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

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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.