8 research outputs found
Host response in sepsis
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
The human antimicrobial peptide LL-37 induces endothelium-dependent vascular smooth muscle relaxation mediated via the lipoxin A4 receptor
Circulating glycosaminoglycan species in septic shock.
Glycosaminoglycans (GAGs) are negatively charged polysaccharides present, e.g., on the luminal face of the blood vessels as heparan sulphate (HS) and hyaluronic acid (HA), in the interstitium as HA, and in neutrofils and plasma as chondroitin sulphate (CS) and HA. Total plasma levels of GAG are increased in human septic shock, but the origin and pathophysiological implications are unclear. In order to determine the source of circulating GAG in sepsis, we compared plasma levels of HS, HA, CS and keratan sulphate (KS) in patients with septic shock and controls
The human antimicrobial peptide LL-37 induces endothelium-dependent vascular smooth muscle relaxation mediated via the lipoxin A4 receptor ALX
Elevated Plasma Levels of Antimicrobial Polypeptides in Patients with Severe Sepsis.
We wanted to investigate if plasma levels of antimicrobial polypeptides (AMPs) are increased in severe sepsis and if they correlate with severity and mortality. Samples were collected from 31 sepsis patients at the intensive care unit. The Sequential Organ Failure Assessment (SOFA) score and 90-day mortality were registered, and inflammatory markers and AMP levels were measured by ELISA. A median SOFA score (13) and cardiovascular SOFA score (3) indicated multiorgan failure with severe circulatory derangement, and elevated cytokine levels indicated inflammatory activation. Levels of bactericidal/permeability-increasing protein, heparin-binding protein, alpha-defensins and lactoferrin but not LL-37 were elevated in sepsis patients compared with controls. Bactericidal/permeability-increasing protein levels correlated with mortality, with lower levels in survivors. Levels of all AMPs, except LL-37, positively correlated with the cardiovascular SOFA score. In conclusion, levels of several AMPs are increased in sepsis and correlate with circulatory derangement. This probably reflects neutrophil activation as part of an innate immune response
The Prognostic Value of suPAR Compared to Other Inflammatory Markers in Patients with Severe Sepsis
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INCREASED LEVELS OF GLYCOSAMINOGLYCANS DURING SEPTIC SHOCK: RELATION TO MORTALITY AND THE ANTIBACTERIAL ACTIONS OF PLASMA.
Glycosaminoglycans (GAGs) are structurally heterogeneous negatively charged polysaccharides. Endothelial GAGs, also known as glycocalyx, are involved in capillary permeability. In rat venules stimulated with proinflammatory substances ex vivo, the GAG-containing proteoglycan, syndecan-1, is shed from the endothelium. We wanted to investigate if we could trace the same response during septic shock as reflected in the circulating GAG levels. Arterial plasma samples were collected from 18 consecutive septic shock patients admitted to our intensive care unit. Plasma GAGs were measured with an Alcian blue slot binding assay, and syndecan-1 levels were measured with enzyme-linked immunosorbent assay. Effects of GAGs on the antibacterial activity of plasma were assessed by a radial diffusion assay. The median plasma GAG level was significantly higher in the septic shock patients than in matched controls (median [interquartile range], 2.7 mug/mL [1.9 - 4.8 mug/mL] vs. 1.8 mug/mL [1.7 - 2.0 mug/mL]). Furthermore, the GAG levels were significantly higher in nonsurvivors (4.6 mug/mL [3.1 - 8.8 mug/mL], n = 8) than survivors (1.8 mug/mL [1.6 - 2.6 mug/mL], n = 10). The syndecan-1 levels were also increased in the patients compared with controls (246 ng/mL [180 - 496 ng/mL] vs. 26 ng/mL [23 - 31 ng/mL]) and correlated to the cardiovascular Sequential Organ Failure Assessment score. The GAGs inhibited the endogenous antibacterial activity of plasma as well as isolated antimicrobial peptides. The concentrations required were in the same range as the GAG levels measured in the patients. These results show that the GAG levels are increased in septic shock patients, possibly reflecting peripheral endothelial cell damage. We also found that GAGs in relevant concentrations neutralize antimicrobial peptides in plasma
INCREASED LEVELS OF GLYCOSAMINOGLYCANS DURING SEPTIC SHOCK: RELATION TO MORTALITY AND THE ANTIBACTERIAL ACTIONS OF PLASMA.
Glycosaminoglycans (GAGs) are structurally heterogeneous negatively charged polysaccharides. Endothelial GAGs, also known as glycocalyx, are involved in capillary permeability. In rat venules stimulated with proinflammatory substances ex vivo, the GAG-containing proteoglycan, syndecan-1, is shed from the endothelium. We wanted to investigate if we could trace the same response during septic shock as reflected in the circulating GAG levels. Arterial plasma samples were collected from 18 consecutive septic shock patients admitted to our intensive care unit. Plasma GAGs were measured with an Alcian blue slot binding assay, and syndecan-1 levels were measured with enzyme-linked immunosorbent assay. Effects of GAGs on the antibacterial activity of plasma were assessed by a radial diffusion assay. The median plasma GAG level was significantly higher in the septic shock patients than in matched controls (median [interquartile range], 2.7 mug/mL [1.9 - 4.8 mug/mL] vs. 1.8 mug/mL [1.7 - 2.0 mug/mL]). Furthermore, the GAG levels were significantly higher in nonsurvivors (4.6 mug/mL [3.1 - 8.8 mug/mL], n = 8) than survivors (1.8 mug/mL [1.6 - 2.6 mug/mL], n = 10). The syndecan-1 levels were also increased in the patients compared with controls (246 ng/mL [180 - 496 ng/mL] vs. 26 ng/mL [23 - 31 ng/mL]) and correlated to the cardiovascular Sequential Organ Failure Assessment score. The GAGs inhibited the endogenous antibacterial activity of plasma as well as isolated antimicrobial peptides. The concentrations required were in the same range as the GAG levels measured in the patients. These results show that the GAG levels are increased in septic shock patients, possibly reflecting peripheral endothelial cell damage. We also found that GAGs in relevant concentrations neutralize antimicrobial peptides in plasma