Prostaglandins, Leukotrienes and Essential Fatty Acids 73 (2005) 197–202 Lipid mediator networks and leukocyte transmigration Nancy A. Louis, Kathryn E. Hamilton, Sean P. Colgan à Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA Abstract In intact tissues, vascular endothelial cells lie anatomically positioned as the central coordinator of inflammation. Endothelia communicate with underlying cells (e.g. smooth muscle, fibroblasts, epithelia) in ways that both coordinate leukocyte trafficking, and control the composition of the inflammatory microenvironment. Such coordination occurs through both direct communication (e.g. cell adhesion) as well as via soluble mediators liberated at sites of inflammation (e.g. chemokines, cytokines, lipids). Locally generated mediators bind to surface receptors, and mediate both physiologic and pathophysiologic functional responses. Important in this regard, both endothelial and subendothelial cell populations express enzymes capable of utilizing arachidonic acid substrates to generate bioactive lipid mediators (e.g. lipoxygenases, cyclooxygenases). Such lipid mediators can signal via autocrine or paracrine pathways and, depending on the tissue microenvironment, can convey a pro- or anti-inflammatory message. This review will highlight recent studies characterizing inflammatory responses to lipid mediators liberated at sites of inflammation, with a particular emphasis on neutrophil (polymorphonuclear leukocyte or PMN) trafficking. r 2005 Elsevier Ltd. All rights reserved. 1. Basic aspects of leukocyte trafficking during inflammation Classic physiologic studies in the past have revealed that approximately 70 million polymorphonuclear leukocytes (PMN) exit the vasculature per minute [1]. These inflammatory cells move into underlying tissue by initially passing between endothelial cells that line the inner surface of blood vessels. This process, referred to as transendothelial migration (TEM), is particularly prevalent in inflamed tissues. Understanding the bio- chemical details of leukocyte–endothelial interactions is currently an area of concentrated investigation, and recent studies in genetically modified animals have suggested that specific molecules may establish ‘‘bottle- necks’’ to control the inflammatory response [2]. For example, detailed studies have revealed that the process of leukocyte TEM entails a concerted sequence of events involving intimate interactions of a series of leukocyte and endothelial glycoproteins that include selectins, b 2 integrins, and members of the immunoglo- bulin supergene family (e.g. ICAM-1) [3–5]. Moreover, histologic studies of TEM reveal that PMN initially adhere to endothelium, move to nearby inter-endothelial junctions via diapedesis, and insert pseudopodia into the inter-endothelial paracellular space [6]. Successful TEM is accomplished by temporary PMN self-deformation with localized widening of the inter-endothelial junction. Following TEM, adjacent endothelial cells appear to ‘‘reseal’’, leaving no residual inter-endothelial gaps [6]. These histologic studies are consistent with the observation that leukocyte TEM may result in little or no change in endothelial permeability to macromole- cules [7–11]. In the absence of this tight and dynamic control of endothelial morphology and permeability, inter-endothelial gap formation during leukocyte TEM could lead to marked increases in endothelial perme- ability. However, only limited information exists regard- ing the biochemical events which maintain and dynamically regulate endothelial permeability in the setting of either PMN activation or TEM [5,6]. In contrast, neutrophils (PMN) have a demonstrated role in mucosal inflammation. At mucosal surfaces, PMN migration into the epithelium is a first line of ARTICLE IN PRESS www.elsevier.com/locate/plefa 0952-3278/$-see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2005.05.006 à Corresponding author. Tel.: +16177325500x1401; fax: +16172786957. E-mail address: colgan@zeus.bwh.harvard.edu (S.P. Colgan).