Among the most important events in inflammation is the emigration of leukocytes from the blood into the tissues by way of postcapillary venules. This process, the subject of intense investigation for more than a century, has been resolved into successive phases of leukocyte margination, rolling, adhesion and, finally, transmigration across endothelial cells (EC), the underlying basal lamina and pericytes. In recent years, much has been learned about the molecular events responsible for leukocyte attachment to venular EC. Relatively less attention has been paid to the pathway(s) by which adherent inflammatory cells cross EC, largely because it has been believed for many years that leukocytes emigrate from venules exclusively by passing through EC junctions. Recent work, however, has shown that neutrophils transmigrate across guinea pig dermal venules in response to an N-formylated chemotactic peptide, FMLP, by passing not between but by pushing cell processes through both EC and pericytes. These findings raise an important question: Do the results obtained with FMLP represent a special case or do they have wider application to other types of inflammation involving other classes of leukocytes (other granulocytes, monocytes, lymphocytes), other inflammatory stimuli (proinflammatory cytokines, irritants, antigens, allergens), other tissue sites (peritoneal cavity as well as skin), and other species (rat, mouse, man)? To address this question, several different types of acute and chronic inflammatory reactions will be elicited with different inflammatory and immunologic stimuli in different species of animals and in human volunteers. Reactions will be harvested at times of maximum leukocyte diapedesis for investigation of the pathway(s) by which leukocytes transmigrate across venules, making extensive use of serial section transmission electron microscopy and three-dimensional reconstructions. The same morphological methods will be applied to the study of leukocyte migration across cultured EC monolayers. The results obtained will provide an important foundation for understanding the molecular basis of leukocyte diapedesis and will also determine whether current in vitro models of leukocyte migration across EC are reliable surrogates for diapedesis as it occurs in vivo.
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