Charakterisierung und Modulation der Wundheilung durch Epoxyeicosatriensäuren an der Defektwunde am Ohr der Maus: normale Wunde vs. Ischämie/Diabetes mellitus

免疫系统是一个脆弱的通道，创伤和脓毒症通过它对伤口愈合过程产生有害影响，从而增加手术患者的发病率和死亡率。尽管先前的研究表明，脓毒症宿主的伤口愈合受到损害，但全身感染改变远程损伤部位(皮肤)的炎症和修复反应的机制尚不完全清楚。最终，这些机制信息可能有助于开发治疗方法，以对抗伤口愈合过程中这种无序的炎症反应。趋化能力的降低可能是多因素的，可能涉及表面受体表达和配体结合的变化，也可能涉及细胞内信号的变化。我们假设有有限数量的中性粒细胞(PMN)、巨噬细胞和造血干细胞(HSC)可被输送到一个或多个损伤部位，并且由于增加的趋化梯度，这些细胞集中在主要损伤部位。基于这一背景，本研究将盲肠结扎穿孔(CLP)诱导的小鼠脓毒症模型与小鼠背部全层创面相结合，研究主要损伤部位和继发性损伤部位的细胞分布特征。由于基质细胞衍生因子(SDF)1-α在脓毒症中有助于中性粒细胞的归巢和存活，以及在创伤愈合过程中HSC细胞的增殖/动员和诱导血管生成，因此SDF1-α通过自分泌或旁分泌机制激活可能构成一条负反馈途径，以控制全身炎症反应，补偿脓毒症伤口愈合的失调。在本研究的第二部分，我们验证了局部应用SDF1-α可以改善脓毒症对皮肤创面愈合的抑制作用的假设，为未来多功能血管生成疗法的发展奠定了坚实的基础。

The immune system represents a vulnerable gateway through which trauma and sepsis exert their deleterious effect on the wound healing process resulting in increased morbidity and mortality for the surgical patient. Though previous studies have suggested that wound healing is impaired in a septic host, the mechanism by which systemic infection alters the inflammatory and reparative response at remote sites of injury (skin) is not fully understood. Ultimately, such mechanistic information may contribute to the development of therapeutic treatments to counteract this disordered inflammatory response in wound healing. The decreased chemotaxis is probably multifactorial and may involve either changes in surface receptor expression and ligand engagement or alterations in intracellular signaling. We postulate that a finite number of polymorphonuclear neutrophils (PMN), macrophages and hematopoietic stem cells (HSC) are available for delivery to one or more sites of injury and that the cells are concentrated in the site of the predominant injury due to an increased chemotactic gradient. Based on this background, the aim of the present study is the characterization of the cell distribution between the site of the predominant and secondary injury by combining the murine cecal ligation and puncture (CLP)-induced sepsis model with full-thickness wounds on the back of mice. Due to the fact that stromal cell-derived factor (SDF) 1-alpha contributes to homing of PMNs and survival in sepsis as well as HSC cell proliferation/mobilization and induction of angiogenesis in wound healing, the activation of SDF1-alpha by autocrine or paracrine mechanisms may constitute a negative feedback pathway to control the systemic inflammatory response and compensate the dysregulation of wound healing in sepsis. In the second part of the present study, we examine the hypothesis that the local application of SDF1-alpha can ameliorate the inhibitory effects of sepsis on cutaneous wound healing to provide a strong foundation for the development of prospective multifunctional angiogenic therapeutics.