Leukocyte adhesion to the vascular endothelium requires a complex and elegant sequence of events involving remark-
Table I Leukocyte Adhesion Molecules.
E-selectin P-selectin L-selectin
LFA-1 (alß2) Mac-1 (aMß2) P150,95 (axß2) VLA-4 (a4ß1)
CD62E CD62P CD62L
CD11a/CD18 CD11b/CD18 CD11b/CD18 CD49d/CD29
SLeX SLeX SLeX
Endothelium Endothelium Leukocytes
Neutrophils, monocytes, lymphocytes Neutrophils, monocytes
Monocytes, granulocytes, NK cells, lymphocytes Lymphocytes able fluid dynamics and a sophisticated array of adhesion molecules. The mechanisms involved have been elucidated using careful analytical methods and mathematical approaches, but there is still much we do not understand. For example, recent studies have shown that the glycocalyx presents a steric barrier to adhesion, and that common inflammatory agents can cause shedding of this glycocalyx, enhancing binding. This exciting finding opens up a new area of research in the field of leukocyte adhesion. Other areas that need more work include those in which the system malfunctions. This is the case in autoimmune diseases such as arthritis where leukocytes adhere to and damage normal tissue. Similarly, overzealous leukocytes are implicated in atherosclerosis in larger arteries, where adhesion is not normally expected. On the other hand, leukocyte infiltration in tumors is generally lower than needed to control tumor growth. The challenge, then, is to determine how the adhesion machinery is breaking down in these pathologies in order to devise new strategies for treatment.
Erythrocyte: Red blood cell; any of the hemoglobin-containing cells that carry oxygen to the tissues and are responsible for the red color of vertebrate blood—called also erythrocyte, red blood corpuscle, red cell, red corpuscle.
Leukocyte: White blood cell; any of the blood cells that are colorless, lack hemoglobin, contain a nucleus, and include the lymphocytes, monocytes, neutrophils, eosinophils, and basophils.
1. Goldman, A. J., Cox, R. G., and Brenner, H. (1967). Slow viscous motion of a sphere parallel to a plane wall—II. Couette flow. Chem. Eng. Sci. 22, 653-660. This is one of the landmark papers in the mathematical analysis of the fluid dynamics ofparticles in shear flow.
Goldsmith, H. L., Cokelet, G. R., and Gaehtgens, P. (1989). Robin Fahraeus: Evolution of his concepts in cardiovascular physiology. Am.
J. Physiol. 257, H1005-H1015. A comprehensive review of the work of Robin Fahraeus, written by a group that also contributed greatly to the field of blood fluid dynamics. Hynes, R. O. (2002). Integrins: Bidirectional, allosteric signaling machines.
Cell 110, 673-687. A recent review on integrin structure and function. Lawrence, M. B., Mclntire, L. V., and Eskin, S. G. (1987). Effect of flow on polymorphonuclear leukocyte/endothelial cell adhesion. Blood 70, 1284-1290. A seminal paper describing the use of the parallel-plate flow chamber to study leukocyte adhesion under dynamic conditions. Lawrence, M. B., and Springer, T. A. (1991). Leukocytes roll on a selectin at physiological flow rates: Distinction from and prerequisite for adhesion through integrins. Cell 65, 859-873. The first detailed analysis of leukocyte rolling on selectins. Ley, K. (2001). Functions of selectins. Results Prob. Cell Differ. 33, 177-200.
Schmid-Schonbein, G. W. (1987). Leukocyte kinetics in the microcirculation. Biorheology 24, 139-151. Sun, C., Migliorini, C., and Munn, L. L. (2003). Red blood cells initiate leukocyte rolling in postcapillary expansions: A lattice-Boltzmann analysis. Biophys. J. 85, 208-222. Blood flow in a "virtual vessel" elucidates the importance of RBC—leukocyte collisions in margination. Zhao, Y., Chien, S., and Weinbaum, S. (2001). Dynamic contact forces on leukocyte microvilli and their penetration of the endothelial glycocalyx. Biophys. J. 80, 1124-1140.
Dr. Munn's laboratory in the Steele Lab for Tumor Biology, Massachusetts General Hospital, focuses on applying quantitative methods to the study of tumor physiology and blood flow. He is Director of Microscopy and Image Analysis of the Steele Lab and is supported by grants from the NCI and NHLBI.
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