Ulmer Tom Florian, Fragoulis Athanassious, Dohmeier Henriette, Kroh Andreas, Andert Anne, Stoppe Christian, Alizai Hamid, Klink Christian, Coburn Mark, Neumann Ulf Peter
Department of General, Visceral, and Transplantation Surgery, University Hospital of RWTH Aachen, Aachen, Germany.
Eur Surg Res. 2017;58(5-6):204-215. doi: 10.1159/000466690. Epub 2017 Apr 22.
The liver can heal up to restitutio ad integrum following damage resulting from various causes. Different studies have demonstrated the protective effect of argon on various cells and organs. To the best of our knowledge, the organ-protective effects of the noble gas argon on the liver have not yet been investigated, although argon appears to influence signal paths that are well-known mediators of liver regeneration. We hypothesized that argon inhalation prior to partial hepatectomy (70%) has a positive effect on the initiation of liver regeneration in rats.
Partial hepatectomy (70%) with or without inhaled argon (50 vol%) was performed for 1 h. Liver tissue was harvested after 3, 36, and 96 h to analyze the mRNA and protein expression of hepatocyte growth factor (HGF), interleukin-6 (IL-6), tumor necrosis factor-α, and extracellular signal-regulated kinase 1/2. Histological tissue samples were prepared for immunohistochemistry (bromodeoxyuridine [BrdU], Ki-67, and TUNEL) and blood was analyzed regarding the effects of argon on liver function. Statistical analyses were performed using 1-way ANOVA followed by the post hoc Tukey-Kramer test.
After 3 h, the primary outcome parameter of hepatocyte proliferation was significantly reduced with argon 50 vol% inhalation in comparison to nitrogen inhalation (BrdU: 15.7 ± 9.7 vs. 7.7 ± 3.1 positive cells/1,000 hepatocytes, p = 0.013; Ki-67: 17.6 ± 13.3 vs. 4.7 ± 5.4 positive cells/1,000 hepatocytes, p = 0.006). This was most likely mediated by significant downregulation of HGF (after 3 h: 5.2 ± 3.2 vs. 2.3 ± 1.0 fold, p = 0.032; after 96 h: 2.1 ± 0.5 vs. 1.3 ± 0.3 fold, p = 0.029) and IL-6 (after 3 h: 43.7 ± 39.6 vs. 8.5 ± 9.2 fold, p = 0.032). Nevertheless, we could detect no significant effect on the weight of the residual liver, liver-body weight ratio, or liver blood test results after argon inhalation.
Impairment of liver regeneration was apparent after argon 50 vol% inhalation that was most probably mediated by downregulation of HGF and IL-6 in the initial phase. However, the present study was not adequately powered to prove that argon has detrimental effects on the liver. Further studies are needed to evaluate the effects of argon on livers with preexisting conditions as well as on ischemia-reperfusion models.
肝脏在受到各种原因导致的损伤后能够完全愈合。不同研究已证明氩气对各种细胞和器官具有保护作用。据我们所知，尽管氩气似乎会影响作为肝脏再生知名介质的信号通路，但尚未对稀有气体氩气对肝脏的器官保护作用进行研究。我们假设在部分肝切除术（70%）前吸入氩气对大鼠肝脏再生的启动具有积极作用。
进行70%的部分肝切除术，术中吸入或不吸入氩气（50体积%），持续1小时。在术后3、36和96小时采集肝组织，分析肝细胞生长因子（HGF）、白细胞介素-6（IL-6）、肿瘤坏死因子-α和细胞外信号调节激酶1/2的mRNA和蛋白表达。制备组织学样本用于免疫组织化学（溴脱氧尿苷[BrdU]、Ki-67和TUNEL），并分析血液以研究氩气对肝功能的影响。采用单因素方差分析及事后Tukey-Kramer检验进行统计分析。
术后3小时，与吸入氮气相比，吸入50体积%氩气时肝细胞增殖的主要观察指标显著降低（BrdU：15.7±9.7对7.7±3.1个阳性细胞/1000个肝细胞，p = 0.013；Ki-67：17.6±13.3对4.7±5.4个阳性细胞/1000个肝细胞，p = 0.006）。这很可能是由HGF（术后3小时：5.2±3.2对2.3±1.0倍，p = 0.032；术后96小时：2.1±0.5对1.3±0.3倍，p = 0.029）和IL-6（术后3小时：43.7±39.6对8.5±9.2倍，p = 0.032）的显著下调介导的。然而，我们未检测到吸入氩气后对残余肝脏重量、肝体重比或肝脏血液检测结果有显著影响。
吸入50体积%氩气后肝脏再生受损明显，最可能是由初始阶段HGF和IL-6的下调介导的。然而，本研究的样本量不足以证明氩气对肝脏有有害影响。需要进一步研究来评估氩气对已有病变肝脏以及缺血再灌注模型的影响。
