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Biomedical subjects

M J Thomas

Publications and source records attributed to M J Thomas.

At least 181 records · Page 10Linked to original sources
PubMed1984

Neutrophil degranulation responses to combinations of arachidonate metabolites and platelet-activating factor.

Polymorphonuclear neutrophils, when stimulated, rapidly form platelet-activating factor (PAF) and metabolize their arachidonate into 5-hydroperoxyeicosatetraenoate (5-HPETE), 5-hydroxyeicosatetraenoate (5-HETE), leukotriene (LT)A4, and LTB4. PAF and LTB4 degranulate neutrophils; 5-HETE, while lacking intrinsic degranulating actions, potentiates these responses. We now find that: a) 5-HPETE similarly potentiates the two lipids and has weak degranulating actions, b) LTA4 and LTB4 degranulate neutrophils by a common pathway, c) PAF degranulates neutrophils by a distinctly different pathway, d) the actions of either LT are additive to those of PAF, e) 5-HETE is particularly effective in potentiating response to combinations of PAF and LTB4, and f) combinations of the lipids partially circumvent requirements for cytochalasin B in these degranulation responses. Thus, the five lipids can be classified into potentiators (i.e., 5-HPETE and 5-HETE) and two types of independently acting agonists (i.e., LT's are one type, PAF a second type). At low concentrations, potentiator, LT, and PAF can all interact to produce prominent responses. They may similarly interact to promote function within their cells of origin.

Arachidonic Acids↗
PubMed1983

5-L-hydroxy-6,8,11,14-eicosatetraenoate potentiates the human neutrophil degranulating action of platelet-activating factor.

Platelet-activating factor (AAGPC) and two of its structural analogues degranulated human neutrophils with respective potencies that were increased up to 100 to 1000-fold by 16 nM to 5 microM of 5-L-hydroxyeicosatetraenoate (5-L-HETE). 5-rac-HETE had similar actions but 8-rac-HETE was without effect. Furthermore, 5-L-HETE did not influence the degranulating actions of C5a, A23187 or a formalated oligopeptide chemotactic factor and none of the HETEs, by themselves, caused degranulation. Thus, 5-L-HETE and AAGPC selectively interact to induce degranulation. Since these products rapidly form in stimulated PMNs, they may serve as potentiator and agonist, respectively, to transduce biological signals into cell function.

Arachidonic Acids↗
PubMed1983

Potentiating actions of hydroxyeicosatetraenoates on human neutrophil degranulation responses to leukotriene B4 and phorbol myristate acetate.

Previous studies demonstrated that the arachidonate metabolite, 5-L-hydroxy-6,8,11,14-eicosatetraenoate (5-L-HETE), potentiates the human polymorphonuclear neutrophil degranulation response to platelet-activating factor without influencing this response when elicited by C5a, a formylated oligopeptide, or ionophore A23187. We now find that the HETE amplifies the degranulation response to phorbol myristate acetate and leukotriene B4. The HETE was active in dosages as low as 50 nM; at 5 microM, it produced 1000-, 30-, and 5-fold enhancements in the potencies of platelet-activating factor, phorbol myristate acetate, and leukotriene B4, respectively. 5-rac-HETE had similar actions but 8-rac-HETE, 9-rac-HETE, and 12-L-HETE possessed little or no effects. Thus, 5-L-HETE potentiates the actions of various structurally unrelated degranulating agents; it particularly influences those compounds which, like 5-L-HETE itself, are formed by stimulus-activated neutrophils, viz., leukotriene B4 and platelet-activating factor. These latter two lipids and 5-L-HETE may interact to mediate neutrophil degranulation responses.

Arachidonic Acids↗
PubMed1982

Identification and quantitation of electron-transport components in human polymorphonuclear neutrophils.

Using dithionite difference spectra we have detected cytochrome b in highly purified human neutrophils at a concentration of 0.08 nmol/mg protein. The presence of quinone was identified in lipid extracts at a concentration of approx. 0.06 nmol/mg protein. It was identified as ubiquinone-10 by mass spectrographic analysis. Simultaneous measurements of cytochrome oxidase indicated that these compounds could not be attributed to mitochondrial contamination. These results are compatible with the hypothesis that initiation of the respiratory burst in human neutrophils involves a multicomponent electron-transport system.

Cytochrome b Group↗
PubMed1982

The role of superoxide in xanthine oxidase-induced autooxidation of linoleic acid.

