Endothelial cells selectins

Selectins include P-selectin (platelet selectin), E-selectin (endothelial cell selectin), and L-selectin (leukocyte selectin). P-selectin enables binding of platelets, polymorphonuclear leukocytes, and monocytes to activated endothelial cells and of leukocytes to activated platelets. P-selectin is expressed in the kidneys in systemic lupus erythematosis [266, 267]. The up-regulation of P-selectin expression in glomerui following binding of anti-GBM antibody may be an... 

These interactions involve adhesion proteins called selectins, which are found both on the rolling leukocytes and on the endothelial cells of the vascular walls. Selectins have a characteristic domain structure, consisting of an N-terminal extracellular lectin domain, a single epidermal growth factor (EGR) domain, a series of two to nine short consensus repeat (SCR) domains, a single transmembrane segment, and a short cytoplasmic domain. Lectin domains, first characterized in plants, bind carbohydrates... 

Frequently, the EAR is followed by a late phase response 4-6 h later and it is caused by the pulmonary sequestration of eosinophils, neutrophils, mast cells, and T-lymphocytes. This leukocyte recruitment depends on mast cell-derived mediators such as TNFa and various chemokines, as well as on the expression of adhesion molecules on leukocytes (e.g. VLA-4, CD11/18) and vascular endothelial cells (e.g. VCAM-1, ICAM-1, E-selectin). Products of these leukocytes have several functions First, they cause the second phase of bron-choconstriction, mucus secretion, and airway swelling second, they cause tissue destruction third, they launch and entertain the chronic inflammation. 

In the very early phases of the acute inflammatory response most of the cells invading the damaged area are polymorphonuclear neutrophils, also denoted as PMNs, which serve as initial line of defense and source of proinflammatory cytokines. These cells, which usually live for 4-5 days, circulate in the blood until they are attracted by chemokines into injured tissues. Whereas physical injury does not recruit many neutrophils, infections with bacteria or fungi elicit a striking neutrophil response. The characteristic pus of a bacterial abscess is composed mainly of apoptotic (apoptosis) and necrotic PMNs. Emigration of neutrophils from the blood starts with a process denoted as margination where neutrophils come to lie at the periphery of flowing blood cells and adhere to endothelial cells (Fig. 1). L-Selectin is expressed... 

Figure 2. (1) Neutrophils circulating passively in blood capillary. (2) Chemoattractants may be detected by the circulating neutrophils, by the endothelial cells lining the lumen, or both in order that the neutrophils become adhesive. This adhesion is mediated by selectins, a group of cell surface proteins. Neutrophils roll on the surface of the endothelial cells and then actively locomote seeking out spaces between the endothelial cells. (3) The adhesive neutrophils begin to squeeze between endothelial cells. (4) Cells move through the extracellular matrix towards the site of infection. Here adhesion is low and may not be necessary for locomotion. (5) At the site of infection, neutrophils become trapped by increased adhesion where they phagocytose bacteria and liberate the contents of their granules. After Lackie (1982,1986).

Adhesion of neutrophils to endothelial cells employs specific adhesive proteins (integrins) located on their surface and also specific receptor proteins in the endothelial cells. (See also the discussion of selectins in Chapter 47.)... 

The cell-to-cell interaction following the expression of adhesion molecules (ICAM-1, VCAM-1 and selectin) in endothelial cells induced by cytokines treatment has been reported to be blocked by hydroflavones and flavanols. Apigenin, the most potent flavone tested in this study, inhibited the expression... 

Oxidatively modified LDL up-regulates the surfece expression of VCAM-1 and intracellular adhesion molecule-1 (ICAM-1) in cultured endothelial cells, promoting the interactions between both cell types (Kume et al., 1992). This may play a pivotal role in the development of atherosclerosis by promoting the penetration of circulating monocytes into the suben-dothelial space whilst inhibiting the mobility of resident macrophages. It has been previously demonstrated that ICAM-1, E-selectin, and VCAM-1 are up-regulated in the microvasculature of rheumatoid but not control synovium (Corkill et al., 1991 Koch et al., 1991). The association between ox-LDL and increased expression of adhesion molecules in the inflamed synovium has yet to be studied. 

Fig. 4. The role of RANTES in recruiting monocytes and T lymphocytes to injured endothelium involves the binding of platelets to activated endothelium in a P-selectin-dependent manner with subsequent secretion of RANTES by bound platelets. RANTES can then attract CCR5-expressing monocytes and T cells to the damaged endothelium as well as causing monocyte firm adhesion to occur via binding to platelet-derived RANTES deposited on the endothelial cell layer.

R2. Rainger, E. S., Wautier, M. P., Nash, G. B., and Wautier, J. L., Prolonged E-selectin induction by monocytes potentiates the adhesion of flowing neutrophil to cultured endothelial cells. Br. J. Haematol. 92,192-199 (1996). 

Haraldsen, G., Kvale, D., Lien, B., Farstad, I.N. and Brandtzaeg, P. (1996) Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (IGAM-1), and vascular cell adhesion molecule-1 (VGAM-1) in human microvascular endothelial cells. Journal of Immunology 156, 2558-2565. 

On the neutrophil, the major selectin expressed is L-selectin. This molecule is constitutively expressed on mature neutrophils but may be expressed at low levels (50% of adult) in neonates. Stimulation of endothelial cells with thrombin, histamine, IL-1 and some other agents induces neutrophils (and other leukocytes) to leave the circulation and adhere to the endothelium. They do this by rolling onto the surface of the endothelium, to which they attach via P-selectin translocated from storage sites in Weibel-Palade bodies to the surface of the endothelium upon activation. The expression of P-selectin is short-lived and is replaced on the endothelial surface by E-selectin (whose expression is also regulated by some cytokines), which continues the endothelial-leukocyte interaction. 

These molecules interact with the leukocyte integrins and thus are important during the later stages of the inflammatory response, which are independent of selectin function. The major molecules present on endothelial cells are shown in Table 3.3. 

Histamine contributes to the progression of allergic-inflammatory responses by enhancement of the secretion of proinflammatory cytokines like IL-la, IL-1(3, IL-6 as well as chemokines like RANTES or IL-8, both in several cell types and local tissues [26-29]. Endothelial cells express functional HRl and HR2 and increased adhesion molecule expression such as ICAM-1, VCAM-1 and P-selectin was demonstrated by histamine infusion via HRl [30-32]. Histamine regulates the expression of its own receptors on endothelial cells and influences the overall inflammatory reaction [33]. 

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