Schmidt Karsten, Hernekamp Jochen Frederick, Doerr Miriam, Zivkovic Aleksandar R, Brenner Thorsten, Walther Andreas, Weigand Markus A, Hofer Stefan
Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Ludwigshafen, University of Heidelberg, Heidelberg, Germany.
BMC Anesthesiol. 2015 Aug 1;15:114. doi: 10.1186/s12871-015-0086-9.
Microvascular permeability and leukocyte adhesion are pivotal mechanisms in sepsis pathophysiology contributing to the development of shock and mortality. No effective pharmacological therapy is currently available to restore microvascular barrier function in sepsis. Cholinergic mediators have been demonstrated to exert anti-inflammatory effects during inflammation. Cytidine-5-diphosphocholine (CDP-choline) is an extensively studied cholinergic drug due to its brain protective characteristics in cerebrovascular diseases. This study evaluated the effect of CDP-choline on microvascular permeability and leukocyte adhesion during endotoxemia.
Macromolecular leakage, leukocyte adhesion, and venular wall shear rate were examined in mesenteric postcapillary venules of rats by using intravital microscopy (IVM). Lipopolysaccharide (LPS) (4 mg/kg/h) or equivalent volumes of saline were continuously infused following baseline IVM at 0 min. IVM was repeated after 60 and 120 min in endotoxemic and nonendotoxemic animals. CDP-choline (100 mg/kg) was applied as an i.v. bolus. Animals received either saline alone, CDP-choline alone, CDP-choline 10 min before or 30 min after LPS administration, or LPS alone. Due to nonparametric data distribution, Wilcoxon test and Dunn's multiple comparisons test were used for data analysis. Data were considered statistically significant at p < 0.05.
Treatment with LPS alone significantly increased microvascular permeability and leukocyte adhesion and decreased venular wall shear rate. CDP-choline significantly reduced microvascular permeability in animals treated with LPS. Leukocyte adhesion and venular wall shear rate were not affected by CDP-choline during endotoxemia.
CDP-choline has a protective effect on microvascular barrier function during endotoxemia. Considering the excellent pharmacologic safety profile of CDP-choline, its use could be an approach for the treatment of capillary leakage in sepsis.
微血管通透性和白细胞黏附是脓毒症病理生理学中的关键机制，与休克的发生和死亡率相关。目前尚无有效的药物疗法可恢复脓毒症中的微血管屏障功能。胆碱能介质已被证明在炎症过程中发挥抗炎作用。胞苷-5-二磷酸胆碱（CDP-胆碱）因其在脑血管疾病中的脑保护特性而成为一种被广泛研究的胆碱能药物。本研究评估了CDP-胆碱在内毒素血症期间对微血管通透性和白细胞黏附的影响。
采用活体显微镜检查（IVM）在大鼠肠系膜毛细血管后微静脉中检测大分子渗漏、白细胞黏附及微静脉壁剪切率。在0分钟进行基线IVM后，持续输注脂多糖（LPS）（4mg/kg/h）或等量生理盐水。在内毒素血症和非内毒素血症动物中，于60分钟和120分钟后重复进行IVM。静脉推注给予CDP-胆碱（100mg/kg）。动物分别接受单独生理盐水、单独CDP-胆碱、LPS给药前10分钟或给药后30分钟给予CDP-胆碱，或单独LPS处理。由于数据分布为非参数性，采用Wilcoxon检验和Dunn多重比较检验进行数据分析。P<0.05时数据被认为具有统计学意义。
单独使用LPS治疗显著增加微血管通透性和白细胞黏附，并降低微静脉壁剪切率。CDP-胆碱显著降低LPS处理动物的微血管通透性。内毒素血症期间，CDP-胆碱对白细胞黏附和微静脉壁剪切率无影响。
CDP-胆碱在内毒素血症期间对微血管屏障功能具有保护作用。鉴于CDP-胆碱良好的药理安全性，其应用可能是治疗脓毒症中毛细血管渗漏的一种方法。
