Leukocyte adhesion: an exquisite balance of hydrodynamic and molecular forces.

eukocyte adhesion to the vascular endothelium (the layer of cells that lines the blood vessel walls) plays a central role in normal and pathological inflammation (e.g., host response to infection, wound healing, atherosclerosis, inflammatory bowel disease, and arthritis). This process involves a cascade of adhesive events commonly referred to as initial tethering, rolling, firm adhesion, and extravasation (16). Initially, circulating leukocytes attach or tether to the endothelium. The initial contact between leukocytes and the endothelium is due, in part, to the interaction of the leukocytes with red blood cells, leading to margination of the leukocytes toward the vessel wall (7). Although the initial contact may be strictly physical in nature, the initial tethering requires a molecular interaction that occurs between the leukocyte and the endothe-lium. After initial tethering, the leukocyte may detach back into the free stream or begin to roll in the direction of the blood flow. This rolling behavior is characterized by a velocity that is typically 10-to 100-fold lower than a nonadherent leukocyte moving next to the vessel wall (5). There is also considerable fluctuation in the rolling velocity (i.e., leukocytes tend to speed up and slow down as they roll on the endothe-lium) (5). After rolling begins, the leukocyte may become " activated " and proceed to adhere firmly to the endothelium and migrate across the endothelium into the extravascular space (i.e., extravasate). As with initial tethering, the other steps of the adhesion cascade involve molecular interactions between the leukocyte and the endothelium. It is easiest to gain an appreciation for the biophysics of this process by considering in greater detail the tethering, rolling, and firm adhesion steps of the adhesion cascade. Figure 1 shows that the flow of the blood exerts a force and torque on a leukocyte that is adherent to the endothelium. The force and torque combine to displace the leukocyte in the direction of flow. These clearly constitute a disruptive (counteradhesive) force. Basic physics dictates that for the leukocyte to be adherent (i.e., not moving), this disruptive force and torque must be balanced by an opposing force (i.e., the sum of the forces and torques must be zero.) The counterforce is an adhesive force that forms at the leukocyte-endothelial interface. Cells carry a significant negative charge on their surfaces. This leads to a variety of weak, nonspecific colloidal forces (electrostatic and whole cell van der Waals) between cells. These forces, however, tend …