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D R Robinson

Publications and source records attributed to D R Robinson.

At least 55 records · Page 3Linked to original sources
PubMed1991

Leukotrienes, thromboxane A2, and prostaglandins during systemic anaphylaxis in sheep.

We investigated the roles of eicosanoid mediators in acute systemic anaphylaxis in anesthetized sheep. Sheep were sensitized with dinitrophenylated Ascaris suum extract and were challenged with an intravenous injection of dinitrophenylated bovine serum albumin. During anaphylaxis, cyclooxygenase inhibitors eliminated the elevation of arterial plasma levels of thromboxane B2 and 6-ketoprostaglandin F 1 alpha but markedly elevated the levels of leukotriene E4 in lung lymph without significantly eliminating elevation of plasma levels of histamine. Most of the measured physiological abnormalities accompanying anaphylaxis were aggravated by cyclooxygenase blockade. Enhancement of this anaphylactic mediator response was associated with an accentuated and prolonged increase of airway pressure (P less than 0.05, compared with sensitized, antigen-challenged but otherwise untreated sheep), a more intense hypoxemia (P less than 0.0001), and leukopenia (P less than 0.001), changes that were largely eliminated by pretreating with the sulfidopeptide leukotriene (SPLT) antagonist FPL 55712, suggesting that the SPLTs were important mediators of these responses. In contrast, the prolonged, but less severe, systemic vascular collapse and the reduced pulmonary hypertension induced by cyclooxygenase inhibitors were not influenced by the SPLT antagonist. These results demonstrate that in sheep cyclooxygenase metabolites are mainly involved in the acute, but transient, systemic and pulmonary vascular response of systemic anaphylaxis, whereas SPLTs are primarily implicated in the airway and secondary cardiovascular response. SPLT may act either directly or by potentiating the release of and reactivity to histamine and other mediators. Our data therefore suggest that a combination of cyclooxygenase and lipoxygenase inhibition will be necessary to more effectively protect against the consequences of an anaphylactic reaction.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Alleviation of autoimmune disease by dietary lipids containing omega-3 fatty acids.

Dietary marine lipids that are enriched in omega-3, or n-3, fatty acids reduce the severity of autoimmune glomerulonephritis in several inbred murine strains. The protective effect of dietary n-3 fatty acids is also seen with a rat model of immune-complex induced vasculopathy, but no protective effects were seen with autoimmune vasculitis in the MRL/lpr mouse or with type II collagen-induced arthritis in rats. Dietary n-3 fatty acids are potential therapeutic agents for the treatment of autoimmune diseases, but careful clinical trials with the purified forms of n-3 fatty acids are needed to determine the usefulness of this intervention.

Animals↗
PubMed1990

Neutralization of low molecular weight heparin by polybrene prevents thromboxane release and severe pulmonary hypertension in awake sheep.

Protamine reversal of heparin anticoagulation in patients is occasionally associated with life-threatening acute pulmonary hypertension. In a sheep model, we evaluated the effect on this adverse cardiopulmonary reaction of modifying the type of heparin (low molecular weight heparin compared with unfractionated heparin) and the type of heparin antagonist (polybrene compared with protamine). Protamine reversal of low molecular weight heparin (LMWH) and polybrene reversal of unfractionated heparin induced more than a 10-fold increase of plasma thromboxane B2 levels, a threefold increase of pulmonary vascular resistance and pulmonary artery pressure, and a 25% decrease of PaO2. A similar adverse reaction followed protamine reversal of conventional unfractionated heparin. However, with polybrene (1 mg/kg) reversal of LMWH (1 mg/kg), we measured neither pulmonary hypertension (pulmonary artery pressure was 22.6 +/- 3.6 mm Hg at 1 minute after polybrene reversal of LMWH compared with 47.9 +/- 4.2 mm Hg after protamine reversal of unfractionated heparin, p less than 0.005 groups differ), hypoxemia (PaO2 was unchanged 2 minutes after polybrene compared with a decrease of 26 mm Hg 2 minutes after protamine, p less than 0.05), nor acute release of thromboxane into arterial plasma (thromboxane B2 was 0.2 +/- 0.1 at 1 minute after polybrene compared with 3.7 +/- 1.7 ng/ml at 1 minute after protamine, p less than 0.005). The hemodynamic effects and mediator release were also benign after neutralization of larger doses of LMWH (3 mg/kg) by polybrene (3 mg/kg). The increases of activated clotting time and activated partial thromboplastin time due to both types of heparin were completely reversed with polybrene. Anti-Xa activity increased to more than 3 IU/ml 4 minutes after LMWH anticoagulation (p less than 0.01) but was only partially neutralized by polybrene. Various polyanion-polycation complexes that are formed when heparin anticoagulation is reversed induce thromboxane release and acute pulmonary vasoconstriction in awake sheep. Reversal of LMWH anticoagulation with polybrene does not elicit this adverse reaction.

