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Review Article

Eicosanoid Transcellular Biosynthesis: From Cell-Cell Interactions to in Vivo Tissue Responses

Center for Cardiopulmonary Pharmacology, University of Milan, Milan, Italy (G.F.); and Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, Colorado (R.C.M.)

Abstract

I. Introduction

II. Prostaglandin Biosynthesis and Prostaglandin H2

A. Biosynthesis Pathway

B. Platelet-Endothelial Cell Interactions

C. In Vivo Transcellular Prostanoid Production

III. Leukotrienes and Leukotriene A4 Transfer

A. Biosynthesis Pathway

B. Neutrophil-Red Blood Cell Interactions

C. Neutrophil-Endothelial Cell Interactions

D. Neutrophil-Platelet Interactions

E. Additional Cell Interactions

F. Intermediate Stabilization and Transport

IV. Lipoxin: Unique Transcellular Eicosanoids

A. Biosynthesis Pathway

B. Aspirin-Triggered Lipoxins

C. Neutrophil-Endothelial Cell Interactions

V. Arachidonate and Transcellular Processes

A. Alveolar Epithelial Cell-Alveolar Macrophage Interactions

B. Neutrophil-Platelet Interactions

C. Transport and Microparticles

VI. Tissue and in Vivo Evidence for Transcellular Biosynthesis

A. Eicosanoid Biosynthesis in Whole Blood

B. Lung Transcellular Events

C. Cardiac Transcellular Events

D. Central Nervous System Transcellular Events

E. Genetic Approach: Chimeric Mice

VII. Conclusions

The biosynthesis of the biologically active metabolites of arachidonic acid involves a number of enzymes that are differentially expressed in cells. Prostaglandins and thromboxanes are derived from the chemically unstable prostaglandin (PG) H₂ intermediate synthesized by PGH synthases (cyclooxygenase-1/2) and leukotrienes from chemically unstable leukotriene A₄ by 5-lipoxygenase. Additional enzymes transform these reactive intermediates to a variety of chemical structures known collectively as the lipid mediators. Although some cells have the complete cassette of enzymes required for the production of biolog-ically active prostaglandins and leukotrienes, the actual biosynthetic events often are a result of cell-cell interaction and a transfer of these chemically reactive intermediates, PGH₂ and leukotriene A₄, between cells. This process has come to be known as transcellular biosynthesis of eicosanoids and requires a donor cell to synthesize and release one component of the biosynthetic cascade and a second, accessory cell to take up that intermediate and process each into the final biologically active product. This review focuses on the evidence for transcellular biosynthetic events for prostaglandins, leukotrienes, and lipoxins occurring during cell-cell interactions. Evidence for arachidonic acid serving as a transcellular biosynthetic intermediate is presented. Experiments for transcellular events taking place in vivo that reveal the true complexity of eicosanoid biosynthesis within tissues are also reviewed.

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