Eicosanoids secretion

Mazzucco CE, Warr GJ. Trichodimerol (BMS-182123) inhibits Upopolysaccharide-induced eicosanoid secretion in THP-1 human monocytic cells. Leukocyte Biol. 1996 60 (2) 271 277. 

Prostaglandins are a group of lipid autacoids known as eicosanoids. They are produced from membrane phospholipids and found in almost every tissue and body fluid. They are involved in a number of physiological processes including inflammation, smooth muscle tone and gastrointestinal secretion. In the central nervous system they have been reported to produce both excitation and inhibition of neuronal activity. 

Adipocytes have an important secretory function. Numerous factors (collectively termed adipokines or adipocytokines), mostly peptides but also eicosanoids are produced by preadipocytes and mature adipocytes (Table 9.3). Some of these factors act in an autocrine or paracrine fashion to regulate adipogenesis, that is differentiation and maturation of adipocytes themselves, whilst others, notably, leptin, adiponectin and some cytokines act in truly endocrine way, having effects on the brain, endothelial cells, liver and skeletal muscle. Disturbance in secretion from adipocytes is associated with eating disorders and metabolic syndrome. 

Eicosanoids are involved in control of a number of physiological processes that are essential to life. Some information on each role is provided below but further detail can be found in other chapters clotting of blood (Chapters 17 and 22) menstruation and parturition (Chapter 19) secretion of protons in the stomach (Chapter 4) pain and fever (Chapter 18). 

Acetylsalicylic acid and related non-steroidal anti-inflammatory drugs (NSAIDs) selectively inhibit the cyclooxygenase activity of prostaglandin synthase [2] and consequently the synthesis of most eicosanoids. This explains their analgesic, antipyretic, and antirheumatic effects. Frequent side effects of NSAIDs also result from inhibition of eicosanoid synthesis. For example, they impair hemostasis because the synthesis of thromboxanes by thrombocytes is inhibited. In the stomach, NSAIDs increase HCl secretion and at the same time inhibit the formation of protective mucus. Long-term NSAID use can therefore damage the gastric mucosa. 

The corticosteroids have an array of actions in several systems that may be relevant to their effectiveness in asthma. These include inhibition of cytokine and mediator release, attenuation of mucus secretion, up-regulation of (3-adrenoceptor numbers, inhibition of IgE synthesis, attenuation of eicosanoid generation, decreased microvascular permeability, and suppression of inflammatory cell influx and inflammatory processes. The effects of the steroids take several hours to days to develop, so they cannot be used for quick relief of acute episodes of bronchospasm. 

Nearly all cells express kinin receptors that mediate the activities of both bradykinin and kallidin. The activation of these G-protein coupled receptors causes relaxation of venular smooth muscle and hypotension, increased vascular permeability, contraction of smooth muscle of the gut and airway leading to increased airway resistance, stimulation of sensory neurons, alteration of ion secretion of epithelial cells, production of nitric oxide, release of cytokines from leukocytes, and the production of eicosanoids from various cell types [11,12]. Because of this broad spectrum of activity, kinins have been implicated as an important mediator in many pathophysiologies including pain, sepsis, asthma, rheumatoid arthritis, pancreatitis, and a wide variety of other inflammatory diseases. Moreover, a recent report demonstrated that bradykinin B2 receptors on the surface of human fibroblasts were upregulated three-fold beyond normal in patients with Alzheimer s disease, implicating bradykinin as a participant in the peripheral inflammatory processes associated with that disease [13]. 

Like eicosanoids (chapter 19), steroid hormones are not stored for subsequent secretion. Instead, they are made in response to a stimulus such as corticotropin, a pituitary hormone, which stimulates the synthesis of aldosterone and cortisol in the adrenals. The steroids act by binding to spe-cific receptors as discussed in chapters 24 and 31. 

Both in vitro and in vivo tests have shown that some of the eicosanoids affect the secretion of anterior pituitary hormones. PGE compounds promote the release of growth hormone, prolactin, TSH, ACTH, FSH, and LH. However, endocrine changes reflecting significant release of these hormones have not been reported in patients receiving PGE compounds. LTC4 and LTD4 stimulate LHRH and LH secretion (see below). 

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.

Gallai, V., Sarchielli, P., Trequattrini, A., Franceschini, M., Floridi, A., Firenze, C., Alberti, A., Di Benedetto, D., and Stragliotto, E. 1995. Cytokine secretion and eicosanoid production in the peripheral blood mononuclear cells of MS patients undergoing dietary supplementation with n-3 polyunsaturated fatty acids. J. Neuroimmunol. 56, 143-153. 

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