cyclic-gmp and Meningococcal-Infections

Despite antibiotic therapy, infections with Neisseria meningitidis still demonstrate a high rate of morbidity and mortality even in developed countries. The fulminant septicaemic course, named Waterhouse-Friderichsen syndrome, with massive haemorrhage into the adrenal glands and widespread petechial bleeding suggest pathophysiological inhibition of platelet function. Our data show that N. meningitidis produces the important physiological platelet inhibitor and cardiovascular signalling molecule nitric oxide (NO), also known as endothelium-derived relaxing factor (EDRF). N. meningitidis -derived NO inhibited ADP-induced platelet aggregation through the activation of soluble guanylyl cyclase (sGC) followed by an increase in platelet cyclic nucleotide levels and subsequent activation of platelet cGMP- and cAMP- dependent protein kinases (PKG and PKA). Furthermore, direct measurement of horseradish peroxidase (HRP) passage through a vascular endothelial cell monolayer revealed that N. meningitidis significantly increased endothelial monolayer permeability. Immunfluorescence analysis demonstrated NO dependent disturbances in the structure of endothelial adherens junctions after co-incubation with N. meningitidis . In contrast to platelet inhibition, the NO effects on HBMEC were not mediated by cyclic nucleotides. Our study provides evidence that NO plays an essential role in the pathophysiology of septicaemic meningococcal infection.

Topics: Adherens Junctions; Blood Platelets; Capillary Permeability; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Endothelium-Dependent Relaxing Factors; Endothelium, Vascular; Guanylate Cyclase; Humans; Meningococcal Infections; Neisseria meningitidis; Nitric Oxide; Platelet Aggregation; Signal Transduction

Identification and characterization of myocardial depressant factors present in meningococcal septicemia.. Laboratory investigation of myocardial depression that used isolated cardiac myocytes as an model of cardiac contractile function.. University hospital and laboratories.. Children with severe meningococcal septic shock requiring intensive care.. Myocytes obtained from adult male Sprague-Dawley rats.. Serum samples obtained from the acute phase of sepsis were evaluated for the presence of myocardial depressant activity. Further characterization of the myocardial depressant factor was undertaken by using cell culture supernatants from whole blood and peripheral blood mononuclear cells that had been exposed to heat-killed meningococci.. Myocardial depressant activity was measured by using isolated rat left-ventricular myocytes. Changes in amplitude of contraction and in the speed of contraction and relaxation were determined after cells were exposed to various stimuli. Serum from patients with meningococcal disease had myocardial depressant activity. This activity was also present in whole blood and peripheral blood mononuclear cells exposed to meningococci. Myocardial depressant activity was found to be heat stable, proteinaceous, and of a molecular weight range of 10-25 kDa. The activity did not elevate concentrations of cyclic guanylic acid. Lipopolysaccharide-binding protein augmented the release of myocardial depressant factor by peripheral blood mononuclear cells exposed to meningococci.. Myocardial depression in meningococcal sepsis is mediated in part by circulating myocardial depressant factors. Myocardial depressant factors are also released when whole blood or peripheral blood mononuclear cells of healthy donors are exposed to heat-killed meningococci. Release of the factors appears to be mediated through endotoxin-induced activation of peripheral blood mononuclear cells, since lipopolysaccharide-binding protein augments release in a dose-responsive manner. Partial physicochemical characterization of the factors has been achieved.

Topics: Adolescent; Animals; Cells, Cultured; Child; Child, Preschool; Cyclic GMP; Female; Humans; In Vitro Techniques; Infant; Interleukin-1; Leukocytes, Mononuclear; Male; Meningococcal Infections; Myocardial Contraction; Myocardial Depressant Factor; Myocytes, Cardiac; Neisseria meningitidis, Serogroup C; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Sepsis; Shock, Septic; Tumor Necrosis Factor-alpha