Host response in sepsis

University dissertation from Avd för anestesiologi och intensivvård

Abstract: Sepsis is a serious condition characterized by a systemic inflammatory response to an infection. Increased vascular leakage, vasodilation and heart failure cause circulatory disturbances challenging the intensivist. Despite modern medication and high technology supportive care, mortality is high. Key strategies include to find and take care of causative agents at the infection site. Unfortunately, the microbes are sometimes “slippery small ones” protecting themselves by for example resistance against antibiotics. But our body is amazing! For example cells, such as neutrophil granulocytes, produce antibiotic substances (antimicrobial peptides, AMPs). Increased knowledge of the host response in sepsis will aid in refining and developing new treatment. We investigated the effect of the AMP, LL-37, on smooth muscle activity in isolated human omental vessels and found that it causes formyl peptide receptor-like 1 mediated dilation in the veins mainly via action of endothelium-derived hyperpolarizing factor. Earlier studies have shown that increased levels of glycosaminoglycans (GAGs) inhibit the action of AMPs in chronic wounds. We found increased plasma levels of GAGs in sepsis patients correlating to mortality and level of circulatory derangement. GAGs at concentrations relevant to sepsis patients inhibited the antimicrobial action of AMPs in vitro. Plasma levels of AMPs were generally higher in sepsis patients than in controls and correlated to inflammatory activation, circulatory derangement and neutrophil activity. Finally, we found that the contact system is activated in patients with severe sepsis reflected by decreased levels of high-molecular-weight kininogen. The levels of the main effector, bradykinin, were, however, also decreased, suggesting substrate depletion in the state of established severe sepsis.