endothelin-1 and Peritonitis

The purpose of the study is to increase the effectiveness of treatment of biliary peritonitis. The studies strongly suggest that in the early stages of the animals biliary peritonitis development against the background of endogenous intoxication in the body occur metabolic and functional disorders. The reason of this disorders is endothelial dysfunction with the violation of synthesis of such biologically active substances as endothelin-1, NO, von Willebrand factor and cytokines in the blood plasma. All of this leads to a change of the number of desquamated endotheliocytes and lymphocyte-platelet adhesion. The detected violation of the studied endothelial dysfunction markers production in choleperitonitis can be regarded as a new direction in improving the diagnosis of biliary peritonitis. The omni directional end-effects of the used methods of treatment to the endothelium functional state, which were identified in comparative analysis in the most cases, suggest that pathogenetic flow paths of biliary peritonitis in the studied groups are different and require further detailed study.

Topics: Animals; Anti-Infective Agents; Bile; Biomarkers; Cytokines; Disease Models, Animal; Dogs; Endothelin-1; Endothelium, Vascular; Fluid Therapy; Laparotomy; Male; Peritonitis; Platelet Adhesiveness; Therapeutic Irrigation; Time Factors; Treatment Outcome; von Willebrand Factor

Our aim was to develop a large animal model of sepsis induced by fecal peritonitis, which reproduces the characteristic macrohemodynamic, microcirculatory and inflammatory changes seen in human sepsis.. Anesthetized minipigs were subjected to fecal peritonitis (n = 9; 0.5 g/kg i.p. autofeces) or sham-operation (i.p. saline, n = 6). Invasive hemodynamic monitoring was started with regular blood gas analyses between the 15-24 hr of the insult. Sublingual microcirculation was characterized by red blood cell velocity changes (with orthogonal polarization spectral imaging), and the extravascular lung water index (EVLWI) was measured. The plasma levels of big-endothelin (big-ET) and high-mobility group box protein-1 (HMGB1) were determined from venous blood samples.. The mean arterial pressure gradually decreased below 70 mmHg in septic animals, while the heart rate and cardiac output increased constantly. In spite of the hyperdynamic reaction, significant elevation of the EVLWI was observed, while the sublingual microcirculation deteriorated, as compared with the control group. The big-ET and HMGB1 plasma concentrations were significantly elevated between 6-24 hr of peritonitis.. The in vivo data suggest that our fecal peritonitis-induced experimental sepsis model is of clinical relevance, and may play useful roles in the development of novel, sepsis-related therapies.

Topics: Animals; Arterial Pressure; Biomarkers; Blood Flow Velocity; Cardiac Output; Disease Models, Animal; Endothelin-1; Feces; Heart Rate; Hemodynamics; HMGB1 Protein; Inflammation; Microcirculation; Peritonitis; Sepsis; Swine; Swine, Miniature; Time Factors

Endotoxemia and/or systemic inflammation may lead to disturbances in the cardiac autonomic nervous system and consequent arrhythmia. The underlying mechanism remains unclear. Therefore, we investigated the expression of nerve growth factor (NGF) and its association with cardiac sympathovagal balance in a rodent model of self-limited peritonitis. Male Wistar rats were randomized into the following groups: normal control, sham, gastric perforation (GP), and GP treated with methylprednisolone. Cardiac expression of NGF, growth-associated protein 43 (GAP43), along with other nerve markers were evaluated at several time points (6 h to 2 weeks) after GP. An autoregressive process was performed on each detrended electrocardiogram to calculate the heart rate power spectrum. Compared with the normal control and sham groups, expression of NGF was significantly elevated for 1 week after GP. We also found the up-regulated GAP43 and tyrosine hydroxylase protein levels in the GP group, which persisted after recovery from peritonitis. Gastric perforation caused a biphasic change in the ratio of low-frequency to high-frequency power (an index of sympathovagal balance), with an initial decrease followed by recovery at 24 h. Increased NGF and cardiac sympathetic marker expression were temporally associated with the restoration of the cardiac sympathovagal balance. Methylprednisolone abrogated the NGF up-regulation induced by GP and delayed the resumption of sympathovagal balance. We conclude that GP resulted in up-regulation of cardiac NGF, GAP43, and tyrosine hydroxylase expression that coincided with recovery of cardiac sympathovagal balance. Moreover, methylprednisolone can effectively block GP-induced NGF up-regulation.

