Cyclooxygenase pathways mechanism

The mechanisms of ibuprofen-induced toxicity have not been clearly defined. Acute renal failure is postulated to result from decreased production of intrarenal prostaglandins via inhibition of the cyclooxygenase pathway. In turn, this will decrease the renal blood flow and glomerular filtration rate. Ibuprofen also interferes with prostaglandin synthesis in the gastrointestinal system that can contribute to its irritating effect on the mucosa of the gastrointestinal tract. 

FIGURE 57-2. Eicosanoid synthesis pathway. Cyclooxygenase is inhibited by nonsteroidal anti-inflammatory drugs and aspirin. (From Widmaier EP, Raff H, Strang KT, et al, (eds.) Vander, Sherman, Luciano s Human Physiology The Mechanisms of Body Function. 9th ed. New York McGraw-Hill 2004, Figure 5-11.)... 

Lipid peroxidation may proceed by both enzymatic and nonenzymatic pathways. Enzymatic peroxidation is catalyzed by enzymes such as lipoxygenases and cyclooxygenases (COXs) and is considered in Chapter 26. One of the most important questions in the study of the mechanisms of lipid peroxidation is the characteristic of an initiation stage. Obvious... 

Another mechanism that potentially contributes to clove oil s effects is inhibition of prostaglandin synthesis through both cyclooxygenase and lipoxygenase pathways (Tyler 1994). Accordingly, local injections of clove oil supressed joint swelling in arthritic rats (Sharma et al. 1994). 

In susceptibie individuais, NSAIDs may precipitate acute bronchospasm. It affects 10-20% of adults with asthma but is rare in asthmatic children. The mechanism is related to cyclooxygenase inhibition, with shunting of arachidonic acid metabolism from the prostaglandin pathway to the biosynthesis of ieukotrienes with increased mucosal permeability and bronchospasm. Susceptible patients should avoid NSAIDs since the bronchospasm may be severe and has been fatal. Paracetamol in doses up to 1000 mg daiiy wiii be toierated by most patients. True type I allergic reactions to NSAIDs, with specific IgE, are rare but anaphyloactoid reactions have occasionally been described in patients with a history of aiiergy or bronchiai asthma. 

Classically, inflammation is a protective reaction of the body in response to some physical, chemical, or microbial injury and insult of the cells. Acute inflammation, rapid onset and shorter duration, is considered as a healthy response. However, when inflammation continues for prolonged period of time, it becomes detrimental and may raise the first step of a chronic disease (Medzhitov, 2008). Arachidonic acid/COX and nuclear factor- (NF- ) are well known inflammatory pathways which induce production of inflammatory mediators such as prostaglandins, thromboxanes, leukotrienes, and cytokines. Most commonly accepted mechanism of anti-inflammation is inhibition of cyclooxygenase (COX) activity. There are two kinds of cyclooxygenases COX-1 is natural protective enzyme of intestinal mucosa while COX-2 is induced by tissue damage as an inflammatory mediator (Maroon et al., 2006). NF- is a recently identified... 

Osteoblasts subjected to fluid shear increase expression of the early response gene, c-fos, and the inducible isoform of cyclooxygenase, COX-2, two proteins linked to anabolic response of bone to mechanical stimulation. Flow-induced responses in osteoblasts are mediated by inositol triphosphate intracellular calcium release. Flow-mediated stress is reported to induce both PGE2 and NO production. Fluid shear stress stimulates NO release by two distinct pathways a G-protein and calcium-dependent phase sensitive to flow gradients, and a G-protein and calcium-independent pathway stimulated by sustained flow. 

Figure 12.2. Alternate pathways of arachidonic acid release (a), and cellular locations of enzymes involved in eicosanoid formation (b). a Arachidonic acid may be directly released by phospholipase (PLA2), or alternatively by the successive action of phospholipase C (PLC) and diacylglycerol (DAG) lipase, b The major mechanism of release involves a cytosohc phospholipase A2 (CPLA2). An increase of Ca in response to an extrinsic signal causes binding of cPL A2 to the nuclear membrane. Cyclooxygenase (COX) and Lipoxygenase (LOX) form their respective intermediates, which are further processed by cytosolic enzymes to prostaglandins (PG), thromboxanes (TG), and leukotrienes (LT), respectively.

What this allows is targeting of either the cyclooxygenase or leukotriene arms of the prostaglandin pathways. Although this is a convenient separation of mechanisms, there is often overlap. It is for this reason, for example, that postoperative cataract patients are administered both topical steroids and NSAIDs. 

A study by W. Breu and M. Hagenlocher, published in the German journal Arzneim-Forsch Drug Research in 1992, used a supercritical carbon dioxide extract of saw palmetto. The researchers were exploring the mechanism of action of this herb for benign prostatic hyperplasia. Most research has studied and confirmed the ability of Serenoa to inhibit 5-alpha-reductase and reduce the formation of DHT. The researchers in this experiment found another mechanism of action for saw palmetto inhibition of the biosynthesis of inflammatory arachadonic acid metabolites, specifically the cyclooxygenase and 5-lipoxgenase pathways. 

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