General Dynamic Events Leading to Leukocyte Migration

Leukocyte recruitment from the blood into tissue sites of inflammation involves initial contact with the vascular endothelium under shear flow. Leukocytes in the circulation generally passage harmlessly through in the center stream of the vessel, where the velocity is greatest. Diffusive forces caused by the microcirculatory network (increasing diameters from the capillary to the venule) allow smaller, faster erythrocytes to pass the more slowly moving leukocytes, driving them toward the vascular wall. This encourages leukocyte-endothelial interactions, resulting in rolling, where leukocytes move more slowly than flowing erythrocytes. Under these conditions, leukocyte rolling velocities on postcapillary venules are reduced to approximately 10 mm/sec. Leukocytes can then overcome shear forces and attach to the endothelium through a sequence of adhesive events, mediated by specific AMs present on both the leukocyte and the endothelium. Subsequently, transmigration across the EC can occur, followed by further migration through the basement membrane and into the surrounding interstitium (Figure 1).

Leukocytes generally do not interact with the endothe-lium on the arteriolar wall, but adhere and migrate at the site of the postcapillary venule. The diffusive forces and shear rates created through the microvascular network can partly explain this typical location of leukocyte extravasation. However, arteriolar and venular ECs exposed to the same shear rates in vitro demonstrated dramatically different leukocyte-EC interactions and adhesion properties, indicating that shear forces alone are not enough to sustain leukocyte trafficking. Venular ECs are specialized in supporting

Figure 1 General mechanisms involved in leukocyte trafficking in the microcirculation. Shown is a schematic representation of the multistep paradigm of leukocyte recruitment. Leukocytes undergo rolling and activation by EC-displayed chemokines, followed by adhesion onto and transmigration across the endothelium to perform their extravascular functions. Illustration by A. K. Khaw. (see color insert)

Figure 1 General mechanisms involved in leukocyte trafficking in the microcirculation. Shown is a schematic representation of the multistep paradigm of leukocyte recruitment. Leukocytes undergo rolling and activation by EC-displayed chemokines, followed by adhesion onto and transmigration across the endothelium to perform their extravascular functions. Illustration by A. K. Khaw. (see color insert)

leukocyte adhesion, distinctly different from the arteriolar ECs, because of particular AMs (e.g., E-selectin) located exclusively on the venular endothelium. In addition, lymphocytes exit the circulation and enter lymph nodes through specialized high endothelial venules that express their own unique, specific AMs for lymphocyte homing.

Techniques Used to Observe Leukocyte Trafficking

Many indirect and endpoint experimental systems have been used to study inflammation and leukocyte infiltration, such as lavages and histology. However, these do not serve to determine the sequences and events leading to leukocyte extravasation. Consequently, a state-of-the-art in vivo technique, known as intravital microscopy, was established to this end, and provides direct visual observation of living circulation in vivo (e.g., in mice, rats, guinea pigs, hamsters, bats and cats). Here, all the events of leukocyte trafficking, that is, rolling, adhesion, and transmigration through the vascular endothelium, can be visualized in real time. Furthermore, the development of in vitro rolling assays, exerting physiologically relevant shear forces on leukocytes over a layer of ECs, allows intricate dissection of the molecules and mediators involved in endothelial activation and leukocyte recruitment. Further, the relative importance of all the AMs involved in leukocyte recruitment has been demonstrated using blocking reagents (e.g., antibodies and small molecule antagonists), gene targeting, or knockout animals. However, because of compensatory mechanisms, overlapping functions and regulatory processes, data from knockout (double or triple) animals need to be more carefully examined.

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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.

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