Animals↗
PubMed1990

Thromboxane receptor blockade prevents pulmonary hypertension induced by heparin-protamine reactions in awake sheep.

We used competitive thromboxane A2-prostaglandin endoperoxide receptor blockade (SQ 30,741) as a probe to evaluate the role of thromboxane in ovine pulmonary vasoconstriction associated with protamine reversal of heparin anticoagulation. Control heparin-protamine reactions induced rapid release of thromboxane into arterial plasma (more than 1 ng/ml plasma), a 2.5-fold increase of pulmonary artery pressure, a 20% decrease of PaO2, and a 30% reduction in arterial white blood cell concentration. After giving SQ 30,741 despite similar thromboxane release into arterial plasma after heparin-protamine challenge, acute pulmonary hypertension was significantly reduced when 94% of pulmonary vascular smooth muscle thromboxane receptors were occupied with SQ 30,741 (p less than 0.01 at 1 minute after protamine versus control heparin-protamine reaction) and was completely abolished by a 10 mg/kg i.v. bolus (p less than 0.0001 at 1 minute after protamine versus control). Peripheral leukopenia was not affected by SQ 30,741 prophylaxis, but hypoxemia was prevented. We conclude that thromboxane causes pulmonary vasoconstriction in ovine heparin-protamine-induced pulmonary hypertension. Pulmonary vasoconstriction and hypoxemia can be completely prevented by thromboxane receptor blockade.

Animals↗
PubMed1989

Defective signal transduction in CD4-CD8- T cells of lpr mice.

Mice homozygous for the lpr gene develop a lymphoproliferative disorder due to expansion of a subset of CD4-CD8- T cells. Triggering of the T-cell receptor in these lpr T cells does not lead to translocation of protein kinase C or phosphorylation of CD3, interleukin-2 production, or proliferation, whereas a combination of phorbol ester and calcium ionophore does. Stimulation with concanavalin A or anti-CD3 induces phosphoinositide hydrolysis. The rise in inositol bisphosphate, inositol triphosphate, and inositol tetrakisphosphate, identified by HPLC, is similar in +/+ and lpr T cells. The concentration of cytoplasmic free calcium ([Ca2+]i), however, under basal and stimulated conditions is significantly lower in lpr T cells. The lower basal [Ca2+]i may explain why induction of proliferation with phorbol ester and calcium ionophore requires a higher concentration of ionophore in these cells than in normal T cells. The lower [Ca2+]i obtained on stimulation may contribute to the activation defect of CD4-CD8- lpr T cells.

Animals↗
PubMed1989

Dietary marine lipid does not alter susceptibility of (NZBxNZW)F1 mice to pathogenic microorganisms.

Female (NZBxNZW)F1 mice were fed for one month with a diet in which the sources of fat were either melted beef tallow or fish oil, the latter regimen being associated with a marked decrease in the expression of auto-immune disease in these animals. To test whether or not this beneficial effect was associated with an increased risk of infection, animals fed each of these diets were challenged intraperitoneally with graded doses of four different classes of microorganisms: a gram positive bacillus that is an intracellular parasite (Listeria monocytogenes), an exotoxin-producing gram negative bacillus (Pseudomonas aeruginosa), a yeast (Candida albicans), and a herpes group virus (murine cytomegalovirus). There was no difference in the susceptibility of the animals fed the two different diets to any of these infections as shown by either determinations of the LD50 for each organism or by assessment of the times of survival for those animals that did succumb. We conclude that the beneficial anti-inflammatory effects of fish oil diets in these mice are not associated with an increased risk of infection with a variety of microbial agents.

