Harder Yves, Amon Michaela, Schramm René, Contaldo Claudio, Metzkow Eva, Matzen Anne, Rücker Martin, Vollmar Brigitte, Menger Michael D
Institute for Clinical and Experimental Surgery, University of Saarland, Germany.
Surgery. 2009 Apr;145(4):372-83. doi: 10.1016/j.surg.2008.12.001.
BACKGROUND: Erythropoietin (Epo), the primary regulator of erythropoiesis, has recently been shown to exert antiinflammatory and antiapoptotic properties in neuronal and myocardial tissue. We herein studied whether Epo pretreatment can reduce cell death and ischemic necrosis in a chronic in vivo model. METHODS: C57BL/6 mice were treated daily for 3 consecutive days with either 500 IU EPO/kg body weight (bw) (group Epo 500, n = 8) or 5000 IU EPO/kg bw (group Epo 5000, n = 8) administered intraperitoneally 24 hours before surgery. Thereafter, a random pattern myocutaneous flap subjected to acute persistent ischemia was elevated and fixed into a dorsal skinfold chamber. Flap elevation in animals receiving the water-soluble vitamin E analog Trolox (6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid) served as a nonspecific antiinflammatory agent control group (Tro); untreated control animals (Con) received saline only. Capillary perfusion, leukocyte-endothelial cell interaction, apoptotic cell death, and tissue necrosis were determined over a 10-day observation period using intravital multifluorescence microscopy. RESULTS: Epo 5000 (44 +/- 26 cm/cm(2)) but, more noticeably, Epo 500 (116 +/- 32 cm/cm(2)) improved capillary perfusion compared with the two control groups, particularly the Con group (9 +/- 7 cm/cm(2); P < .05). The ischemia-associated leukocytic inflammation was found drastically attenuated in both Epo-pretreatment groups. Epo 500 further decreased apoptotic cell death and was effective in significantly reducing tissue necrosis (16% +/- 4% vs Tro: 48% +/- 7% and Con: 52% +/- 4%; P < .001). No angiogenic blood vessel formation could be observed in either of the Epo groups. Of interest, Epo 5000-but not Epo 500-increased systemic hematocrit. CONCLUSION: Despite the lack of neovascularization, Epo pretreatment was capable of reducing ischemic tissue necrosis by protecting capillary perfusion, ie, nutrition of the tissue. Low-dose pretreatment was more effective, a result that was most likely due to the better perfusion conditions without an increase of the hematocrit values. Thus, low-dose Epo pretreatment might represent a promising strategy to protect critically perfused ischemic tissue.
背景：促红细胞生成素（Epo）是红细胞生成的主要调节因子，最近研究表明其在神经元和心肌组织中具有抗炎和抗凋亡特性。我们在此研究Epo预处理是否能在慢性体内模型中减少细胞死亡和缺血性坏死。 方法：将C57BL/6小鼠连续3天每天腹腔注射500 IU EPO/kg体重（bw）（Epo 500组，n = 8）或5000 IU EPO/kg bw（Epo 5000组，n = 8），于手术前24小时给药。此后，掀起一块随机模式的肌皮瓣并使其遭受急性持续性缺血，然后固定于背部皮褶小室。接受水溶性维生素E类似物曲洛司坦（6-羟基-2,5,7,8-四甲基苯并二氢吡喃-2-羧酸）的动物掀起皮瓣作为非特异性抗炎剂对照组（曲洛司坦组）；未治疗的对照动物（对照组）仅接受生理盐水。在10天观察期内，使用活体多荧光显微镜测定毛细血管灌注、白细胞-内皮细胞相互作用、凋亡细胞死亡和组织坏死情况。 结果：与两个对照组相比，Epo 5000组（44±26 cm/cm²），更显著的是Epo 500组（116±32 cm/cm²）的毛细血管灌注得到改善，尤其是对照组（9±7 cm/cm²；P <.05）。在两个Epo预处理组中，缺血相关的白细胞炎症均显著减轻。Epo 500进一步减少了凋亡细胞死亡，并有效显著降低了组织坏死（16%±4% vs曲洛司坦组：48%±7%和对照组：52%±4%；P <.001）。在两个Epo组中均未观察到血管生成性血管形成。有趣的是，Epo 5000组而非Epo 500组使全身血细胞比容升高。 结论：尽管缺乏新生血管形成，但Epo预处理能够通过保护毛细血管灌注即组织营养来减少缺血性组织坏死。低剂量预处理更有效，这一结果很可能是由于更好的灌注条件且血细胞比容值未升高。因此，低剂量Epo预处理可能是保护严重灌注不足的缺血组织的一种有前景的策略。
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