Leukocyte, adhesion, inhibition

Vascular Tone Immune Surveillance Cellular Adhesion Vascular Permeability Neurotransm ission Bronchodilation Platelet Adhesion Inhibition Renal Function Antioxidant Leukocyte Adhesion Inhibition Protection Against TNF Toxicity Enzyme Function Inhibition DNA Damage Induction Lipid Peroxidation Induction Increased Susceptibility to Radiation Alkylating Agents Toxic Metals Antioxidant Stores Depletion... 

Inhibition of leukocyte adhesion Inhibition of cellular protein synthesis ... 

The antiinflammatory effects of statins likely result from their ability to inhibit the formation of mevalonic acid. Downstream products of this molecule include not only the end product, cholesterol, but also several isoprenoid intermediates that covalently modify ( pre-nylate ) certain key intracellular signaling molecules. Statin treatment reduces leukocyte adhesion, accumulation of macrophages, MMPs, tissue factor, and other proinflammatory mediators. By acting on the MHC class II transactivator (CIITA), statins also interfere with antigen presentation and subsequent T-cell activation. Statin treatment can also limit platelet activation in some assays as well. All these results support the concept that in addition to their favorable effect on the lipid profile, statins can also exert an array of antiinflammatory and immunomodulatory actions. 

In the recent review Carr et al. [54] considered potential antiatherogenic mechanisms of a-tocopherol and ascorbic acid. These authors concluded that these antioxidants are able to inhibit LDL oxidation, leukocyte adhesion to the endothelium, and vascular endothelial dysfunction. They also believe that ascorbic acid is more effective than a-tocopherol in the inhibition of these pathophysiological processes due to its capacity of reacting with a wide spectrum of oxygen and nitrogen free radicals and its ability to regenerate a-tocopherol. 

Murase, T., Kume, N., Hase, T., Shibuya, Y., Nishizawa, Y., Tokimitsu, I., and Kita, T., Gallates inhibit cytokine-induced nuclear translocation of NF-kappaB and expression of leukocyte adhesion molecules in vascular endothelial cells, Arterioscler. Thromb. Vase. Biol, 19, 1412, 1999. 

Protein C exerts an antithrombotic effect by inhibiting Factors Va and Villa. In vitro data indicate that it has indirect prohbri-nolytic activity through its abhity to inhibit plasminogen activator inhibitor-1 (PAI-1) and to hmit production of activated throm-bin-activatable-hbrinolysis inhibitor. In vitro data also indicate that Activated Protein C may exert an anti-inflammatory effect by inhibiting human tumor necrosis factor production by monocytes, by blocking leukocyte adhesion to selectins, and by hmiting thrombin-induced inflammatory responses within the microvascular endothehum. 

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. 

Evangelista V Manarini S, Dell ElbaG, etal. Clopidogrel inhibits platelet-leukocyte adhesion and platelet-dependent leukocyte activation. Thromb Haemost 2005 94 568-577. 

NO also inhibits leukocyte adhesion to the endothelium (von der Leyen et al. 1995). NO and PGI2 have antiplatelet actions as well. Thus, via NO synthesis, VEGF can provide protection against proatherogenic factors (Zachary 2001). The overall vascular protective action of VEGF mediated by NO and PGI2 is illustrated in Figure 16.6. 

Risk and protective factors of atherosclerosis influence VCAM-1 expression [10,19]. A possible relation between VC AM expression and oxidized LDL was established when an important component of this modified lipoprotein, lysophosphatidylcholine, was shown to stimulate VCAM expression and increase adhesion of monocytes on endothelium in cell cultures [10,18,19]. Modified LDL and its constituents augment c)4 okine-activated VCAM-1 expression in human vascular endothelial cells [10,20]. In contrast, HDL inhibits cytokine-induced expression of endothelial cell adhesion molecules [10,21]. -3 Fatty acids have been found to decrease mRNA levels and surface expression of VCAM-1 in endothelial cells [10,22]. Aspirin inhibits induction of mRNA and cell surface expression of VCAM-1 by TNF-a and thereby inhibits monocyte adhesion on stimulated endothelial cells [10,23]. In contrast to ICAM-1, E-selectin, and P-selectin, endothelial VCAM-1 can mediate leukocyte adhesion via its sole interaction with the integrins 4P1 or 4P7 [10]. 

Finally, Heavner et al. reported that the P-selectin regions 37 to 50 [167] and the regions E-, L-and P-selectin 109 to 118 [168] inhibit the leukocyte adhesion to P- and E-selectin chimeras in the low p.M range. 

Its formation in vascular endothelial cells, in response to chemical stimuli and to physical stimuli such as shear stress, maintains a vasodilator tone that is essential for the regulation of blood flow and pressure. NO also inhibits platelet aggregation and adhesion, inhibits leukocyte adhesion and modulates smooth muscle cell proliferation. NO is also synthesized in neurons of the central nervous system (CNS), where it acts as a neuromediator with many physiological functions, including the formation of memory, coordination between neuronal activity and blood flow, and modulation of pain. In the peripheral nervous system, NO is now known to be the mediator released by a widespread network of nerves. ... 

Moderate to high doses. Inhibits COX 2, an enzyme form that is induced in cells that are involved-in inflammatory responses. Also interferes with formation of cell surface selectins and integrins, which promote leukocyte adhesion, a process necessary for their tissue infiltration via endothelial cell junctions. 

Cyclamenol A is one of the very few noncarbohydrate and nonpeptide natural products that inhibits leukocyte adhesion to endothelial cells. Bis-vinyl iodide (70), a precursor for cyclamenol A, is prepared from iodo acid 68 and amine 69.27... 

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