Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents - Volume 1, Issue 3, 2002

Prostaglandin E2 (PGE2) mediates fever and pain in various diseases through its action on the central nervous system (CNS). For the development of drugs that interfere with PGE2 action in the CNS, it is of importance to understand the nature of the PGE2 system there. Current studies on the PGE2 system in the CNS highlighted 2 groups of molecules on which drugs may act to interfere with the PGE2 action, i.e., (i) PGE2-synthesizing enzymes and (ii) PGE2 receptors. With respect to the first group, inducible-type cyclooxygenase (COX-2) and microsomal-type of PGE synthase (mPGES) were co-induced in CNS endothelial cells after systemic challenge with lipopolysaccharide or other inflammatory stimuli. Accumulating evidence has indicated that PGE2 produced through this endothelial COX-2-mPGES cascade is responsible for fever and pain. Of great importance is the fact that COX-2 and mPGES were co-induced preferentially in endothelial cells of the CNS and little in those of peripheral organs. Since drugs in the blood stream have quite effective access to the endothelial cells, it is theoretically possible to develop drugs that preferentially inhibit PGE2 synthesis in the CNS endothelial cells with lesser action on PGE2 synthesis in non-endothelial cells of peripheral organs, in which PGE2 might play housekeeping roles. Regarding the second group of potential drug targets, the EP3 subtype of PGE2 receptor is abundantly expressed in neurons of various brain regions including those involved in fever and pain modulation. However, in most of the brain regions, the pathophysiological roles of EP3 receptors are still unknown. Since EP3 receptors are expressed in parenchymal neurons, drugs that interfere with PGE2 at the receptor sites would need to pass through the blood-brain-barrier.

Inducible, glutathione-dependent microsomal prostaglandin E synthase (mPGES) catalyzes the formation of prostaglandin (PG) E2 from cyclooxygenase (COX) derived PGH2. There is a strong association between mPGES and COX-2 protein expression in various cells and tissues. The same types of proinflammatory stimuli induce both enzymes and they co-localize in the cells. In cancer, however, the expression of these two enzymes seems uncoordinated, a fact that should be considered when interpreting recent data from clinical trials testing nonsteroidal anti-inflammatory drugs (NSAIDs) as chemoprotectants against cancer. The importance of mPGES for induced PGE2 biosynthesis was recently demonstrated in mice lacking mPGES.This review intends to summarize briefly the data that have been published on mPGES and discuss the assumed pathophysiological roles of this enzyme in inflammation, atherosclerosis, cancer, and in centrally mediated responses to inflammation.

Lipoxins (LX) are trihydroxytetraene-containing eicosanoids generated within the vascular lumen during platelet-leukocyte interactions and at mucosal surfaces of gastrointestinal, respiratory, and oral cavities during phagocyteepithelial cell interactions. Recent findings and several new concepts are reviewed here regarding the generation of LX, 15 epi-LX and related novel chemical mediators, considering their impact in resolution of acute inflammation. During cell-cell interactions, transcellular biosynthetic pathways are used as major LX biosynthetic routes, and thus, in humans, LX are formed in vivo during multicellular responses such as vascular inflammation, reperfusion injury and asthma. This branch of the eicosanoid cascade generates specific chemical mediators that serve as neutrophil “stop signals”, as they regulate key steps in leukocyte trafficking and prevent neutrophil-mediated acute tissue injury. In addition, aspirin's mechanism of action also involves the triggering of endogenous carbon 15 epimers of lipoxins and omega n-3 fatty acids that mimic the bioactions of native LX and dampen inflammation as well as enhance resolution. An overview of these recent developments brings forth a novel repertoire of endogenous chemical signals and pathways that serve as antiinflammatory lipid mediators and also facilitate the resolution of acute inflammatory responses.

Cytosolic phospholipases A2 are a diverse group of enzymes with a growing number of members. These enzymes hydrolyze membrane glycerophospholipids into arachidonic acid and 1-acyl-lysophospholipids. Arachidonic acid and its metabolites (eicosanoids) play critical roles in the initiation and modulation of inflammation and oxidative stress. It is generally thought that the release of arachidonic acid by cytosolic phospholipase A2 is the rate-limiting step in the generation of eicosanoids. Neurological disorders, such as ischemia, spinal cord injury, and Alzheimer's disease, are characterized by inflammatory reactions, oxidative stress, and increased cytosolic phospholipase A2 activity. Several cytosolic phospholipase A2 inhibitors were discovered recently. However, nothing is known about their neurochemical effects, mechanism of action, or toxicity in human or animal models of neurological disorders. Our recent studies have indicated that the use of cytosolic PLA2 inhibitors in kainic acid-induced toxicity model of neural injury can provide useful information on the beneficial effects of these compounds in brain tissue.

CD14 may be considered as the major receptor of lipopolysaccharide (LPS), the causative factor of Gramnegative shock. CD14 is expressed on the surface of myeloid cells and is present in the serum as a soluble isoform. In this review both forms of CD14 and their biological functions are discussed. Emphasis is placed upon their differential role in infections. Possibilities and problems of the CD14 blockade during infection in animal models are summarized. Blockade of cellular activation by anti-CD14 antibodies diminishes bacterial clearance, whereas bacterial clearance is enhanced in CD14 knock-out mice, which completely lack both soluble CD14 and membrane bound CD14. These data suggest that therapeutic strategies using CD14 blockade should take both soluble and membrane bound forms of CD14 into account.