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Biomedical subjects

J M Bailey

Publications and source records attributed to J M Bailey.

At least 181 records · Page 10Linked to original sources

Reye's syndrome and aspirin use: a possible immunological relationship.

Reye's syndrome is a serious childhood disease usually associated with an antecedent viral illness such as influenza or chicken pox. Recent reports indicate a relationship between moderate aspirin use during the viral infection and the development of Reye's disease. The blastogenic response of cultured lymphocytes to lectins mimics their in vivo response to viral antigens. We report here that physiological doses of the cyclooxygenase inhibitor aspirin, induce marked hyperactivity in this response. Mouse spleen lymphocyte cultures were treated with phytohemagglutinin (PHA) and mitogenesis was assayed after 72 hours by measuring incorporation of 3H thymidine. Addition of aspirin produced up to 3-fold increases in the PHA response. The effect was specific for T-lymphocytes and response to the B lymphocyte mitogen LPS was not significantly affected. The hyperproliferative effect was dose-dependent being maximum at aspirin levels of 300-400 microM and was reversed by addition of prostaglandin E2 (10-9M). Maximum effects were observed when aspirin was added to cells within 8-10 hours of exposure to antigen. The observations suggest that Reye's syndrome may result from an aspirin-induced aberration in the immune response to a viral infection.

Animals↗

Role of lipoxygenases in regulation of PHA and phorbol ester-induced mitogenesis.

The experiments described here confirm the critical involvement of products of arachidonic acid metabolism in immune cell function. The results suggest opposing activities of the cyclo-oxygenase versus the lipoxygenases products in these systems. However, in contrast to the situation with the prostaglandins, where addition of the pure compounds has reproduced the effects predicted from the inhibitor studies, identification of the specific lipoxygenase products involved and the induction of the predicted biological response by addition of these compounds remains to be accomplished.

Animals↗

A platelet phospholipase inhibitor from the medicinal herb feverfew (Tanacetum parthenium).

Feverfew has been used since antiquity to treat fevers and other inflammatory conditions. Feverfew extracts were found to inhibit ADP, thrombin, or collagen-induced aggregation of human platelets, but significantly, did not affect aggregation induced by arachidonic acid. Synthesis of thromboxane B2 from exogenous 14C-arachidonic acid was also not inhibited. Washed platelets prelabelled with 14C-AA responded normally to thrombin by releasing 14C-TXB2. This was completely blocked by feverfew. A purified platelet phospholipase A2 was inhibited by the material with an I50 of 0.1 antiplatelet units. The pharmacological properties of feverfew may thus be due to an inhibitor of cellular phospholipases, which prevents release of arachidonic acid in response to appropriate physiological stimuli.

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

Inhibition of leukotriene biosynthesis by the leukocyte product 15-hydroxy-5,8,11,13-eicosatetraenoic acid.

Rabbit peritoneal polymorphonuclear leukocytes, elicited with glycogen, metabolized added [1-14C]arachidonic acid to the 5-lipoxygenase products 5-hydroxy-6,8,11,14-eicosatetraenoic acid and 5,12-dihydroxy-6,8,10,14-eicosatetraenoic acid (leukotriene B) and the 15-lipoxygenase product 15-hydroxy-5,8,11,13-eicosatetraenoic acid. These metabolites were isolated by high pressure liquid chromatography and converted to the trimethylsilyl-ether methyl ester derivatives, and the structures were confirmed by gas chromatography-mass spectrometry. When polymorphonuclear leukocytes were preincubated with 15-HETE (16 microM), the formation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid and 5,12-dihydroxy-6,8,10,14-eicostatetraenoic acid from [1-14C]arachidonic acid was strongly suppressed. The concentration required for 50% inhibition of the 5-lipoxygenase pathway in these cells was approximately 6 microM, which is comparable to the concentrations (0.20 to 1.8 microM) of 15-hydroxy-5,8,11,13-eicosatetraenoic acid produced in incubations of polymorphonuclear leukocytes with arachidonic acid alone. Recent reports indicate that slow-reacting substance of anaphylaxis (leukotriene C/D) and chemotactic substance leukotriene B are arachidonic acid metabolites formed via the 5-lipoxygenase pathway. Our observations thus suggest that 15-hydroxy-5,8,11,13-eicosatetraenoic acid can regulate the formation of these vasoactive and inflammatory mediators intracellularly.

Animals↗

Aspirin: an unexpected side effect on prostacyclin synthesis in cultured vascular smooth muscle cells.

Monolayer cultures of rat aorta smooth muscle cells synthesized the anti-aggregatory substance prostacyclin via the cyclooxygenase pathway from 14C-labeled arachidonic acid. The product was identified both by bioassay and by mass spectrometry. Labeled cells produced prostacyclin only when exposed to the initiator thrombin: treatment with therapeutic concentrations of aspirin (0.2 millimolar) for 30 minutes completely destroyed the cells' ability to synthesize prostacyclin. Prostacyclin synthesis from exogenous arachidonic acid recovered fully within 1 to 2 hours by a cycloheximide-sensitive process. Thrombin responsivness, which was permanently impaired in confluent nondividing cultures, recovered substantially and within 24 hours only when cells were stimulated to divide by subculturing. These results indicate that resting vascular cells can rapidly synthesize new cyclooxygenase, but that aspirin destroys additional components of the prostacyclin system which can only be replaced during cell division.

Animals↗

15-hydroxy-5,8,11,13-eicosatetraenoic acid: A potent and selective inhibitor of platelet lipoxygenase.

The functional interrelationships between the cyclooxygenase and lipoxygenase systems for arachidonic acid metabolism in platelets have not yet been clarified. Although a number of specific inhibitors of the cyclooxygenase, such as aspirin and indomethacin, have been described, few inhibitors of the lipoxygenase have been found. Several hydroxy and hydroperoxy derivatives of arachidonic acid were prepared and purified by high performance liquid chromatography, and their structures were confirmed by gas chromatography-mass spectrometry. The effect of these compounds on oxygenation of [1-14C]arachidonic acid by platelet cyclooxygenase and lipoxygenase enzymes was monitored both with an oxygen electrode and by analysis of radioactive products formed. It was found that 15-hydroxy-5,8,11,13-eicosatetraenoic acid selectively inhibited platelet lipoxygenase activity at micromolar concentrations (I50 = 8 microM) without inhibiting the cyclooxygenase. The 15-hydroperoxy analog, although more potent, was less selective, whereas neither 12-hydroxy-5,8,10,14-eicosatetraenoic acid nor 12-hydroxy-9-octadecenoic acid (ricinoleic acid) appeared to affect either enzyme. The high degree of selectivity of the 15-hydroxy derivative of eicosatetraenoic acid makes it the most suitable inhibitor so far discovered for studying the functions of the platelet lipoxygenase system.

Arachidonic Acids↗