Eicosanoids in Inflammation: Biosynthesis, Pharmacology, and Therapeutic Frontiers

Abstract

In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A2 and the release of arachidonic acid (AA) from membrane phospholipids. The AA is subsequently transformed by cyclooxygenase (COX) and lipoxygenase (LO) pathways to prostaglandins, thromboxane and leukotrienes collectively termed eicosanoids. Eicosanoid production is considerably increased during inflammation. Both COX and LO pathways are of particular clinical relevance. The COX pathway is the major target for non-steroidal anti-inflammatory drugs (NSAIDs), the most popular medications used to treat pain, fever and inflammation. Although their anti-inflammatory effects are well known, their long-term use is associated with gastrointestinal (GI) complications such as ulceration. In 1991, it was discovered that COX exists in two distinct isozymes, COX-1 and COX-2, of which COX-2 is primarily expressed at sites of inflammation and produces pro-inflammatory eicosanoids. For this reason, COX-2 selective inhibitors (COXIBs) have been developed recently as anti-inflammatory agents to minimize the risk of GI toxicity. Recently, some COX-2 selective inhibitors have shown adverse cardiovascular side effects, resulting in the withdrawal of rofecoxib and valdecoxib from the market. Selective inhibition of COX-2 without reducing COX-1-mediated thromboxane production could alter the balance between prostacyclin and thromboxane and promote a prothrombotic state, thereby explaining the observed COX-2 cardiovascular risk. In this review, we describe mechanisms for the production of pro-inflammatory eicosanoid mediators contributing to inflammation and summarize promising options for the prevention of inflammatory mediator formation and the therapeutic inhibition of pain and inflammation.

Polarization of Macrophages toward M2 Phenotype Is Favored by Reduction in iPLA2β (Group VIA Phospholipase A2)

“…Under different stimuli, macrophages produce multiple lipid mediators including lysophospholipids and eicosanoids, and these bioactive lipids can impact cells of surrounding tissues and the function of macrophages themselves (20,36,47). A major source of lyso- iPLA 2 ␤ and Macrophage Polarization OCTOBER 28, 2016 • VOLUME 291 • NUMBER 44 phospholipids and arachidonic acid, the common eicosanoid precursor, is the lipase activity of PLA 2 s (19).…”

“…The PLA 2 s hydrolyze the sn-2 substituent from membrane phospholipids to generate a free fatty acid and a 2-lysophospholipid. The fatty acid arachidonic acid can be further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOs) to generate bioactive eicosanoids that include prostaglandins and leukotrienes (19). Several eicosanoids are proinflammatory and linked to macrophage phagocytosis, adhesion, apoptosis, and amplification of macrophage-derived eicosanoid release (20 -23).…”

n-3 Polyunsaturated fatty acids and mast cell activation

“…3), which are derived from 20 carbon chain n-3 (EPA) and n-6 PUFAs (AA and DGLA [C20:3, n-6]) [188]. Eicosanoids, including PGs, LTs, thromboxanes, and lipoxins, are signaling molecules that modulate a broad range of body functions, including body temperature, immune function, wound healing, pain, and smooth muscle relaxation/contraction [189,190].…”

Anti-inflammatory potential of 2-styrylchromones regarding their interference with arachidonic acid metabolic pathways

“…Although the major pathophysiological implication of LTs was considered to be the bronchial asthma, these eicosanoids contribute to the pathogenesis of other human inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, and psoriasis (see [11][12][13] for reviews). Recently, the 5-LOX pathway has also been associated with atherosclerosis, osteoporosis and certain types of cancer like prostate cancer [12].…”

“…However, they cause several adverse effects, the most important being gastric injury up to gastric ulceration, renal failure and asthma [14]. On the other hand, the COX-2 selective drugs, generically known as COXIBs, have recently been a cause of controversy due to the enhanced cardiovascular risk they carry [13]. Thus, alternative therapeutic solutions, with similar anti-inflammatory potency but with fewer side effects, are needed, especially for the control of chronic inflammatory diseases, which implicate longer therapies.…”