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SUMMARY

The effects of exogenous platelet-activating factor (paf) were determined in anesthetized ponies. Administration of paf induced a decrease in cardiac index that resulted in systemic hypotension. This was followed by tachycardia, hypertension, and a return of cardiac index to baseline. Pulmonary aterial pressure increased markedly because of pulmonary vasoconstriction. Exogenous paf also caused leukopenia and thrombocytopenia. The specific PAP receptor antagonist (WEB 2086) blocked all paf-induced changes. Flunixin meglumine, a cyclooxygenase inhibitor, abolished the pulmonary hypertension and tachycardia, and attenuated the systemic hypotension but did not change the paf-induced peripheral cellular changes. The paf antagonist also inhibited platelet aggregation induced by paf in vitro. The paf-induced changes are similar to those reported after endotoxin exposure in horses.

Free access
in American Journal of Veterinary Research

Abstract

Objective—To develop an in vitro model of the bovine alveolar-capillary interface and to evaluate the roles of interleukin-8 (IL-8) and platelet-activating factor (PAF) in neutrophil-mediated endothelial injury induced by infection with Mannheimia haemolytica.

Sample Population—Cultured bovine pulmonary microvascular endothelial cells, freshly isolated bovine neutrophils, and monocyte-derived bovine macrophages.

Procedure—A coculture system was developed in which endothelial cells were grown to confluence in tissue culture inserts, neutrophils were added to the inserts, and macrophages were added to tissue culture wells. Mannheimia haemolytica-derived lipopolysaccharide (LPS) or supernatant was added to activate macrophages, and inhibitors of PAF or IL-8 were added to the insert. Endothelial cell cytotoxicity and permeability (ie, albumin leakage) and neutrophil activation (ie, adhesion, degranulation [lactoferrin expression], and superoxide production) were assessed.

Results—The addition of M haemolytica-derived LPS to bovine macrophages in the coculture system resulted in significant increases in endothelial cell cytotoxicity and permeability and neutrophil degranulation and adhesion. Inhibition of IL-8 reduced endothelial cell permeability and neutrophil degranulation induced by exposure to M haemolytica-derived supernatant, whereas inhibition of PAF decreased superoxide release by neutrophils.

Conclusions and Clinical Relevance—In vitro activation of bovine macrophages by M haemolyticaderived LPS resulted in neutrophil activation and neutrophil- mediated endothelial damage. Neutrophilmediated endothelial injury and neutrophil degranulation were, at least in part, mediated by IL-8, whereas PAF promoted superoxide release by neutrophils in this in vitro system designed to mimic the in vivo events that occur during the early stages of bovine pneumonic pasteurellosis. (Am J Vet Res 2002; 63:394–401)

Full access
in American Journal of Veterinary Research

Summary

Baseline plasma norepinephrine (ne) and epinephrine (epi) concentrations were measured in dogs with naturally acquired heart failure (hf) caused by either degenerative mitral valve disease and mitral regurgitation (mr) or idiopathic dilated cardiomyopathy (dcm). Compared with controls (clinically normal), dogs with hf had increased plasma ne concentration, which was correlated positively with clinical severity of hf. Dogs with the most severe degree of hf (New York Heart Association functional class IV) had mean ne concentration significantly (P < 0.05) greater than that of dogs with all other functional classes of hf. Overall, mean ne concentration in dogs with dcm was greater than that in dogs with mr. Plasma epi concentration was not different between control dogs and dogs with hf or between dogs with dcm or mr. Correlations were not found between the echocardiographically derived end systolic volume index (used as an estimate of myocardial function) and plasma ne and epi concentrations or serum sodium or potassium concentration. Dogs with dcm, as a group, had a small but Significant (P < 0.05) decrease in serum sodium concentration, compared with dogs with mr. This difference was maintained only for class-IV hf when dogs were separated according to functional hf class. In dogs with dcm, Significant inverse correlation was found between plasma ne and serum sodium concentrations. When grouped together, all dogs with hf maintained this relationship; however, dogs with mr did not have correlation between plasma ne and serum sodium concentrations. Plasma epi and serum sodium concentrations were not correlated for any group. It was concluded that in dogs, plasma ne, but not epi, concentration is high in relation to the clinical severity of naturally acquired hf. Although dogs with dcm overall had greater increase in plasma ne concentration than did dogs with primary mr, a direct relation was not evident between a noninvasive estimate of myocardial function and plasma ne concentration. The lower serum sodium values found in dogs with dcm, especially those with most severe clinical hf, along with the higher mean plasma ne concentration, may indicate a greater degree of decompensation and neurohumoral activation, compared with that in dogs with mr.

Free access
in Journal of the American Veterinary Medical Association

SUMMARY

The role of platelet-activating factor in mediating the cardiovascular and peripheral cellular responses to large-colon ischemia and reperfusion, was explored in anesthetized ponies. A specific platelet-activating factor (PAF) antagonist (WEB 2086) was administered to a group of 6 ponies, and another 6 ponies (controls) were given an equivalent volume of saline solution, prior to 1 hour of large-colon torsion. After correction of the torsion, ponies were monitored during the reperfusion period. Significant (P < 0.05) hypotension and metabolic acidosis developed in all ponies after correction of colonic torsion, cardiac index increased initially, but then decreased significantly (P < 0.05) over the study period. Mean times between correction of torsion and onset of cardiac failure and death were not different between groups. Significant (P < 0.05) thrombocytopenia developed during the reperfusion period in control ponies, but not in WEB-treated ponies. Blood leukocyte concentration in control ponies was more variable and significantly (P < 0.05) decreased immediately upon reperfusion, compared with that in WEB-treated ponies. We conclude that although the cardiovascular responses to colonic ischemia and reperfusion are not prevented by use of a specific paf-antagonist, specific peripheral cellular responses are mediated by paf.

