Endothelium eicosanoids

TNF (17.5) Monocyte/macrophage, lymphocyte, neutrophil, endothelium, fibroblast, keratinocyte Activation of T and B cells, natural killer cells, neutrophils, and osteoblasts. Stimulation of endothelial cells to release chemotactic proteins, NO and PGI2. Tumoricidal activity. Induces fever, sleep, hepatic acute phase protein synthesis, catabolism, ACTH release. Lead to myocardial depression, hypotension/shock, hypercoagulability, and death. Stimulates production of IL-1, IL-6, IL-8, IFN-y, and H202. Suppression of cytochrome P-450, thyroglobulin, and lipoprotein lipase. Induces complement activation, release of eicosanoids, including PAF. Procoagulant activity. 

The cerebrovasculature is also an abundant source of eicosanoids. Platelets, leukocytes and vascular endothelium are all capable of synthesizing eicosanoids (see above). Brain microvessels isolated from ischemic rat brain demonstrate enhanced synthesis of eicosanoids, and leukocytes and platelets may account for much of the LTD4 produced during ischemia-reperfusion in the gerbil. 

Dipyridamole exerts its antiplatelet action by several mechanisms [7]. One of these is through the inhibition of phosphodiesterase enzyme in platelets, resulting in an increase in intraplatelet cyclic AMP and the consequent potentiation of the platelet inhibiting actions of prostacyclin. Another is the direct stimulation of the release of this eicosanoid by vascular endothelium, and the third is the inhibition of cellular uptake and metabolism of adenosine (thereby increasing its concentration at the platelet vascular interface). 

Figure 12.10. Role of eicosanoids in thrombocyte (platelet) aggregation, and rationale of low-dose acetylsalicylic acid treatment. a Thrombocyte aggregation is suppressed by the intact vascular endothelium by a constant secretion of PGE and PGI. b Inhibition subsides at lesions. This sets off aggregation, which is sustained and amplified by the secretion of thromboxanes by the platelets themselves. Aggregation will also promote plasmatic coagulation (i.e., fibrin clot formation), b Effects of low dose application of acetylsalicylic acid. Endothelial cells are nucleated covalently inactivated cyclooxygenase molecules will be replaced by newly synthesized ones, so that the activity is not substantially diminished. In contrast, thrombocytes lack protein synthesis, so that the effect of repeated doses will be cumulative.

The system that enables platelets to distinguish between healthy and damaged endothelium is shown in simplified form in Figure 28.3. It is a continuation of, and should be studied in conjimction with, the general diagram for eicosanoids on page 281. 

Muller C, Endlich K, Elelwig JJ AT2 antagonist-sensitive potentiation of angiotensin ll-induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature. Br J Pharmacol 124 946-52,1998... 

Gauthier KM, Baewer DV, Hittner S, Hillard CJ, Nithipatikom K, Reddy DS, Falck JR, Campbell WB (2005) Endothelium-derived 2-arachidonylglycerol an intermediate in vasodilatory eicosanoid release in bovine coronary arteries. Am J Physiol Heart Circ Physiol 288 1344-1351... 

Tumor necrosis factor-a (TNF-a) is a pivotal proinflammatory cytokine in Crohn s disease. TNF-a can recruit inflammatory cells to inflamed tissues, activate coagulation, and promote the formation of granulomas. Production of TNF-a is increased in the mucosa and intestinal lumen of patients with Crohn s disease. Eicosanoids such as leukotriene B4 are increased in rectal dialysates and tissues of IBD patients and are related to disease activity. Leukotriene B4 enhances neutrophil adherence to vascular endothelium and acts as a... 

Fig. 6.3 Eicosanoids and Tumor-platelet interactions in metastasis and the role of 12-HETE in tumor cell extravasation. Studies have clearly shown that hematogenous route of metastasis spread of cancer cells, involves interactions with platelets. Tumor-platelet interactions and subsequent aggregation is critically controlled by a delicate balance between the level of endothelium derived PGI2 and platelet or tumor derived TXA2. Elevated TXA2 levels in the circulation can tip the balance towards platelet aggregation and tumor metastasis to distant organs, whereas increases in PGI2 levels can block this interaction preventing spread of cancer cells. Shown in this illustration is a schematic of a blood vessel, with metastatic tumor cells interacting with platelets. Interactions of tumor cells with platelets and endothelial cells have been demonstrated to induce 12(S)-HETE production, which leads to retraction of endothelial cell layers enabling metastatic tumor cells to extravasate and set up secondary colonies of metastasis...

Tang DG, Diglio CA, Honn KV. Activation of microvascular endothelium by eicosanoid 12(S)hydroxyeicosatetraenoic acid leads to enhanced tumor cell adhesion via up-regula-tion of surface expression of alpha v beta 3 integrin a posttranscriptional, protein kinase C-and cytoskeleton-dependent process. Cancer Res. 54 (1994) 1119-1129. 

After arachidonic acid is released into the cytosol, it is converted to eicosanoids by a variety of enzymes with activities that vary among tissues. This variation explains why some cells, such as those in the vascular endothelium, synthesize prostaglandins E2 and I2 (PGE2 and PGI2) whereas cells, such as platelets, synthesize primarily thromboxane A2 (TXA2) and 12-hydroxyeicosatetraenoic acid (12-HETE). 

EPA, the precursor of the 3 series, and, like AA, is a substrate for eicosanoid formation. In particular, EPA competitively inhibits the utilization of AA by cyclooxygenase [3]. Human platelets can convert EPA to TXA3, which is less proag-gregatory than TXA2 [3, 4]. Additionally, EPA can be metabolized by vascular endothelium to PGI3, which is a vasodilator and has the same platelet-inhibitory properties as PGI2 [5]. 

Eicosanoids as Candidates for the Endothelium-Derived Relaxing Factor 28 Actions of Eicosanoids on Cerebral Arterial Contraction in vitro and in vivo 28... 

Eicosanoids as Candidates for the Endothelium-Derived Relaxing Factor ... 

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