Unresolved Questions

Postcapillary venules are formidable machines for leukocyte recruitment. More than 90 percent of all neutrophils in capillaries begin rolling in postcapillary venules, and more than 90 percent of rolling leukocytes (neutrophils) arrest successfully in cytokine-activated venules. Yet, the overall extraction efficiency during inflammation is less than 50 percent, suggesting that some arresting neutrophils may detach again, or that transmigration may be inefficient. This process is not understood at the quantitative level. The role of the endothelial surface glycocalyx is just beginning to be explored. Rolling, arrest, and transmigration of many lymphocyte subsets including activated Th1 and Th2 CD4 helper cells, CD8 cytotoxic cells, natural killer cells, gd T cells, and NKT cells have not been studied in vivo. Very little is known about eosinophil and basophil recruitment and the resolution of inflammation, a process that likely also involves cell interactions in postcapillary venules. Finally, the mechanisms mentioned previously are valid for some tissues, but not the lungs, liver, spleen, kidney, or brain. Suitable intravital microscopy systems and other models need to be developed to address these issues.

Reference

1. Ley, K., and Gaehtgens, P. (1991). Endothelial, not hemodynamic differences are responsible for preferential leukocyte rolling in venules. Circ. Res. 69, 1034-1041.

2. Vink, H., and Duling, B. R. (1996). Identification of distinct luminal domains for macromolecules, erythrocytes, and leukocytes within mammalian capillaries. Circ. Res. 79, 581-589. Discovery of the endolumi-nal endothelial surface layer.

3. Smith, M. L., Long, D. S., Damiano, E. R., and Ley, K. (2003). Near-wall micro-PIV reveals a hydrodynamically relevant endothelial surface layer in venules in vivo. Biophys. J. 85, 637-645.

3a. Long, D. S., Smith, M. L., Pries, A. R., Ley, K., and Damiano, E. R. (2004). Microviscometry reveals reduced blood viscosity and altered shear rate and shear stress profiles in microvessels after hemodilution. Proc. Natl. Acad. Sci. USA 101, 10060-10065.

4. Kansas, G. S. (1996). Selectins and their ligands: Current concepts and controversies. Blood 88, 3259-3287. Comprehensive review on selectins and selectin ligands.

5. Shimaoka, M., Xiao, T., Liu, J. H., Yang, Y., Dong, Y., Jun, C. D., McCormack, A., Zhang, R., Joachimiak, A., Takagi, J., Wang, J. H., and Springer, T. A. (2003). Structures of the alphaL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regula tion. Cell 112, 99-111. Discovery of major conformational shape change upon integrin activation.

6. Jung, U., Norman, K. E., Ramos, C. L., Scharffetter-Kochanek, K., Beaudet, A. L., and Ley. K. Transit time of leukocytes rolling through venules controls cytokine-induced inflammatory cell recruitment in vivo. J. Clin. Invest. 102, 1526-1533.

6a. Dunne, J. L., Collins, R. G., Beaudet, A. L., Ballantyne, C. M., and Ley, K. (2003) Mac-1, but not LFA-1, uses intercellular adhesion molecule-1 to mediate slow leukocyte rolling in TNF-alpha-induced inflammation. J. Immunol. 171, 6105-6111.

7. Alon, R., Grabovsky, V., and Feigelson, S. (2003). Chemokine induction of integrin avidity on rolling and arrested Leukocytes: Local signaling events or global stepwise activation? Microcirculation 10, 297-311. Recent review showing two different mechanisms of arrest for T cells and neutrophils.

8. Smith, M. L., Olson, T. S., and Ley, K. (2004) CXCR2- and E-selectin-induced neutrophil arrest during inflammation in vivo. J. Exp. Med. 200, 935-939.

9. Campbell, J. J., Hedrick, J., Zlotnik, A., Siani, M. A., Thompson, D. A., and Butcher, E. C. (1998). Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279, 381-384. Discovery of arrest chemokines.

Capsule Biography

Dr. Ley has headed the Cardiovascular Research Center at the University of Virginia since 2001 and was the winner of the 1986 Abbott Microcirculation Award and the 2001 Curt A. Wiederhielm Award of the Microcirculatory Society. His laboratory primarily focuses on inflammatory processes in the microcirculation, in atherosclerosis and inflammatory bowel disease. His work is supported by grants from the NIH.

Cell Adhesion Molecules: Structure, Function, Organization, and Role in Leukocyte Trafficking through the Lung

Was this article helpful?

0 0
Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

Get My Free Ebook


Post a comment