Free access
in American Journal of Veterinary Research

after exposure to moldy hay. 2 Although the exact role neutrophils play in the pathogenesis of the condition is not clear, there is evidence that circulating blood neutrophils are activated in horses with severe equine asthma. 3–5 Neutrophils are the

Full access
in American Journal of Veterinary Research

laboratory to test for responsiveness of bovine T-cell subsets to specific antigens. Initially, 2-color flow cytometry 2–8 was used to detect a single T-cell marker and an activation marker CD25 on each cell. This method was improved to 4-color flow

Full access
in American Journal of Veterinary Research

Summary

Before dogs with lung tumors were treated by adoptive immunotherapy, the ability of canine blood lymphocytes (pbl) from the peripheral circulation to differentiate in vitro in the presence of human recombinant interleukin-2 (rIL-2) and become tumoricidal was investigated. The pbl from healthy dogs (n = 6) and dogs with lung tumors (n = 5) were grown in culture medium alone, in the presence of rIL-2 to generate lymphokine-activated killer (lak) cells, or with phytohemagglutinin (pha) and rIL-2 to generate autologous-stimulated lymphocytes (asl). After 4 days, cytotoxicity by the asl, lak, and pbl was determined in a 4-hour 51chromium-release assay. Target cells in the assay were short-term cultured enzyme digests of autologous (self), allogeneic (genetically different) primary tumors, and Raji, the xenogeneic human lymphoma cell line. The pbl cultured without rIL-2 were not cytotoxic against any tumor. However, when a dog's pbl were activated in vitro, they killed the dog's own tumor, asl more effectively than lak cells. Pulmonary adenocarcinomas and an osteosarcoma metastasis to lung were among the autologous tumors assayed. Against an allogeneic canine osteosarcoma, asl generated from healthy dogs were significantly more cytolytic than lak from healthy dogs, or than asl generated from tumorbearing dogs. Cytotoxicity was greater against allogeneic tumor than against Raji. Lectin-dependent cellular cytotoxicity, tested by including pha in the assay medium with lymphocytes and Raji cells, by asl and lak was greater than cytotoxicity of Raji without pha. Because asl were more cytolytic than lak against all targets in vitro, they may be more beneficial than lak for immunotherapy of canine tumors.

Free access
in American Journal of Veterinary Research

Summary

The role of platelet-activating factor (paf) in mediating the colonic damage that develops after large-colon torsion was studied in 14 ponies. Morphologic changes in areas of the ascending colon and selected abdominal and thoracic viscera after 1 hour of large-colon torsion and 3 to 5 hours of reperfusion were determined, as well as the protective effects of systemic administration of a specific paf antagonist (WEB 2086). Ponies were selected then allocated at random and in equal numbers to 2 groups that received 1 of 2 treatments prior to induction of large-colon torsion: group 1 —control (saline solution), and group 2 — WEB 2086 (3 mg/kg of body weight loading dose and 3 mg/kg/h for the remainder of the study). In each pony, full-thickness tissue specimens from the gastrointestinal tract —cecum, pelvic flexure, left and right ventral colon, and right dorsal colon —heart, left lung, liver, left adrenal gland, spleen, and right kidney were collected and histologically evaluated. Edema, mucosal necrosis, and neutrophil infiltration in colonic sections were graded from 0 (normal) to 3 (most severe changes). Sections of liver and lung from 3 ponies in each group, and colon from 1 pony in each group, also were examined by transmission electron microscopy to determine the presence of ultrastructural alterations.

Ischemia and reperfusion induced marked changes in all sections of colon in all ponies: moderate to severe submucosal edema, moderate necrosis of the superficial epithelium and lamina propria, and necrosis of the mucosal crypt epithelium. Extra-vascular neutrophil accumulation was evident in all sections of colon and cecum, but not in other tissues. Ultrastructural lesions were not present in hepato-cytes or pneumocytes, or in the endothelial cells of liver, lung, and colon. Bacteria were observed by electron microscopy in 5% of hepatic sinusoids. Administration of a specific paf antagonist, WEB 2086, failed to reduce severity of the observed lesions, indicating that it was not cytoprotective at the dosage used in this model of ischemia-reperfusion injury.

Free access
in American Journal of Veterinary Research

Summary

Labor and delivery stimulate increased release of catecholamines and endogenous opioid peptides in neonates. Catecholamines promote adaptation to the extrauterine environment after birth. Enkephalins are stored together with catecholamines in the adrenal medulla and have an inhibitory effect on catecholamine release. We investigated the influence of labor and neonatal hypoxia on epinephrine, norepinephrine, and met-enkephalin release in calves. Blood samples were taken from the umbilical artery before rupture of the umbilical cord and from the jugular vein repeatedly after birth. Highest plasma norepinephrine concentration was found in calves delivered at the end of gestation (term calves) before umbilical cord rupture. In calves delivered before the physiologic end of gestation (preterm calves), norepinephrine values increased after cord rupture, but remained lower than values in term calves. Epinephrine release followed a similar pattern, but norepinephrine was clearly predominant. In term calves, met-enkephalin values were significantly higher than values in preterm calves. In calves of both groups, met-enkephalin release increased after cord rupture. During birth, the increase in catecholamine release seems to take place earlier than that of enkephalins. Norepinephrine-dominated stimulation during expulsion of the calf might be followed by increasing enkephalinergic inhibition after cord rupture and onset of respiration. Reduced release of catecholamines and enkephalins in preterm calves may be connected with delayed adaptation to the extrauterine environment.

Free access
in American Journal of Veterinary Research
in Journal of the American Veterinary Medical Association