This review focuses on the role of monocytes in the early phase of atherogenesis, before foam cell formation. An emerging consensus underscores the importance of the cellular inflammatory system in atherogenesis. Initiation of the process apparently hinges on accumulating low-density lipoproteins (LDL) undergoing oxidation and glycation, providing stimuli for the release of monocyte attracting chemokines and for the upregulation of endothelial adhesive molecules. These conditions favor monocyte transmigration to the intima, where chemically modified, aggregated, or proteoglycan- or antibody-complexed LDL may be endocytotically internalized via scavenger receptors present on the emergent macrophage surface. The differentiating monocytes in concert with T lymphocytes exert a modulating effect on lipoproteins. These events propagate a series of reactions entailing generation of lipid peroxides and expression of chemokines, adhesion molecules, cytokines, and growth factors, thereby sustaining an ongoing inflammatory process leading ultimately to lesion formation. New data emerging from studies using transgenic animals, notably mice, have provided novel insights into many of the cellular interactions and signaling mechanisms involving monocytes/macrophages in the atherogenic processes. A number of these studies, focusing on mechanisms for monocyte activation and the roles of adhesive molecules, chemokines, cytokines and growth factors, are addressed in this review.
Tissue factor (TF) exhibits a distinct nonuniform tissue distribution. Thus, high levels are found in highly vascularized organs such as the lung, brain, and placenta; intermediate levels in the heart, kidney, intestine, testes, and uterus; and low levels in the spleen, thymus, and liver. Several cell types are known to express TF constitutively, such as astrocytes in the brain, epithelial cells enveloping organs and body surfaces, adventitial fibroblasts and pericytes, and cardial myocytes in the heart. Smooth muscle cells in the media of the vessel wall and monocytes/macrophages contain small amounts of TF, which is enhanced substantially upon activation of the cells. Endothelial cells probably do not express TF. The popular concept of TF serving predominantly as a hemostatic envelope encapsulating the vascular bed has been challenged recently by the observation that blood of healthy individuals may form TF-induced thrombi under conditions entailing shear stress and activated platelets, corroborating the notion of blood-borne TF. Accordingly, small amounts of decrypted TF activity is detected in calcium ionophore-stimulated monocytes, and microparticles from plasma of healthy subjects possess TF-like activity subject to partial inactivation by anti-TF antibody. In addition to microparticles, plasma TF also comprises the soluble alternatively spliced human TF and truncated TF, both of which probably require factor VIIa to be physiologically active. Although it has been suggested that activated platelets possess active TF, the notion of TF as an integral platelet component is contested by more recent data. Rather, platelets may be very important in decrypting monocyte TF activity in a process entailing transfer of TF to activated platelets.
In most instances, tissue factor (TF) exposed to the circulation is the sole culprit underlying the initiation of disseminated intravascular coagulation (DIC), although notable exceptions because of a more direct activation of the coagulation system, by snake venoms, for example, do occur. Peripheral monocytes and subendothelial structures are the potential sources of such TF; in the former, TF emerges on the cell surface on synthesis induction and in the latter it becomes available subsequent to permeability changes or damage to the endothelium. Subendothelial TF is constitutively present in fibroblasts, pericytes, and macrophages and at a higher than normal level in tumor-associated macrophages. This scenario of coagulation activation probably describes the principal events underlying emerging acute DIC states under pathophysiological conditions such as abruptio placentae, septic abortion, amniotic fluid embolization, and pregnancy toxemia. Under disease conditions associated with DIC, the continuous exposure to excess TF typically exhausts the available tissue factor pathway inhibitor (TFPI), leading to rampant thrombin generation, persistent feedback activation of factor XI (FXI) by the generated thrombin, and hence virtually uncheckable ongoing fibrin generation (DIC). Recently, it was shown that patients subject to meningococcal sepsis had comparatively large amounts of mainly monocyte-derived circulating TF-containing microparticles. Because phosphatidylserine (PS) is exposed on such particles, in addition to TF, they probably contribute crucially to DIC during meningococcal sepsis. Although endothelial cells (EC) have been shown to express large amounts of TF in vitro, this observation hardly relates to the situation in vivo, where, in contrast, synthesis and exposure of EC TF is very limited and not likely to be of any significance in emerging and ongoing DIC.
DNA replication in isolated nuclei from synchronized HeLa cells has been studied in an effort to optimalize the system and characterize the product. The synthesis was highly dependent on the four deoxyribonucleoside triphosphates, ATP, and Mg2+. Optimum pH was about 7.8. The system was further stimulated by monovalent ions with NH4Cl and Tris-HCl (each 65 mM) being the most effective. The four ribonucleoside triphosphates and glycerol gave a slight but very reproducible and additive stimulation. Low concentrations of spermine and spermidine (0.2-1.5 X 10(-4) M) were also slightly stimulatory (10-15%) whereas higher concentrations were inhibitory. The reaction product was DNase sensitive, and banded at 1.699 g/ml in neutral CsCl together with bulk HeLa nuclear DNA. When studied by neutral CsCl and alkaline Cs2SO4 gradients, the incorporation of [3H]TTP was mainly (more than 85%) due to further elongation of strands initiated in vivo as evidenced by BrdUrd labeling.
The protein component of tissue thromboplastib (Factor III) from human brain was purified by extraction of a microsomal fraction with sodium deoxycholate, gel filtration of the extract on Sephadex G-100 and preparative polyacrylamide-gel electrophoresis in the presence of sodium dodecyl sulphate. The product, apoprotein III, was homogeneous by anayltical polyacrylamide-gel electrophoresis, and it induced monospecific antibodies in rabbits and goat as shown by immunodiffusion and immunoelectrophoresis. Amino acid- and carbohydrate-analysis data for apoprotein III are presented. The carbohydrate moiety of the protein consists of fucose, mannose, galactose, N-acetylglucosamine and N-acetylneuraminate, amounting to a total content of 6.3g/100g. The apoprotein alone had no procoagulant activity. When Factor III was reconstituted by combining the pure apoprotein with a purified lipid fraction from the deoxycholate extract of crude Factor III, a high and optimal procoagulant activity was obtained at a phospholipid/protein ratio of 1.1g/g. Phosphatidylethanolamine alone had a weak but significant ability to restore activity, whereas phosphatidylcholine and phosphatidylserine separately had almost none. Two-component mixtures were on average more effective, and three-component mixtures far more effective, than the single phospholipids. The inclusion of a small amount of phosphatidylserine was very important for high activity.
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