Topics: Animals; Anti-Inflammatory Agents; Autonomic Pathways; Blotting, Western; C-Reactive Protein; Endothelin-1; Enzyme-Linked Immunosorbent Assay; GAP-43 Protein; Heart Rate; Inflammation; Interleukin-6; Male; Methylprednisolone; Nerve Growth Factor; Peritonitis; Polymerase Chain Reaction; Random Allocation; Rats; Rats, Wistar

Endothelin (ET)-1 has been detected in many inflammatory pathologies, including rheumatoid arthritic patients, asthma, and ischemic-reperfusion injury. In this study, we have investigated the effect of a panel of different ET-1 antagonists displaying different selectivities for the receptors in a murine model of experimental inflammatory peritonitis. Systemic treatment of mice with the ETA antagonist C33H44N6O5, N-[N-[-N(hexahydro-1H-azepin-1-yl)carbonyl]-L-leucyl]-1-methyl-D-tryptophyl]-3-(2-pyridinyl)-D-alanine (FR139317) inhibited neutrophil accumulation. However, a greater degree of inhibition was observed with the ETB antagonist C34H51N5O7, N-cis-2,6-dimethylpiperidinocarbonyl-b-tBu-Ala-D-Trp(1-methoxycarbonyl)-D-Nle-OH (BQ-788) and the ET(A and B) antagonist C52H65N7O10, N-acetyl-alpha-[10,11-dihydro-5H-dibenzo-[a,d]cycloheptadien-5-yl]-D-Gly-Leu-Asp-lle-lle-Trp (PD145065); all these effects occurred without altering peripheral blood cell counts. Release of the CXC chemokine KC was significantly reduced by the FR139317 and PD145065 but not by BQ-788. Evaluation of the therapeutic potential of these antagonists showed that PD145065 inhibited neutrophil migration and KC release, whereas the others caused a nonsignificant reduction in these parameters. Parameters of endothelial cell activation showed that urate-stimulated interleukin-1beta release was inhibited by BQ-788 and PD145065 but not by FR139317, whereas ET-1 was only inhibited by the mixed antagonist. A different scenario was observed with respect to release of the CXC chemokine KC with FR139317 and PD145065 being effective, whereas with a marker of polymorphonuclear activation the ETA and mixed antagonist inhibited adhesion molecule expression. These data show that ET-1 antagonists elicit different mechanisms of actions in the way they display their antimigratory effects in a murine model of monosodium urate crystal peritonitis.

Topics: Animals; Azepines; Chemokines; Endothelin Receptor Antagonists; Endothelin-1; Indoles; Interleukin-1; Mice; Neutrophils; Oligopeptides; Peritonitis; Piperidines; Platelet Activating Factor; Time Factors; Uric Acid

Endothelin-1 (ET-1) is a 21-amino-acid peptide, derived from vascular endothelial cells, with potent vasoconstrictor activity. ET-1 has been implicated in diverse physiological or pathological processes, including the vascular changes associated with sepsis. However, the factors that regulate ET-1-associated toxicity during bacterial infections, or in other settings, are not fully understood. Both the pathology associated with certain allergic and autoimmune disorders, and optimal host defence against bacterial and parasitic infections are mediated by mast cells. In vitro, mast cells can produce ET-1 (ref. 11), undergo ET-1-dependent and endothelin-A receptor (ET(A))-dependent activation, and release proteases that degrade ET-1 (ref. 14). Although the potential relationships between mast cells and the ET-1 system thus may be complex, the importance of interactions between ET-1 and mast cells in vivo is obscure. Here we show that ET(A)-dependent mast-cell activation can diminish both ET-1 levels and ET-1-induced pathology in vivo, and also can contribute to optimal survival during acute bacterial peritonitis. These findings identify a new biological function for mast cells: promotion of homeostasis by limiting the toxicity associated with an endogenous mediator.

Topics: Animals; Body Temperature; Body Weight; Cell Degranulation; Cell Survival; Chymases; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Egtazic Acid; Endothelin-1; Female; Homeostasis; Injections, Intraperitoneal; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Oligopeptides; Peptides, Cyclic; Peritonitis; Proto-Oncogene Proteins c-kit; Serine Endopeptidases; Stem Cells; Survival Rate

To define the profiles of endothelin (ET), both big ET and active 21 amino acid ET (ET 1-21) in the plasma and peritoneal cavity of rats with peritonitis.. Open laboratory study.. University hospital, Norway.. 170 adult male Wistar rats.. Lethal peritonitis was induced by making a 4 mm caecal perforation.. Mortality, together with concentrations of total ET, ET 1-21 (measured by two radioimmunoassays), bacteria, endotoxin, tumor necrosis factor (TNF), interleukin 6 (IL-6), and lactate at baseline, two hours, and then four-hourly intervals for 24 hours.. ET reached its maximum at 8 hours, and had returned to baseline after 24 hours. In the first phase of septicaemia there was more big ET than ET 1-21, but the proportions had equalised by 8 hours. There were higher concentrations of both big ET and ET 1-21 in peritoneal fluid than in plasma.. In rats with peritonitis the profiles of big ET and ET 1-21 closely followed mortality, and blood concentrations of bacteria, endotoxin, TNF, IL-6, and lactate.

Topics: Animals; Bacteremia; Endothelin-1; Endothelins; Gram-Negative Bacterial Infections; Interleukin-6; Lactates; Lactic Acid; Lipopolysaccharides; Male; Peritonitis; Protein Precursors; Radioimmunoassay; Rats; Rats, Wistar; Time Factors; Tumor Necrosis Factor-alpha