Animal platelets thromboxane

Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in processes often involving cyclization and oxygenation, to produce so-called local hormones that (1) exert their effects at very low concentrations and (2) usually act near their sites of synthesis. These substances include the prostaglandins (PG) (Figure 25.27) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids. Thromboxanes, discovered in blood platelets (thrombocytes), are cyclic ethers (TxBg is actually a hemiacetal see Figure 25.27) with a hydroxyl group at C-15. 

Malonaldehyde is found in human and animal tissue as an end-product of lipid peroxidation. It is also a side-product of prostaglandin and thromboxane biosynthesis. Malonaldehyde is present in blood platelets and in serum (lARC, 1985). 

Subsequently, Qureshi (169) extended his investigations to TRF (Palm Vitee) from palm oil in both animal and human models. In a double-blind crossover study involving 20 hypercholesterolaemic human subjects (serum cholesterol >294 mg/dL), Palm Vitee supplementation was found to cause a significant drop in serum TC and LDL-C. The LDL-associated apolipoprotein Apo B was also decreased by 9-11%. Moreover, Palm Vitee supplementation resulted in a significant decrease (25%) in serum thromboxane and platelet factor PF4 by 16%. Similar cholesterol-lowering effects of Palm Vitee have also been indicated in genetically hypercholesterolemic swine (170). 

Gerhard J. Johnson, M.D. is Professor of Medicine, University of Minnesota Medical School, and Staff Physician, Hematology/Oncology Section, Medical Service, Veterans Affairs Medical Center, Miimeapolis, Minnesota. His platelet research program, funded by VA Merit l view and NIH grants since 1972, has focused on the study of platelet signal transduction via thromboxane receptors, with emphasis on the study of dog platelets. He has served as Chairman of the VA Merit Review Board for Hematology and the Subcommittee on Animal Models of the Scientific and Standardization Committee, ISTH. 

Thromboxane A2 is produced by alveolar macrophages, fibroblasts, epithelial cells, neutrophils, and platelets within the lung. Indirect evidence from animal models suggests that thromboxane A2 may have several effects, including bronchoconstriction, involvement in the late asthmatic response, and involvement in the development of airway inflammation and BHR. Potent and specific thromboxane synthetase inhibitors will be crucial tools for understanding the role of thromboxanes in asthma. 

Dietary intake of n-6 fatty acids such as linoleic acid, and n-3 fatty acids, such as the fish oils eicosapentanoic acid and docosahexaenoic acid, lowers plasma cholesterol and antagonizes platelet activation, but the fish oils are much more potent in this regard [26]. In particular, n-3 fatty acids competitively inhibit thromboxane synthesis in platelets but not prostacyclin synthesis in endothelial cells. These fatty acids have also been shown to have other potentially anti-atherogenic effects, such as inhibition of monocyte cytokine synthesis, smooth muscle cell proliferation, and monocyte adhesion to endothelial cells. While dietary intake of n-3 fatty acid-rich fish oils appears to be atheroprotective, human and animal dietary studies with the n-6 fatty acid linoleic acid have yielded conflicting results in terms of effects on both plasma lipoproteins and atherosclerosis. Indeed, excess amounts of both n-3 and n-6 fatty acids may actually promote oxidation, inflammation, and possibly atherogenesis (M. Toberek, 1998). In this context, enzymatic and non-enzymatic oxidation of linoleic acid in the sn-2 position of LDL phospholipids to 9- and 13-hydroxy derivatives is a key event in LDL oxidation (Section 6.2). 

Whether endogenous prostacyclin modulates platelet activity in vivo is uncertain, but studies using cyclo-oxygenase and thromboxane synthase inhibitors in animal models of thrombosis support this hypothesis. Inhibition of platelet deposition on de-endothelialized rabbit abdominal aorta by aspirin is dose dependent, being less at higher doses at which coincident inhibition... 

Platelets from cows, mink, and pigs change shape but do not aggregate in response to sodium arachidonate. This lack of response may be due to the low activity of thromboxane synthase in platelets from these animals compared with human platelets . Sheep platelets do not aggregate in response to either sodium arachidonate or 9,ll-azo-PGH2. Thus, their platelets may not possess TXA2/PGH2 receptors. 

Eicosanoids possess hormone activity in higher animals (E 3.1). Most important is the influence of prostaglandins and leucotrienes on inflammation and of prostaglandins and thromboxanes on blood platelet aggregation. 

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