Summary

This review has described the general mechanisms involved in leukocyte recruitment, focusing on the important roles of AMs. Recruitment characteristics in the lung microcirculation have been outlined. The inflammatory stimuli and disease condition may play a role in the site and regulation of leukocyte recruitment and EC activation in the lungs. Various conditions that affect the central conducting airways may induce recruitment in the systemic airway circulation, while the pulmonary network may be more important in other more acute lung injuries from invading organisms, septicemia, or chemicals. The mechanisms of leukocyte recruitment in this circulation are not well elucidated, but it appears that the bronchial microvasculature is similar to other systemic microcirculation. This suggests CD18-dependent recruitment, with selectin-mediated rolling and transmigration across ECs in bronchial/tracheal vessels. This also indicates that the events leading to leukocyte infiltration from the bronchial systemic circulation may differ from those in the more well-studied pulmonary circulation. It is here where cells are sequestered without rolling, and CD18-independent migration occurs. It can be suggested that in the lung, two different endothelial phenotypes may exist, depending on the structure and function of the circulation they support, i.e., gaseous exchange or blood supply, for the pulmonary and airway circulation, respectively. Future studies should elucidate the differences between these two circulations in the same functioning organ, enhancing the understanding of the pathophysiology of lung disorders, and possibly validating novel targets to treat diseases that primarily affect the lungs.

Glossary

Adhesion molecule: A cell surface glycoprotein or glycolipid that functions in the interaction between cells or between cells and the extracellular matrix. Adhesion molecules are found on virtually all cell types.

Alveoli: The air sacs in the lungs where oxygen and carbon dioxide are exchanged between blood and inhaled air.

Bacterial endotoxin (LPS): A component of Gram-negative bacterial cell wall released from bacteria. Once released, it stimulates many inflammatory reactions.

Capillaries: The smallest of vessels, with the thinnest walls, where gas exchange takes place between the blood and the surrounding tissues.

Endothelial cells: These exist as a monolayer of cells lining the insides of blood vessels. They act together (endothelium) to form a selective barrier that regulates movement of cells, proteins, and fluids from the circulation to the tissue. They are also important in blood vessel growth, tissue repair, and coagulation.

Gram-negative bacteria: Bacteria characterized by two outer membranes that fail to stain with Gram's stain. Organisms include E. coli, Salmonella, and cholera.

Gram-positive bacteria: Bacteria characterized by two outer membranes that do stain with Gram's stain. Organisms include Staphylococcus, Streptococcus, and Pneumococcus.

Intravital microscopy: A technique used in live animals to directly observe the microcirculation of tissues in real time using video microscopy Leukocytes: Also known as white blood cells, these migratory cells function in immune surveillance and host defense.

Nude mice: Mice lacking thymus development and T-lymphocytes. Polymorphonuclear cells (PMNs): Also called granulocytes, these are leukocytes with a characteristic multilobed nucleus and cytoplasmic granules. They can be classified as neutrophils, eosinophils, and basophils. Neutrophils are the most abundant circulating leukocyte important in responses to bacterial infections, whereas eosinophils and basophils are more rare in the circulation and important in allergic and parasitic diseases.

Pulmonary circulation: This is the circulation carrying blood from the heart to the lungs and back for oxygen and carbon dioxide exchange.

Systemic circulation: This is the circulation carrying blood from the heart to the whole body for oxygen consumption and back to the heart and lungs for reoxygenation.

Transgenic (or knockout) mice: These are mice with specific mutations (or deletions) and altered genetics used for study of specific gene function.

References

1. Wagner, J. G., and Roth, R. A. (2000). Neutrophil migration mechanisms, with an emphasis on the pulmonary vasculature. Pharmacol. Rev. 52, 349-374.

2. Bochner, B. S. (2003). Cellular adhesion in inflammation. In: Middle-ton's Allergy Principles and Practice, 6th ed. (N. F. Adkinson, Jr., J. W. Yunginger, W. W. Busse, B. S. Bochner, S. T. Holgate, and F. E. R. Simons, eds.). St. Louis, MO: Mosby, pp. 117-134. This is a complete review on the function and regulation of adhesion molecules found on the EC and the leukocyte, with a focus on allergic inflammatory responses.

3. Patel, K. D., Cuvelier, S. L., and Wiehler, S. (2002). Selectins: Critical mediators of leukocyte recruitment. Semin. Immunol. 14, 73-81.

4. von Andrian, U. H., and M'Rini, C. (1998). In situ analysis of lymphocyte migration to lymph nodes. Cell. Adhes. Commun. 6, 85-96.

5. Girard, J. P., and Springer, T. A. (1995). High endothelial venules (HEVs): Specialized endothelium for lymphocyte migration. Immunol. Today 16, 449-457.

6. Muller, W. A., and Randolph, G. J. (1999). Migration of leukocytes across endothelium and beyond: Molecules involved in the transmigration and fate of monocytes. J. Leukoc. Biol. 66, 698-704.

7. Burns, A. R., Smith, C. W., and Walker, D. C. (2003). Unique structural features that influence neutrophil emigration into the lung. Physiol. Rev. 83, 309-336. This is a comprehensive review on the recruitment of neutrophils in the lungs, through the pulmonary circulation and migration in the extracellular matrix, focusing on the structural features of the lungs that differ from other tissues.

8. Lim, L. H., Bochner, B. S., and Wagner, E. M. (2002). Leukocyte recruitment in the airways: An intravital microscopic study of rat tracheal microcirculation. Am. J. Physiol. Lung Cell Mol. Physiol. 282, L959-L967.

9. Sikora, L., Johansson, A. C., Rao, S. P., Hughes, G. K., Broide, D. H., and Sriramarao, P. (2003). A murine model to study leukocyte rolling and intravascular trafficking in lung microvessels. Am. J. Pathol. 162, 2019-2028.

10. Hogg, J. C., and Doerschuk, C. M. (1995). Leukocyte traffic in the lung. Annu. Rev. Physiol. 57, 97-114. This is a good clear review on previous experiments done to elucidate CD 18-dependent and independent mechanisms. It also discusses leukocyte traffic in the bronchial circulation.

Capsule Biography

Dr. Bochner is Professor of Medicine at the Johns Hopkins University School of Medicine and became the Director of the Division of Allergy and Clinical Immunology at the Johns Hopkins Asthma and Allergy Center in 2003. Dr. Bochner's laboratory focuses on mechanisms of human allergic inflammation, with a particular interest in eosinophil, basophil, and mast cell adhesion, migration, survival, and apoptosis. His work is supported by grants from the NIAID branch of the NIH.

Dr. Lim is an assistant professor in the National University of Singapore. Her laboratory focuses on cellular recruitment during inflammation and cancer. Her research is currently supported by grants from the University Research Committee and the National Medical Research Council of Singapore.

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