MECHANISMS OF NEUTROPHIL MARGINATION IN THE NORMAL LUNG

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For unknown reasons, more than half of the neutrophils in the circulation normally marginate in the lungs. As part of host immune defense, these cells can release a variety of potent secretory products to kill invading microorganisms. While this destructive potential is usually controlled and protects the host, neutrophils can also injure the microvascular endothelium, producing increased vascular permeability and ultimately adult respiratory distress syndrome with high attendant morbidity and mortality. The inevitable presence of neutrophils at the site of pulmonary vascular leak has drawn investigative attention to the mechanisms that normally cause neutrophils to marginate preferentially in the pulmonary circulation. Currently, two hypotheses are being tested. In the first, the mechanical impediment hypothesis, the slowly deforming, spherical-shaped neutrophils (compared to the high flexible, disc-shaped red blood cells) are thought to be mechanically impeded as they encounter narrow places in the capillary bed. In the second, the adhesion hypothesis, it is postulated that one of the neutrophil cell surface adhesion-promoting molecules, so important in inflammatory processes, interact with the pulmonary vascular endothelium to cause transient arrest of the neutrophils thereby forming the marginated pool. Because of the difficulty of studying the pulmonary microcirculation directly, the details about virtually all aspects of pulmonary neutrophil kinetics, including the important mechanisms of normal margination, remain obscure. To study these processes directly, we have made microscopic observations of the living lung, a technique unique to our laboratory. We have established that the majority of neutrophils normally marginate at discrete sites scattered throughout the dense capillary network, as well as in a second, quantitatively less important compartment, along venular endothelium. We now propose further investigations using in vivo microscopy and techniques to alter either neutrophil deformability or adhesion to answer the following questions. What causes neutrophils to stop in capillaries: mechanical impediments or adhesive interactions? Do geometric factors in the capillary bed, such as the numerous intercapillary junctions, individual segment diameter, or the capacity of individual segments to dilate, play a role in neutrophil transit? Do neutrophils marginate in venules by adhesion, and if so by which neutrophil adhesion molecules? Are changes in neutrophil adhesion or mechanical properties responsible for increased neutrophil margination in response to intravascular stimuli? What is the relationship between the mechanisms which cause neutrophil margination and neutrophil emigration at sites of inflammation? From what location does emigration occur: capillaries or venules? These studies, specifically focused on the role of the neutrophil in neutrophil-endothelial interactions in the pulmonary microcirculation, will serve as a unique and important bridge between our increasing understanding of the molecular determinants of neutrophil function in vitro and the more classical study of whole organ physiology which so often points the way to solving important clinical problems.