Selectins P-selectin

Mycophenolate mofetil (MMF) is converted to mycophenolic acid, the active form of the drug. The active product inhibits cytosine monophosphate dehydrogenase and, secondarily, inhibits T-cell lymphocyte proliferation downstream, it interferes with leukocyte adhesion to endothelial cells through inhibition of E-selectin, P-selectin, and intercellular adhesion molecule 1. MMF s pharmacokinetics and toxicities are discussed in Chapter 55. 

P-selectin plays an essential role in the initial recruitment of leukocytes. When endothelial cells are activated by molecules such as histamine or thrombin during inflammation, P-selectin moves from an internal cell location to the endothelial cell surface. Thrombin is one trigger of endothelial-cell release of P-selectin. Ligands for P-selectin on eosinophils and neutrophils are similar they are sialylated carbohydrates, but clearly different from those reported for E-selectin. P-selectin attaches to the actin cytoskeleton through anchor proteins. 

Thirdly, there are the selectins, a family of Ca Mependent carbohydrate-binding proteins which function to control leukocyte interactions with vascular endothelium (Tedder et al, 1995). There are three closely related members of the selectin family, namely L (leukocyte)-, P (platelet)-, and E (endothelial)-selectin. P-selectin is expressed in the Weibel-Palade bodies of endothelial cells and in the a-granules of platelets. It is rapidly mobilized to the sur ce of endothelial cells and platelets in response to a variety of inflammatory agents such as fiuombin, histamine, complement factors, fiee radicals and cytokines (Tedder et al, 1995). P-selectin mediates the adhesion of neutrophils and monocytes to activated platelets and endothelial cells. Platelets can be bound to the endothelium indirectly by adhering to leukocytes bound to the endothelium. 

P. Karlheinz, P. Nawroth, C. Conradt, T. Nordt, T. Weiss, M. Boehme, A. Wunsch, J. Allenberg, W. KUbler and C. Bode, Circulating Vascular Cell Adhesion Molecule-1 Correlates with the Extent of Human Atherosclerosis in Contrast to Circulating Intercellular Adhesion Molecule-1, E-Selectin, P-Selectin, and Thrombomodulin, Arteriosclerosis, Thrombosis, and Vascular Biology 17 (1997) 505-512. 

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... 

Asthma, allergy E Selectins P Selectins in plasma L Selectins [121,125]... 

Kawashima H, Hirose M, Hirose J, Nagakubo D, Plaas AH, Miyasaka M. Binding of a large chondroitin sulphate/dermatan sulphate proteoglycan, versican, to L-selectin, P-selectin, and CD44. J Biol Chem 2000 275 35448-35456. 

P-selectin, VEGFR2, VCAM, pPAR, CD55, Eotaxin-3, MCP-1... 

P-selectin EC, platelets P-selectin glycoprotein ligand-1 (PSGL-1) Sialyl-Lewis" and others... 

Figure 47-10. Schematic diagram of the structure of human L-selectin. The extracellular portion contains an amino terminal domain homologous to C-type lectins and an adjacent epidermal growth factor-like domain. These are followed by a variable number of complement regulatory-like modules (numbered circles) and a transmembrane sequence (blackdiamond). A short cytoplasmic sequence (open rectangle) is at the carboxyl terminal. The structures of P- and E-selectin are similar to that shown except that they contain more complement-regulatory modules.The numbers of amino acids in L-, P-, and E- selectins, as deduced from the cDNA sequences, are 385,789, and 589, respectively. (Reproduced, with permission, from Bevilacqua MP, Nelson RM Selectins. J Clin Invest 1993 91 370.)...

PPD Purified protein derivative PPME Polymeric polysaccharide rich in mannose-6-phosphate moieties PRA Percentage reactive activity PRD, PRDII Positive regulatory domain, -II PR3 Proteinase-3 PRBC Parasitized red blood cell proET-1 Proendothelin-1 PRL Prolactin PRP Platelet-rich plasma PS Phosphatidylserine P-selectin Platelet selectin formerly known as platelet adctivation-dependent granule external membrane protein (PADGEM), granule membrane protein of MW 140 kD (GMP-140)... 

Fig. 1. Surface phenotype of HSPCs. Primitive HSPCs have the phenotype of c-KitThy-ll0WLin CD34+CD33 in humans, and the mouse counterparts have the phenotype of c-KifThy-llowLin Sca-l+. Primitive HSPCs express CXCR4 as the major chemokine receptor and various adhesion molecules such as VLA-4, VLA-5, LFA-1, P-selectin glycoprotein ligand-1 (PSGL-1), and CD44 for migration to the stem cell niche.

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.

Schober A, Manka D, von HP, et al. Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury. Circulation 2002 106(12) 1523-1529. 

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). 

CD62P or P-selectin, which is a component of the platelet a granule membrane of resting platelets. It is expressed on the platelet surface membrane only after a granule secretion. P-selectin mediates the adhesion of activated platelets to neutrophils and monocytes. 

Of the four markers just mentioned, the expression of P-selectin on the activated platelets is the most widely studied. However, CD62P may not be the ideal marker for detection of circulating degranulated platelets, because they may rapidly lose their surface P-selectin but yet may continue to function. The decrease in the platelet surface expression of the GPIb-IX-V complex (CD42) perhaps represents a more sensitive marker of in vivo platelet activation. Apparently platelet activation related to strenuous exercise is more readily detected using CD42 than other markers (99). 

The CTAD additive mixture has found application in the monitoring of heparin therapy by either the chromogenic substrate assay or the APTT and in the measurement of platelet markers such as P-selectin (CD62) by flow cytometry (108, 109). 

Nemmar, A. et al. (2007) Enhanced peripheral fhrombogenidty after lung inflammation is mediated by platelet-leukocyte activation role of P-selectin. Journal of Thrombosis and Haemostasis,... 

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. 

Garcfa-Martfnez MC, Labios M, Hermenegildo C, Tarfn JJ, O Connor E, Cano A (2004) The effect of hormone replacement therapy on Ca2+ mobilization and P-selectin (CD62P) expression in platelets examined under flow cytometry. Blood Coagul Fibrinolysis 15 1-8... 

A Compound P-selectin (IC50 mM) L-selectin (IC50 mM) E-selectin (IC50 mM)... 

SIN-1 spontaneously releases NO and superoxide under physiological conditions thereby stimulating cGMP production. SIN-1 significantly decreased expression of P-selectin and both total and activated GP Ilb/IIIa and also promoted reversal of activated GP Ilb/IIIa complex in platelets stimulated with thrombin [61]. However, in rats SIN-1 could only partially reduce the degree of platelet activation [62]. SIN-1 stimulated VASP Ser157 phosphorylation and inhibited GP Ilb/IIIa activation. Threshold... 

SNAC is the most potent inhibitor of collagen-induced platelet aggregation in vitro compared to other S-nitrosothiols (SNAP, GSNO, CysNO and HomocysNo). Although it increased cGMP-levels in platelets [47], SNAC only partially inhibited thrombin-induced P-selectin expression on a platelet surface [79]. 

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