The impact of synthetic antimicrobial peptides on macro- and microcirculatory dysfunction in sepsis

严重脓毒症和脓毒性休克是由感染引起的复杂的全身炎症反应，可导致多器官功能障碍综合征和死亡。潜在的病理生理学特征是宏观和微循环功能障碍，代表不良结局的独立风险因素。然而，尽管在基础和临床研究方面做出了大量努力，但仍然缺乏因果治疗剂。天然存在的抗菌肽（AMP）是天然免疫的重要组成部分。由于它们的治疗用途由于内在毒性而受到限制，因此挑战是在天然存在的AMP的基础上开发基于合成肽的药物而不造成伤害。因此，英国伦敦玛丽玛丽大学威廉哈维研究所的拟议项目旨在研究合成抗菌肽对脓毒症中的宏观和微循环功能障碍的影响。此外，目的是研究内源性危险分子乙酰肝素酶和硫酸乙酰肝素在引发脓毒症相关的宏和微循环功能障碍中的作用，以及它们作为合成抗菌肽的治疗靶点的潜力。因此，我们在小鼠体内和离体模型中使用功能和分子分析。该项目的研究结果将有助于理解脓毒症中宏循环和微循环功能障碍的潜在机制。此外，它们将有助于开发新的抗炎剂，用于持续高发病率和死亡率的疾病。

Severe sepsis and septic shock are complex systemic inflammatory reactions due to infections resulting in a multiple organ dysfunction syndrome and death. The underlying pathophysiology is characterized by a dysfunction of macro- and microcirculation, representing independent risk factors for poor outcome. However, despite intensive efforts in basic and clinical research causal therapeutic agents are still lacking. Naturally occurring antimicrobial peptides (AMP) are an important part of innate immunity. Since their therapeutic use is limited due to intrinsic toxicity, the challenge is to develop synthetic peptide-based drugs on the basis of naturally occurring AMP without causing harm. Thus, the proposed project at the William Harvey Research Institute der Queen Mary University of London, United Kingdom, aims to investigate the impact of synthetic antimicrobial peptides on macro- and microcirculatory dysfunction in sepsis. Furthermore, the objective is to investigate the role of the endogenous danger molecules heparanase and heparan sulfates in triggering sepsis-associated macro- and microcirculatory dysfunction and their potential as therapeutic targets of the synthetic antimicrobial peptides. Therefore, we use functional and molecular analyses in murine in vivo and ex vivo models. The findings of the proposed project will essentially help to understand the underlying mechanisms of macro- and microcirculatory dysfunction in sepsis. Moreover, they will help to develop new anti-inflammatory agents for a disease with persistent high morbidity and mortality.