mediators and activation of anti-apoptotic pathways. To our knowledge, this is the first report demonstrating CO inhalation attenuated hepatic IRI following WI in a large animal model.
开发针对肝脏缺血再灌注损伤（IRI）的治疗策略不仅对肝脏手术很重要，而且对于增加对边缘供体肝脏的利用也很重要。在这项研究中，我们研究了吸入一氧化碳（CO）治疗是否可以减轻迷你猪模型中 45 分钟（min）热缺血（WI）后的 IRI。
6 只 CLAWN 迷你猪接受了门静脉和肝固有动脉夹闭引起的 45 分钟肝 WI。3 只动物处于对照条件下，而其余 3 只动物接受 CO 吸入治疗，总共 345 分钟，包括再灌注后 120 分钟以维持 CO-Hb 浓度在 15%以下（CO 处理组）。通过肝功能试验、血清促炎细胞因子和肝活检评估肝脏的 IRI。
所有对照动物的肝酶水平均明显高于 CO 处理组（p<0.05）。在对照组中，再灌注后 2 小时的肝活检显示出明显的组织学变化，包括弥漫性出血、充血、坏死、空泡化和中性粒细胞浸润伴凋亡。相比之下，CO 处理组的组织学变化不太明显或仅为轻微变化。此外，IRI 引起的对照组血清中高迁移率族蛋白 1（HMGB1）、TNF-α 和 IL-6 的增加被 CO 治疗明显抑制。
我们证明了低剂量 CO 吸入可减轻肝脏热 IRI，可能是通过下调促炎介质和激活抗凋亡途径。据我们所知，这是首次在大型动物模型中报告证明 CO 吸入可减轻 WI 后的肝脏 IRI。
