Yamada T, Hisanaga M, Nakajima Y, Kanehiro H, Aomatsu Y, Ko S, Kin T, Nishio K, Sho M, Nagao M, Harada A, Matsushima K, Nakano H
First Department of Surgery, Nara Medical University, Japan.
Surgery. 1999 Mar;125(3):304-14.
We have recently developed a simple method of hyperthermochemohypoxic isolated liver perfusion (HILP) as a regional therapy for unrecognized liver micrometastases. However, little is known about the influence of HILP on cytokine production and liver function. We investigated the influence of HILP on interleukin 8 (IL-8) production and the hepatic mitochondrial function and assessed the relationship between these 2 parameters. We also measured the serum tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) levels to examine the involvement of HILP-induced cytokines in the tumor response.
Sixteen patients with metastatic liver tumors were randomly assigned to undergo hepatectomy with HILP (group A, n = 9) or hepatectomy alone (group B, n = 7). The isolated liver was perfused for 30 minutes with Ringer's lactate solution containing chemotherapeutic agents warmed to 42 degrees C to 43 degrees C without oxygenation.
The serum IL-8 levels in group A were markedly increased, with peaks at 3 hours after reperfusion, which was significantly higher than levels in group B (P < .01). In group A the arterial ketone body ratio, which reflects the hepatic mitochondrial redox state, decreased during perfusion and was gradually restored to the preperfusion level 1 hour after reperfusion. However, in group B it decreased during hepatectomy but rapidly recovered 5 minutes after hepatectomy. There was a significant negative correlation between the peak serum IL-8 level and the initial velocity of arterial ketone body ratio recovery for the first 5 minutes after reperfusion r = -0.83, P < .001). The serum TNF-alpha and IL-1 beta were temporarily detected only in 3 of 9 patients in group A.
We have shown that HILP resulted in augmented IL-8 release but not TNF-alpha and IL-1 beta and that the serum IL-8 level reflects the hepatic mitochondrial redox state. These findings suggest that IL-8 production may be associated with hepatic mitochondrial impairment during ischemia. This work may contribute to new therapeutic strategies not only for hepatic ischemia reperfusion injury but also for metastatic liver tumors.
我们最近开发了一种简单的热化疗低氧离体肝灌注（HILP）方法，作为一种针对未被识别的肝微转移的区域治疗方法。然而，关于HILP对细胞因子产生和肝功能的影响知之甚少。我们研究了HILP对白细胞介素8（IL-8）产生和肝线粒体功能的影响，并评估了这两个参数之间的关系。我们还测量了血清肿瘤坏死因子-α（TNF-α）和白细胞介素1β（IL-1β）水平，以研究HILP诱导的细胞因子在肿瘤反应中的作用。
16例肝转移瘤患者被随机分为接受HILP肝切除术的A组（n = 9）或单纯肝切除术的B组（n = 7）。将离体肝脏用含有化疗药物的乳酸林格液在42℃至43℃下灌注30分钟，且不进行氧合。
A组血清IL-8水平显著升高，在再灌注后3小时达到峰值，明显高于B组（P <.01）。在A组中，反映肝线粒体氧化还原状态的动脉酮体比值在灌注期间下降，并在再灌注后1小时逐渐恢复到灌注前水平。然而，在B组中，它在肝切除术中下降，但在肝切除术后5分钟迅速恢复。再灌注后前5分钟血清IL-8峰值水平与动脉酮体比值恢复的初始速度之间存在显著负相关（r = -0.83，P <.001）。血清TNF-α和IL-1β仅在A组9例患者中的3例中被暂时检测到。
我们已经表明，HILP导致IL-8释放增加，但不导致TNF-α和IL-1β释放增加，并且血清IL-8水平反映肝线粒体氧化还原状态。这些发现表明，IL-8的产生可能与缺血期间的肝线粒体损伤有关。这项工作不仅可能有助于肝缺血再灌注损伤的新治疗策略，也可能有助于肝转移瘤的治疗。