Animals↗
PubMed1989

Effect of fish-fat or beef-fat supplemented diet on immune complex-induced enteropathy in the rat.

In contrast to animals on a beef fat-supplemented diet (BFD), animals maintained on a fish fat-supplemented diet (FFD) incorporate increased amounts of eicosapentaenoic acid (EPA) into membrane phospholipids. Generation of lipid mediators from such tissues favors the formation of compounds with less pro-inflammatory activity than are derived from tissues poor in EPA. Nevertheless, the FFD has not had a uniformly beneficial effect on animal models of inflammatory diseases. We previously showed that intravenous injection of rat anti-BSA-BSA complexes (IC) prepared in 5x antigen excess rapidly induced a striate pattern of serosal (to mucosal) hemorrhage and vascular congestion throughout the small intestine. In this study, we tested the effect of a BFD and FFD on immune complex-induced enteropathy. After six (Expt. 1) or eight weeks (Expt. 2) on the diet, rats were injected with IC and the severity of serosal hyperemia in the small intestine was scored. In some FFD, no lesions were seen under conditions which elicited moderate to severe lesions in BFD rats. In Expt. 1 involving 22 rats and in Expt. 2 involving 28 rats, those on the FFD had a significantly lower composite lesional score compared to those on the BFD, p less than 0.005 and p less than 0.005, respectively. These results indicate that the FFD had a beneficial effect on IC-induced enteropathy. It is suggested that this effect of the FFD may be mediated primarily by a reduction in availability of platelet-activating factor.

Animals↗
PubMed1989

Dietary marine lipids suppress murine autoimmune disease.

Dietary marine lipids reduce both mortality and the severity of glomerulonephritis in inbred murine strains which develop spontaneous autoimmune disease. The protective effects of marine lipids appear to be accounted for by the major n-3 fatty acids in these preparations, 20:5 and 22:6. The n-3 fatty acids in dietary fish oil are extensively incorporated into several lipid classes in the spleen of autoimmune mice, including phosphatidylinositol, phosphatidylethanolamine, plasmalogens and saturated ether-linked phospholipids as well as diacylphosphoglycerides. The effects of dietary marine lipids on autoimmune disease in experimental models are highly specific. Careful controlled trials will be required to establish the role of dietary marine lipids in the therapy of human autoimmune disease.

Animals↗
PubMed1989

Effect of platelet depletion on lung vasoconstriction in heparin-protamine reactions.

In six awake sheep the control heparin-protamine reaction was associated with a 150-fold rise in arterial plasma thromboxane B2 (TxB2) levels, a 4.5-fold increase in pulmonary vascular resistance, a 20% decrease in cardiac output, a 30% decrease in arterial PO2, and a 30% reduction in arterial white blood cell concentrations. Depletion of 99% of circulating platelets by antibodies did not prevent either acute and severe pulmonary hypertension or increased plasma TxB2 levels induced by heparin-protamine administration. We produced sheep platelet aggregation in vitro with bovine thrombin and measured marked TxB2 release (36.3 +/- 16.3 ng/10(9) platelets). In contrast, neither heparin, protamine, nor heparin-protamine complexes over a 10,000-fold range of concentrations induced platelet aggregation and release of thromboxane in vitro. Therefore sheep platelets are not the source of thromboxane production associated with acute pulmonary hypertension during the heparin-protamine reaction, and other cells must produce the thromboxane.

Animals↗
PubMed1989

Tolerance to low-dose endotoxin in awake sheep.

Dose response and tolerance to a small intravenous dose of Serratia marcescens lipopolysaccharide (LPS) were studied in awake sheep. Core temperature significantly increased after a dose of 0.002 micrograms/kg; changes in pulmonary arterial pressure, pulmonary vascular resistance, plasma thromboxane B2, and circulating leukocyte concentration occurred after 0.02 micrograms/kg; plasma 6-keto-prostaglandin F1 alpha increased after 0.2 micrograms/kg. Development of acute tolerance was studied by injection of S. marcescens LPS (0.02 micrograms/kg iv) on 3 consecutive days: pulmonary arterial pressure and thromboxane B2 levels were significantly lower than controls after the second dose, whereas fever and the degree of leukopenia were not diminished until the third dose. After intravenous administration of LPS given in increasing doses from 0.1 to 3.2 micrograms/kg three times weekly over 7 wk, there were no measurable changes in any of the above parameters after challenge with S. marcescens LPS (0.02 micrograms/kg) after a 1-wk rest period. In awake sheep, small intravenous doses of LPS can cause physiologically important changes of the pulmonary circulation and can alter the hemodynamic and eicosanoid mediator responses to subsequent challenges with LPS. Large intravenous doses of LPS can ablate the physiological responses to subsequent small doses of LPS.

