Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers.
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.
Khanapure
Subhash P
SP
NitroMed, Inc., 125 Spring Street, Lexington, Massachusetts 02421, USA. subhashpk@gis.net
Garvey
David S
DS
Janero
David R
DR
Letts
L Gordon
LG
D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015777:Eicosanoids / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D008084:Lipoxygenase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D015777:Eicosanoids; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases