lexipafant and Ischemia

Intestinal ischemia and reperfusion (I/R) injury may result in development of the systemic inflammatory response syndrome (SIRS). The interactions between activated leukocytes and endothelial cells, mediated by adhesion molecules, seem to be pivotal in these conditions, leading as they do to extravasation of circulating leukocytes within the inflamed tissue. The intercellular adhesion molecule-1 (ICAM-1) mediating firm adhesion of activated leukocytes is upregulated in many organs after I/R injury, but the regulatory mechanisms are complex and have not been fully investigated.. We evaluated whether ICAM-1 expression was linked with a potential protective effect of N-acetyl-L-cysteine (NAC) and the platelet activating factor (PAF) inhibitor (Lexipafant), administered 15 min after the start of reperfusion, in a model of intestinal ischemia (40 min) and reperfusion (12 h) in the rat.. ICAM-1 expression increased significantly in the ileum, colon, lungs and pancreas after intestinal I/R. Treatments with NAC and the PAF inhibitor did not affect this response. An increased endothelial albumin-leakage was observed in the same organs after I/R. Treatment with NAC reduced the endothelial leakage of albumin in the ileum, colon and lungs, whereas administration of the PAF inhibitor alone demonstrated a protective effect only in the ileum. Furthermore, neutrophil sequestration in the lungs and IL-1beta levels in plasma increased significantly after I/R, and these changes were markedly reduced by both treatment regimes.. The protective effect of NAC and the PAF inhibitor Lexipafant in intestinal I/R injury is not due to a decreased expression of ICAM-1.

Topics: Acetylcysteine; Animals; Cytoprotection; Free Radical Scavengers; Imidazoles; Intercellular Adhesion Molecule-1; Interleukin-1; Intestinal Mucosa; Intestines; Ischemia; Leucine; Male; Neutrophil Infiltration; Permeability; Platelet Activating Factor; Rats; Rats, Sprague-Dawley; Reperfusion Injury

This study aimed at evaluating the role of platelet-activating factor (PAF) on cardiovascular dysfunction in postischemic shock in pigs. Sixteen pigs were randomly allocated to two groups of eight each. Their aorta was clamped above the celiac axis for 45 min and then declamped. The animals were studied for 2 h after declamping. They were given a continuous infusion of Hartmann's solution 6.75 ml/kg/h throughout the experiment. The experimental group was given a potent specific PAF receptor antagonist 15 min before reperfusion (BB-882 1 mg/kg bolus followed by continuous infusion of 1 mg/ kg/h till the end of the experiment). The control group was given vehicle instead. Reperfusion in the control group caused prolonged hypotension (mean arterial pressure (SEM): 29 (1) mm Hg, immediately after declamping, compared with 74 (3) at baseline), an increase in pulmonary vascular resistance (491.6 (51.5) dyn.s.cm-5, 2 h after declamping, compared with 274.2 (19.4) dyn.s.cm-5 at baseline), a reduction in cardiac output (1.75 (0.15) liters/min, 2 h after declamping, compared with 2.8 (0.21) liters/min at baseline), hyperglycemia (13.7 (0.8) mmol/l, immediately after declamping, compared with 6.26 (0.6) mmol/l at baseline), and lactic acidemia (11.28 (0.5) mmol/l, immediately after declamping, compared with 4.55 (0.67) mmol/l at baseline). BB-882 did not improve any of these variables. PAF does not play a major role on cardiovascular dysfunction in postischemic shock in pigs.

Topics: Animals; Hemodynamics; Heparin; Ischemia; Leucine; Platelet Activating Factor; Shock; Swine