Animals↗
PubMed1989

Effects of recombinant human tumor necrosis factor alpha, lymphotoxin, and Escherichia coli lipopolysaccharide on hemodynamics, lung microvascular permeability, and eicosanoid synthesis in anesthetized sheep.

We infused recombinant human tumor necrosis factor alpha (rhTNF alpha), lymphotoxin (rhLT), and Escherichia coli 0111:B4 lipopolysaccharide (LPS) into anesthetized sheep with a lung lymph fistula to compare their effects on systemic and pulmonary hemodynamics, lung lymph dynamics, and eicosanoid release. rhTNF alpha (25-150 micrograms/kg, n = 6 sheep), but not rhLT (25 micrograms/kg, n = 3), rapidly increased lung lymph and plasma levels of 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha) and caused profound systemic vasodilation and hypotension. Meclofenamate pretreatment (10 mg/kg) of three other sheep given 25 micrograms/kg rhTNF alpha prevented the increase of lymph and plasma 6-k-PGF1 alpha levels, systemic vasodilation, and the early (less than 2 hrs) but not the late (4-6 hours) hypotension caused by rhTNF alpha. LPS (1 micrograms/kg, n = 11) induced a briefer increase of lymph 6-k-PGF1 alpha levels than did rhTNF alpha while plasma 6-k-PGF1 alpha levels did not increase. LPS induced more gradual hypotension than did rhTNF alpha but did not cause systemic vasodilation. LPS and rhTNF alpha, but not rhLT, increased lymph thromboxane B2 (TXB2) levels during the first hour of study, whereas only LPS acutely increased plasma TXB2 levels. LPS caused acute pulmonary vasoconstriction and greater acute pulmonary artery hypertension than did either rhTNF alpha or rhLT. Whereas LPS-treated sheep required less fluid transfusion than rhTNF alpha-treated sheep to maintain mean systemic arterial pressure greater than 50 mm Hg, LPS infusion caused a greater increase of lung lymph protein clearance. rhTNF alpha caused minimal alterations of lung microvascular permeability. We conclude that eicosanoid mediators contribute importantly to differences of systemic and pulmonary hemodynamics caused by these agents in sheep. rhTNF alpha cannot account for all of the LPS-induced hemodynamic, lung lymph, and eicosanoid responses in sheep.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Management of gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs during the therapy of rheumatic diseases. The rheumatologist's perspective.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapeutic agents for many important rheumatic diseases. A large body of evidence indicates that the anti-inflammatory effects as well as the toxic side effects of NSAIDs can be attributed to their ability to inhibit prostaglandin synthesis. The most frequent side effect leading to discontinuation of NSAID therapy is upper gastrointestinal toxicity. This is a major problem for rheumatologists and their patients since alternatives to NSAIDs are not readily available. The mechanism of upper gastrointestinal toxicity associated with NSAIDs can be attributed to their common ability to inhibit gastric PGE2 synthesis, which suggests that gastrointestinal side effects often may not be avoided by substituting another NSAID, a prediction borne out by many patients with rheumatic diseases. However, there is some evidence that some patients may differ in their susceptibility to gastrointestinal and other toxic effects, though this concept has not been rigorously studied in clinical trials. Thus, although changing the specific NSAID may prevent gastrointestinal toxicity in some patients, many are intolerant to all NSAIDs. Patients who benefit from a specific NSAID, but in whom gastrointestinal toxicity develops, have limited options. Another NSAID may be substituted but at the risk of losing therapeutic efficacy and/or of continuing toxicity. Alternatively, the side effects may be controlled while continuing therapy with the NSAID by one of several measures, including the use of antacids or a histamine (H2)-receptor antagonist, such as cimetidine. The use of enteric-coated salicylates or nonacetylated salicylates may also provide satisfactory alternatives. However, patients who have experienced major gastrointestinal toxicity, such as massive bleeding or active peptic ulcers, should usually avoid NSAID therapy.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Heat cleavage of bacteriophage T4 gene 23 product produces two peptides previously identified as head proteins.

