leukotriene-b4 and bepafant

We investigated the contribution of eicosanoids, platelet-activating factor, tumor necrosis factor and nitric oxide to the neutrophil influx and development of pulmonary haemorrhagic lesions following immune-complex-induced pneumonitis in rats and possible interactions between these mediators. Increased levels of leukotriene B4 and tumor necrosis factor, measured by enzyme immunoassay and L-929 cytotoxicity assay, were found in the bronchoalveolar lavage 1 and 4 h after induction of the reaction, respectively, and their release was dependent on the previous generation of platelet activating factor. Antagonism of leukotriene B4 receptors by RO-0254094 (2-[(5-carboxypentyl])oxy]-6-[6-[3,4-dihydro-4-oxo-8-propyl-2H-1-benzopy ran-7-yl)oxy]hexyl] benzenepropanoic acid), inhibition of nitric oxide synthesis by L-NAME (Nw-nitro-L-arginine methyl ester) and antagonism of PAF-receptors by WEB-2170 (5-(2-chlorphenyl)-3-4-dihydro-10-methyl-3-((4-morpholinyl)carbony l)-2 H,7H-cyclopenta (4,5)thieno(3,2-f)(1,2,4)-triazolo-4,3,a)91,4)diazepine), significantly inhibited the intensity of haemorrhage, evaluated by the increased levels of extravascular hemoglobin in homogenates of lung tissues. Little evidence support the role of tumor necrosis factor in these lesions. The infiltration of neutrophils, evaluated by measuring myeloperoxidase in homogenates of lungs, was reduced by compounds L-663,536 (3-[1-(4 chlorobenzyl)-3-t-butyl thio-5-isopropylindol-2-yl]-2-2-dimethylpropanoic acid), WEB-2170 and L-NAME. These results indicate that neutrophil infiltration and haemorrhagic lesions in immune-complex-induced lung inflammation are mediated by platelet activating factor, leukotriene B4 and nitric oxide and point out to interesting interactions between these mediators.

Topics: Animals; Azepines; Bronchoalveolar Lavage Fluid; Immune Complex Diseases; Leukotriene B4; Lung; Male; Neutrophils; Nitric Oxide; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Triazoles; Tumor Necrosis Factor-alpha

Platelet-activating factor (PAF) is an endogenous phospholipid which may be an important mediator of shock and inflammation. Recent evidence suggests that PAF plays a role in the development of ischemic colitis and inflammatory bowel disease. Its effects are mediated by second messengers, including the arachidonic acid metabolites. Using an ex vivo isolated left colon rabbit perfusion model, our aims were to determine whether exogenously administered trinitrobenzene sulfonic acid (TNB), which produces experimental colitis, stimulates both PAF and eicosanoid release in the colon, and if so, whether this effect can be blocked by a PAF antagonist. Colonic inflammation was induced by the intracolonic administration of 0.25 ml of 50% ethanol containing 30 mg of TNB. Tissue and perfusate concentrations of the eicosanoids, [prostaglandin E (PGE2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2), leukotriene B4 (LTB4)] and the autocoid PAF were measured by ELISA. During TNB infusion there was a significant increase in tissue levels of PAF compared to control colons. Additional studies performed pretreating the colons with the PAF receptor antagonist WEB-2170 prior to TNB infusion blocked PAF release. TNB stimulated release of luminal eicosanoids except LTB4 and suppressed release of tissue prostanoids. Pretreatment with WEB-2170 prior to TNB inhibited luminal eicosanoids, and inhibited PGE2 and prostacyclin, but not TX tissue suppression. Inhibition of TNB-stimulated PAF release by WEB-2170 suggests that PAF may play a role in TNB-induced colitis and this phenomenon may mediate tissue injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Azepines; Colitis; Colon; Dinoprostone; Eicosanoids; Gastrointestinal Contents; Leukotriene B4; Platelet Activating Factor; Rabbits; Second Messenger Systems; Thromboxane B2; Triazoles; Trinitrobenzenesulfonic Acid

Previous studies have demonstrated that low shear rates promote leukocyte adherence to microvascular endothelium in postcapillary venules. The objective of this study was to determine whether an accumulation of inflammatory mediators such as platelet activating factor and leukotriene B4 is responsible for shear rate-dependent leukocyte-endothelial cell adhesion. Postcapillary venules (25-39 microns in diameter) in cat mesentery were studied by intravital microscopy. Venular wall shear rate was varied over a wide range by graded occlusion of the mesenteric artery. Red blood cell velocity, vessel diameter, leukocyte rolling velocity, and the numbers of rolling and adherent leukocytes were measured at each shear rate. In one series of experiments, shear rate-dependent leukocyte adherence was monitored at different superfusion rates (1.0 and 2.5 ml/min). At the lower superfusion rate, the number of adherent leukocytes was significantly higher at any given shear rate when compared with results obtained at the higher superfusion rate. This suggests that reduced washout of inflammatory mediators contributes to shear rate-dependent leukocyte adhesion. Pretreatment with different platelet activating factor receptor antagonists (WEB 2086 or WEB 2170) had no effect on the number of adherent leukocytes normally observed at lower shear rates, suggesting that platelet activating factor does not play a major role in this process. However, shear rate-dependent leukocyte adhesion was largely prevented by pretreatment with either a leukotriene B4 receptor antagonist (SC-41930) or a leukotriene synthesis inhibitor (L663,536). The results of this study indicate that a reduced washout of leukotriene B4 is responsible for the enhanced leukocyte adherence that occurs at low venular wall shear rates.

Topics: Animals; Antigens, CD; Azepines; Benzopyrans; Cats; CD18 Antigens; Endothelium, Vascular; Indoles; Leukocytes; Leukotriene B4; Mesenteric Veins; Platelet Activating Factor; Receptors, Leukocyte-Adhesion; Triazoles; Venules