The Scent of a Phagocyte

To maintain its health, an organism must be able to repel infectious invaders. In animals, phagocytic cells—profes-sional hunters—are essential to this process. This creates another level of challenge: how to get the phagocytic cells to the site(s) where they are needed without activating them prematurely. Several molecular events are required to orchestrate this properly. For example, endothelial cells must display appropriate adhesion proteins to supply the spatial specificity (1), and the phagocyte must be able to " smell " and respond to chemical stimuli that direct its activation and migration. Identification of the scents that attract the hunters and signals from phagocyte to phagocyte has progressed over the past two decades, and one of the first endogenous compounds to be chemically characterized was leukotriene B 4 (LTB 4). In the first experiments that led to the discovery of leu-kotrienes, Borgeat et al. (2) reported a novel 5-lipoxygen-ase, and subsequent analysis of the products of this pathway led to the structural elucidation of three major compounds (3, 4), one of which was LTB 4. The biological function of LTB 4 , which is generated by polymorphonuclear leukocytes (PMNs), was elucidated in experiments by Ford-Hutchin-son et al. (5). At the time, it was a significant challenge to separate mono-, di-, and tri-hydroxy eicosatetraenoic acids (HETEs). This was problematic because several isomers of 5,12-di-HETE were present in the extracts from activated PMNs, and it was difficult to determine which of them carried biological activity. Ford-Hutchinson et al. tested fractions eluted from an HPLC separation and found a single major peak of chemoattractant activity. They also reported that this compound, which was subsequently shown to be LTB 4 , was a potent stimulator of chemokinesis and aggregation. These findings led the field away from a prior focus on mono-HETE as primary mediator. A battery of papers that determined the complete structure of LTB 4 was published in this journal in the early 1980s. The first paper established the complete stereochemistry of LTB 4 as 5(S), 12(R)-dihydroxy-eicosa-6,8,10-(trans/trans/cis), 14(cis)-tet-raenoic acid and showed that it was this isomer alone that accounted for the proinflammatory activity of LTB 4 (6). The second paper used materials prepared by total organic synthesis and confirmed that, of the several stereoisomers present in biological preparations, LTB 4 that was the relevant compound (7). This precise chemical characterization was important for many reasons, but one of the most profound insights was that the …