In contrast to the synthesis of prostaglandins and LTs that follows more canonical pathways in a single cell type, the release of the LXs results from transcellular and cell-cell interaction-mediated biochemical events. In humans, the generation of LXs is the result of LOX-LOX or COX-LOX interactions . There are now three defined routes for their generation. In eosinophils, monocytes, or epithelial cells, the first biosynthetic step involves the insertion of O2 to the OH group on carbon 15 of AAby 15-LOX, yielding hydroperoxyeicosatetraenoic acids. Following their release from these cell sources and entry into either polymorphonu-clear cells or monocytes, a 5,6-epoxytetraene is generated by the 5-LOX, which is then hydrolyzed within these recipient cells by either LXA4 hydrolase or LXB4 hydrolase to bioactive LXA4 and LXB4, respectively.
The second route of LX biosynthesis results from the generation of LTA4 by the leukocyte 5-LOX, its release, and its subsequent uptake by platelets that contain a 12-LOX to generate LXA4 and LXB4.
The third route for LX generation results from the acety-lation of COX-2 by acetylsalicylic acid in endothelial cells and other cell types. This results in the synthesis of (15.R)-hydroxyeicosatetraenoic acid (15-^-HETE), which is rapidly metabolized in a transcellular manner by adherent leukocyte, vascular endothelial, or epithelial 5-LOX to 15-epiLXA4 or 15-epiLXB4.
Within seconds or minutes from their synthesis, LXs are converted to inactive metabolites, characterized by dehydro-genation at the C-15 position. Once formed these intermediate LXs are no longer further metabolized by PMN but are rapidly inactivated, as a result of dehydrogenation, to inactive oxo-LXs by monocytes.
Having detailed the three potential biosynthetic pathways, it is natural to ask how, in practice, are LXs formed?
Biological Properties of LXs
LXs exert a range of biological effects . LXA4 and LXB4 promote vasorelaxation and relax aorta and pulmonary arteries. LXA4 also reverses precontraction of the pulmonary artery induced by PGF2a and the potent vasoconstrictor mediator endothelin-1. The mechanisms of LXA4- and LXB4-induced vasodilation involve endothe-lium-dependent vasorelaxation as well as prostaglandin-dependent and -independent pathways. In endothelial cells, LXs can stimulate the synthesis of PGI2 and nitric oxide, both of which produce vasodilation.
In terms of cell trafficking, LXs inhibit neutrophil and eosinophil chemotaxis in the nanomolar range. LXA4 inhibits neutrophil transmigration across endothelial and epithelial cells in vitro, whereas in vivo it blocks leukocyte diapedesis from postcapillary venules; the end point would be inhibition of white blood cell entry into inflamed tissues as seen in animal models of vascular inflammation. Because of the very short half-lives of the LXs, a range of stable biologically active analogs have been designed and tested for their anti-inflammatory effects in experimental animal models. The LXA4 analog 16-phenoxy-LXA4 and the stable analog of the aspirin-triggered epi-LXs, 15-epi-16-phenoxy-LXA4, markedly reduced LTB4-induced ear swelling in the mouse. In this assay, the LX analogs were as effective as dexamethasone in preventing both leukocyte infiltration and changes in vascular permeability (edema).
Interestingly, unlike neutrophils and eosinophils, LXs are potent chemoattractants from monocytes. LXA4 and LXB4 stimulate monocyte chemotaxis and adherence to endothelial monolayers, and these effects may be related to the recruitment of monocytes to sites of wound injury. However, such LX-recruited monocytes do not generate superoxide anions or degranulate in the presence of LXs. In fact, they exhibit a greater capacity to phagocytose effete and apoptotic leukocytes, leading to resolution of acute inflammation.
Arachidonic acid: Polyunsaturated fatty acid, with 20 carbon atoms, liberated from the phospholipid membrane by the action of phospholipases.
Eicosanoids: This term refers to all products derived from arachidonic acid metabolism.
Nonsteroidal anti-inflammatory drugs: Also referred to as aspirinlike drugs, these therapeutic agents are effective because they block the catalytic action of COX, thereby blocking prostanoid generation.
Prostanoids: This term refers to all products derived from COX activity, and thus to prostaglandins and thromboxanes.
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Both Mauro Perretti (Ph.D., Professor of Immunopharmacology) and Derek W. Gilroy (Ph.D., Senior Research Fellow) are at The William Harvey Research Institute, Queen Mary University of London. Though their research activities are independent of one another, the scientific interests of the authors can be grouped under the umbrella of anti-inflammation, that is, the study of the endogenous mediators/pathways that operate in the host to ensure the transient nature of the inflammatory response. Perretti's major research efforts have been spent in the field of annexin-1, glucocor-ticoids, and melanocortins, whereas Gilroy has pioneered the anti-inflammatory role of COX-2 and derived products, as well as nitric oxide, in acute inflammation. DWG: Center for Clinical Pharmacology, Rayne Institute, 5 University Street, University College London WC1 6JJ, UK.
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