During studies on the intracellular protein pools of bacteriophage T4, we found that amber mutants in gene 23 blocked the synthesis of a 20-kilodalton (kDa) protein. Radiolabeled amino acid pulses showed that the protein appears at 8 min postinfection with kinetics similar to those of other major late species. Pulse-chase experiments demonstrated that the 20-kDa protein behaves like a primary product and also revealed a 29-kDa protein which, like other proteins cleaved during head assembly, appeared only after a long chase. Both species have been identified as constituents of the T4 head and have resisted previous efforts to identify their genetic origin. The dependence of the 20- and 29-kDa head proteins on the presence of gene 23 protein (gp23) and the observation that the sum of their masses equalled that of mature cleaved gp23 suggested that these two proteins were derived from this major capsid species. Evidence is presented demonstrating that heating samples before electrophoresis causes peptide bond cleavages in gp23, leading to the formation of the two peptides. As predicted by the results of Rittenhouse and Marcus (Anal. Biochem. 138:442-448, 1984), the cleavage occurs at Asp-336-Pro-337 and at two other Asp-Pro sites. Limited heat-induced proteolysis followed by two-dimensional gel analysis provided a peptide map of gp23 useful in the characterization of its assembly-related cleavages.

Alleles↗
PubMed1988

Acute pulmonary vasoconstriction and thromboxane release during protamine reversal of heparin anticoagulation in awake sheep. Evidence for the role of reactive oxygen metabolites following nonimmunological complement activation.

When protamine (2 mg/kg) was injected intravenously into awake sheep 5 minutes after infusing heparin (200 units/kg), there was transient diffuse pulmonary vasoconstriction with mean pulmonary arterial pressure increasing from 18.0 +/- 0.7 to 43.8 +/- 2.7 mm Hg at 1 minute (x +/- SEM; n = 10). In addition, there was profound leukopenia (36.9 +/- 7.7% of baseline values at 2 minutes) with transpulmonary leukocyte sequestration and transiently elevated plasma concentrations of C3a (from 420 +/- 146 to 1,599 +/- 249 ng/ml; n = 3, p less than 0.01) and thromboxane B2 (from 0.30 +/- 0.05 to 6.3 +/- 2.8 ng/ml; n = 10, p less than 0.0001), without significant increases of plasma 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, leukotrienes, or histamine. Intravenous injection of protamine alone produced no hemodynamic effects and did not increase plasma levels of vasoconstrictor eicosanoids. Intravenous pretreatment with either a cyclooxygenase inhibitor or a hydrogen peroxide scavenger (dimethylthiourea) blocked both the increases of thromboxane levels and the pulmonary vasoconstriction.

Animals↗
PubMed1988

Bicyclists, helmets and head injuries: a rider-based study of helmet use and effectiveness.

We interviewed 516 bicyclists over age 10 regarding helmet use and head injuries. Although 19 per cent owned helmets, only 8 per cent were wearing them when interviewed. Riders wearing helmets were more highly educated and reported higher car seat belt use. Nearly 4 per cent of the bicyclists reported striking their heads in a cycling mishap during the previous 18 months; those wearing helmets at the time of the mishap were less likely to have sustained head injuries.

Adult↗
PubMed1988

Dietary marine lipids after the course of autoimmune disease.

Dietary marine lipids reduce both mortality and the severity of glomerulonephritis in inbred murine strains which develop spontaneous autoimmune disease. The protective effects of marine lipids appears to be accounted for by the major n-3 fatty acids in these preparations, 20:5 and 22:6. The n-3 fatty acids in dietary fish oil are extensively incorporated into several lipid classes in the spleen of autoimmune mice, including phosphatidylinositol, phosphatidylethanolamine, plasmalogens and saturated ether-linked phospholipids as well as diacylphosphoglycerides. The effects of dietary marine lipids on autoimmune disease in experimental models are highly specific. Careful controlled trials will be required to establish the role of dietary marine lipids in the therapy of human autoimmune disease.

Animals↗