Schuerholz Tobias, Doemming Sabine, Hornef Mathias, Martin Lukas, Simon Tim-Philipp, Heinbockel Lena, Brandenburg Klaus, Marx Gernot
Crit Care. 2013 Jan 9;17(1):R3. doi: 10.1186/cc11920.
Increasing rates of multi-resistant bacteria are a major problem in the treatment of critically ill patients. Furthermore, conventional antibiotics lead to the release of bacterial derived membrane parts initiating pro-inflammatory cascades with potential harm to the patient. Antimicrobial peptides (AMP) may kill bacteria without releasing pro-inflammatory factors. Thus, we compared three newly developed synthetic anti-lipopolysaccharide peptides (SALPs) with a broader range of efficacy to suppress cytokine release in plasma and CD14 mRNA expression in organ tissue in a murine, polymicrobial sepsis model.
A randomized, experimental trial was conducted in an animal research facility. Male NMRI mice (n = 90; 8- to 12-weeks old) were randomized to the following six groups: (i) sham operation and parenteral vehicle (NaCl 0.9%) administration (sham); (ii) cecal ligation and puncture (CLP) and vehicle infusion (sepsis-control), (iii) CLP and polymyxin B infusion (polyB), or (iv to vi) CLP and infusion of three different synthetic antimicrobial peptides Peptide 19-2.5 (Pep2.5), Peptide 19-4 (Pep4) or Peptide 19-8 (Pep8). All animals underwent arterial and venous catheterization for hemodynamic monitoring 48 hours prior to CLP or sham-operation. Physical appearance and behavior (activity), plasma cytokine levels, and CD14 mRNA expression in heart, lung, liver, spleen and kidney tissue were determined 24 hours after CLP or sham operation.
Only Pep2.5 significantly enhanced the activity after CLP, whereas none of the therapeutic regimens elevated the mean arterial pressure or heart rate. The strongly elevated IL-6, IL-10 and monocyte chemoattractant protein serum levels in septic animals were significantly reduced after Pep2.5 administration (P < 0.001, P < 0.001, and P < 0.001, respectively). Similarly, Pep2.5 significantly reduced the sepsis-induced CD14 mRNA expression in heart (P = 0.003), lung (P = 0.008), and spleen tissue (P = 0.009) but not in kidney and liver.
Structurally variable SALPs exhibit major differences in their anti-inflammatory effect in vivo. Continuous parenteral administration of Pep2.5 is able to reduce sepsis-induced cytokine release and tissue inflammation.
多重耐药菌发生率的不断上升是重症患者治疗中的一个主要问题。此外，传统抗生素会导致细菌来源的膜成分释放，引发促炎级联反应，对患者有潜在危害。抗菌肽（AMP）可能在不释放促炎因子的情况下杀死细菌。因此，我们在小鼠多微生物败血症模型中比较了三种新开发的具有更广泛疗效的合成抗脂多糖肽（SALP），以抑制血浆中的细胞因子释放和器官组织中的CD14 mRNA表达。
在动物研究设施中进行了一项随机实验性试验。将雄性NMRI小鼠（n = 90；8至12周龄）随机分为以下六组：（i）假手术并给予肠胃外赋形剂（0.9%氯化钠）（假手术组）；（ii）盲肠结扎和穿刺（CLP）并输注赋形剂（败血症对照组），（iii）CLP并输注多粘菌素B（多粘菌素B组），或（iv至vi）CLP并输注三种不同的合成抗菌肽肽19 - 2.5（Pep2.5）、肽19 - 4（Pep4）或肽19 - 8（Pep8）。所有动物在CLP或假手术前48小时进行动脉和静脉插管以进行血流动力学监测。在CLP或假手术后24小时测定身体外观和行为（活动）、血浆细胞因子水平以及心脏、肺、肝、脾和肾组织中的CD14 mRNA表达。
只有Pep2.5能显著增强CLP后的活动，而所有治疗方案均未提高平均动脉压或心率。给予Pep2.5后，败血症动物中显著升高的白细胞介素 - 6、白细胞介素 - 10和单核细胞趋化蛋白血清水平显著降低（分别为P < 0.001、P < 0.001和P < 0.001）。同样，Pep2.5显著降低了败血症诱导的心脏（P = 0.003）、肺（P = 0.008）和脾组织（P = 0.009）中的CD14 mRNA表达，但对肾和肝组织没有影响。
结构可变的SALP在体内的抗炎作用存在重大差异。持续肠胃外给予Pep2.5能够减少败血症诱导的细胞因子释放和组织炎症。
