Intercellular cell adhesion molecule ICAM

Losartan was shown to increase uric acid excretion by inhibiting its tubular reabsorption. This effect does not lie within the spectrum of the blockade of AT, receptors, but rather is a genuine action of the drug on renal tubuli. Losartan was also shown to decrease ocular pressure in normotensive as well as in hypertensive patients with or without glaucoma. Losartan and eprosartan also reduce central sympathetic tone. A metabolite of losartan, EXP-3179 (Fig. 5.8), does not block AT, receptors but may inhibit the atherosclerotic process by suppressing intercellular cell adhesion molecules (ICAM-1), cyclooxygenase-2 (COX-2) and thrombox-ane-A2 (TXA-2). These effects of losartan may lead to potential indications other than blood pressure reduction in hypertensive patients [7]. 

Figure 1. Interaction between leukocytes and endothelial cells of Mood vessels (modified from [3e]). Top overview bottom single steps with explanation of the symbols. Stimulation of endothelial cells by various mediators and factors leads to the expression of selectins and platelet-activating factor (PAF). The extravasation of leukocytes from the postcapillary venules starts with a weak, low-affinity, selectin-mediated adhesion of the leukocytes to endothelial cells, which leads to a slowing down of the leukocyte velocity (rolling). In the second phase a PAF-mediated activation of the leukocyte integrins occurs. In the third phase the activated integrins bind with high affinity to their ligands which are located on the endothelial cell surface. These ligands are called intercellular cell adhesion molecules (ICAM) and are members of the immunoglobulin superfamily. The firm adhesion of the leukocyte cells to the endothelium and finally their departure from the blood vessel (extravasation) results.

FPPS farnesyl pyrophosphate synthase ICAM intercellular cell adhesion molecule... 

Hulthe J, Wikstrand J, Mattsson-Hulten L, Fagerberg B. Circulating ICAM-1 (intercellular cell-adhesion molecule 1) is associated with early stages of atherosclerosis development and with inflammatory cytokines in healthy 58-year-old men the Atherosclerosis and Insulin Resistance (AIR) study. Clin Sci 2002 103 123-129. 

Haraldsen, G., Kvale, D., Lien, B., Farstad, I. N., and Brandtzaeg, P. (1996). Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells. J. Immunol. 56, 2558-2565. 

The quaternization method is also highlighted by the short asymmetric synthesis of cell adhesion molecule BIRT-377 (Scheme 5.24), which is a potent inhibitor of the interaction between intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) [16]. Thus, asymmetricp-bromobenzylation of the alanine derivative 42 (R1 = Me) with (S)-18 under similar phase-transfer conditions as described above gave rise to p-bromobenzylalanine ester 10 in 97% ee (83% yield). A similar asymmetric p-bromobenzylation of alanine ethyl ester 42 (R1 = Me, R= Et) gave the amino ester 47 (R= Et) in 90% ee (86% yield). The amino ester 47 (R = t-Bu or Et) was treated with 3,5-dichlorophenyl isocyanate in the presence of sodium carbonate in dimethylsulfoxide (DMSO) to furnish the hydantoin 48 in 86%... 

Since adhesion molecules are of pivotal importance in cell trafficking and thus inflammation, they could constitute good therapeutic targets in RA. In fact, a murine mAb to intercellular adhesion molecule (ICAM)-l proved to lead to clinical improvement, (140) but repeated administration may have less effects, and the side-effect profile was also of major concern (141). Thus, anti-ICAM-1 may not be the strategy of choice. In this context it should be mentioned that TNFa blockade leads not only to clinical benefit but also to reduction of adhesion molecule expression. 

Other groups have emphasized that previous infections are an independent risk factor for acute stroke. This phenomenon might be at least in part attributable to the activation of cytokines and adhesion molecules such as the vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) (5). 

GMP, granular membrane protein ODFR, oxygen-derived free radicals ELAM, endothelial leukocyte adhesion molecule IL-1, interleukin-1 TNF-alpha, tumor necrosis factor-alpha ICAM, intercellular adhesion molecule IFN-gamma, interferon -gamma VCAM, vascular cell adhesion molecule LFA, lymphocyte-associated antigen CR, complement receptor. 

Figure 31.4. Time course of cellular and molecular activation folowing stroke. Diagrammatic representation of the time course of cellular activation (PNL, polymorphonuclear leukocytes M( ), macrophages) and inflammatory molecular expression (GM, granulocyte and monocyte colony-stimulating factor ICAM, soluble intercellular adhesion molecule-1 VCAM, soluble vascular cell adhesion molecule-1 TNF-a, tumor necrosis factor a IL-1 3, interleukin 1(3 lL-6, interleukin 6 IL-8, interleukin 8 lL-10, interleukin 10) in human brain, cerebrospinal fluid (CSF) and blood after stroke. Reproduced from Nilupul Perera M, Ma HK, Arakawa S, Howells DW, Markus R, Rowe CC, Donnan GA (2006). Inflammation following stroke. J Clin Neurosci, 13 1-8 (with permission from Elsevier).

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