The effect of hydroxyperoxyoctadecadienoic acid, e.g. 13-hydroperoxy-cis,9,trans-11-octadecadienoic acid, on the autooxidation of linoleic acid induced by superoxide radical was examined in a system containing xanthine oxidase, acetaldehyde, and diethylenetriaminepentaacetic acid dissolved in an aqueous phosphate buffer containing 10% ethanol. The superoxide radical is required for autooxidation, as shown by essentially complete inhibition on the addition of superoxide dismutase. Pure linoleic acid was not readily oxidized, but the addition of lipid hydroperoxide markedly stimulated the autooxidation. Addition of 2.8 microM FeCl3 did not produce an increase in the rate of xanthine oxidase-induced autooxidation. Spontaneous autooxidation, a process slower than xanthine oxidase-induced autooxidation, was detectable on the time scale of these observations but was slower than the xanthine oxidase-induced autooxidation. Initiation of linoleic acid autooxidation is postulated to result from a reaction between superoxide and lipid hydroperoxide. The nature of this reaction is uncertain, but it does not appear to depend on iron catalysis.

Animals↗
PubMed1982

Plasma lactoferrin levels in pregnancy and cystic fibrosis.

Plasma lactoferrin levels were determined by radioimmunoassay for the different weeks of normal pregnancy, in normal healthy adults and in children with and without cystic fibrosis. The lactoferrin levels were higher in pregnancy than in both male and female normal adults and showed a slight progressive increase up to week 29 and thereafter remained high. Five our of seven children with cystic fibrosis had markedly raised plasma lactoferrin levels from six to 16 times higher than the mean of a control group of children.

Adolescent↗
PubMed1982

Platelet activating factor. Stimulation of the lipoxygenase pathway in polymorphonuclear leukocytes by 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine.

1-O-Alkyl-2-O-acetyl-sn-glycero-3-phosphocholine (AAGPC) triggered the release of [3H]arachidonate but not [14C]stearate from cellular phospholipids in cytochalasin B-treated rabbit polymorphonuclear leukocytes. Concentrations of AAGPC up to 20 nM caused a dose-dependent release and subsequent metabolism of the released [3H]arachidonic acid. Most of the release of the [3H]arachidonate had taken place within the first 2 min of stimulation. Phosphatidylinositol and phosphatidylcholine served as the sources of [3H]arachidonate with about 50% of the label coming from each pool. Challenge of cytochalasin B-treated polymorphonuclear leukocytes with AAPGC led to the production of [3H]hydroxyeicosatetraenoic acids and [3H]dihydroxyeicosatetraenoic acids. No significant production of [3H]prostaglandins or [3H]thromboxanes was detected. AAGPC also caused a dose-dependent degranulation of cytochalasin B-treated rabbit polymorphonuclear leukocytes as shown by the release of beta-glucuronidase and lysozyme. Both the AAGPC-stimulated production of arachidonate metabolites and the degranulation response were blocked by eicosatetraynoic acid and non-dihydroguaiaretic acid at similar inhibitor concentrations. These findings suggest the bioactions of AAGPC on polymorphonuclear leukocytes may be mediated by the release of arachidonic acid and the production of mono- and dihydroxyeicosatetraenoic acids.

Animals↗
PubMed1982

Bilirubin and alkaline phosphatase values before and after surgery for biliary obstruction.

From a study of 178 patients who underwent operation for biliary obstruction, we found that preoperative bilirubin values above 14 mg/dl and alkaline phosphatase values over 5 times normal meant that common duct stones were an unlikely cause of the obstruction. Jaundice for more than 4 weeks before operation, bilirubin values greater than 10 mg/dl and the presence of significant fibrosis in the portal spaces indicated a lower than average chance of postoperative resolution of jaundice. After successful biliary surgery, the rate of decrease in serum alkaline phosphatase was haphazard and of little diagnostic value. The postoperative rate of decrease in the bilirubin values followed first-order kinetics and averaged 8 percent/day. This rate was not significantly influenced by the disease process, the length of preoperative clinical jaundice or the absolute height of the preoperative serum bilirubin level.

Alkaline Phosphatase↗
PubMed1982

Usefulness of diagnostic tests for biliary obstruction.

We studied the value of tests commonly used in diagnosing obstructive jaundice in 188 patients operated on for biliary obstruction. Ultrasonography had a diagnostic accuracy of 87 percent for gallbladder stones, 82 percent for dilated ducts, and 80 percent for pancreatic masses. Computed tomography was 93 percent accurate in diagnosing dilated ducts, and 93 percent accurate in diagnosing a pancreatic mass. Intravenous cholangiography gave useful information in only 4 of 21 patients. Among 45 patients, endoscopic retrograde cholangiopancreatography was technically successful in 91 percent and gave accurate diagnostic information in 86 percent and partially diagnostic information in 7 percent; it detected all cases of common duct stones and had a 91 percent sensitivity for detecting pancreatic cancer. Among 75 patients, transhepatic cholangiography was technically successful in 95 percent and provided accurate diagnostic information in 90 percent and partially diagnostic information in 3 percent; it detected all cases of common duct stones and 95 percent of cases of benign strictures. With persistent jaundice, ultrasonography should be the first test because it is less costly than computed tomography and provides similar information. If more information is needed, transhepatic cholangiography and endoscopic retrograde cholangiopancreatography are equally accurate; transhepatic cholangiography more often opacifies the proximal biliary tree and endoscopic retrograde cholangiopancreatography provides direct access to the ampulla of Vater and the pancreatic duct.

Bile Duct Diseases↗
PubMed1982

The effect of free radical derived hydroxyeicosatetraenoic acids on hexose transport in the human polymorphonuclear leukocyte.

The following racemic hydroxyicosatetraenoic acids were prepared and assayed for their ability to stimulate hexose transport in human polymorphonuclear leukocytes: 15-, 12-, 11-, 9-, 8-, and 5-hydroxyicosatetraenoic acids. The compounds were isolated from reduced, autoxidized arachidonic acid. The results demonstrate that only the 12- and 5-hydroxyicosatetraenoic acids are biologically active inducing half-maximal responses at 820 and 176 nM, respectively. Thus, the bioactions of hydroxicosatetraenoates ae crucially dependent upon the position of the hydroxy residue. Response to both hydroxyicosatetraenoates was effectively blocked by two inhibitors of arachidonic acid metabolism: nordihydroguaiaretic acid and indomethacin. A third arachidonic acid antimetabolite, 5, 8, 11, 14-eicosatetraynoic acid, completely inhibited the response to 12-HETE but caused only partial inhibition of the response to 5-HETE.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1982

Neutropenia induced by systemic infusion of 5,12-dihydroxy-6,8,10,14-eicosatetraenoic acid: correlation with its in vitro effects upon neutrophils.

5(S), 12(S)-Dihydroxy-cis-14,trans-6,8,10-eicosatetraenoate (compound I), 5(S),12(R)-dihydroxy-cis-14,trans-6,8,10-eicosatetraenoate (compound II), and 5(S),12(R)-dihydroxy-cis-6,14,trans-8,10-eicosatetraenoate (compound III) were prepared from rabbit peritoneal neutrophils challenged with arachidonic acid plus ionophore A23187. Each arachidonate metabolite caused rabbit neutrophils to aggregate and, in cells treated with cytochalasin B, release granule-bound enzymes. Compound III was 10- to 100-fold more potent than compounds II and I. When intravenously infused into rabbits at doses of 100--1,000 ng/kg, compound III induced abrupt, profound, transient neutropenia associated with a rapidly reversing accumulation of neutrophils in the pulmonary circulation. This in vivo action correlated closely with the ability of the fatty acid to activate neutrophils in vitro: neutropenia, aggregation, and degranulation occurred at similar doses of stimulus and the rapid, reversing kinetics of the neutropenic response paralleled the equally rapid, reversing formation of aggregates. The fatty acid did not alter the circulating levels of lymphocytes or platelets and did not aggregate platelets in vitro. At comparable doses (i.e., 100--1,000 ng/kg), compounds I and II did not cause neutropenia. Thus, compound III possesses a high degree of structural and target-cell specificity in stimulating neutrophils in vitro and in vivo. Clinical and experimental syndromes associating neutropenia with increased levels of circulating arachidonate metabolites may involve compound III as a mediator of neutrophil sequestration in lung.

Agranulocytosis↗
PubMed1982

MEHP/DEHP: gonadal toxicity and effects on rodent accessory sex organs.

The phthalate acid esters (PAEs), and, in particular, di(2-ethylhexyl) phthalate (DEHP) and its monoester, monoethylhexyl phthalate (MEHP), can adversely affect rodent testes but only at high doses. Rat gonadal zinc levels can be decreased by the injection of DEHP, but not MEHP. The rat prostate gland seems to be particularly sensitive to PAE-induced zinc depletion. PAE-induced changes in male reproductive organs were more evident in the rat than in the mouse. Some of the effects of MEHP can be demonstrated in vitro since it can alter the uptake of 65Zn in rodent gonads and accessory sex organs.

Animals↗