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Pivotal mechanisms involved in atherogenesis include.
1. Focal intimal influx and accumulation of plasma lipoproteins at lesion-prone sites.
2. Focal intimal monocyte-macrophage recruitment.
3. Generation within the intima of reactive oxygen species of free radicals by smooth muscle cells, macrophages and endothelial cells.
4. Oxidative modification of intimal lipoproteins by these reactive oxygen species to produce such oxidatively modified lipoproteins species as oxidized LDL and Lp(a).
5. Foam cell formation due to the uptake of oxidatively modified lipoproteins by the non-down-regulating macrophage scavenger receptors.
6. Foam cell necrosis, most likely due to the cytotoxic effects of oxidatively modified LDL. This process gives rise to the extracellular lipid core, and is an important event in the transition from the reversible fatty streak to the less readily reversible, more advanced atherosclerotic lesion.
7. Smooth muscle cell migration to and proliferation in the arterial intima, a process in which platelet-derived growth factor is believed to act as a chemo oattractant. Fibroblast growth factors likely regulate smooth muscle cell proliferation.
8. Plaque rupture, primarily at sites of greatest macrophage density. Proteolytic enzymes released by macrophages may stimulate plaque rupture, which ultimately leads to mural or occlusive thrombosis. Thrombosis contributes significantly to the stages of plaque growth.
9. Autoimmune inflammation, likely the result of anti-genic epitopes of oxidized LDL. Lipoproteins, such as LDL and Lp(a), enter the subendothelial space and intercept free radicals generated by endothelial cells. Following oxidation, these charge-modified lipoproteins are taken up by the non-down-regulating macrophage scavenger receptors pathway, resulting in lipid-rich, cholesteryl ester rich foam cells. Concurrently, circulating monocytes continue to attach to the endothelium, attracted by the chem oattractant MCP-1, and oxidized LDL. The expression and synthesis of MCP-1 by endothelial and smooth muscle cells is augmented by oxidatively modified lipoproteins, allowing the process to continue.
The next phase in atherogenesis is the development of the classic fatty streak as result of the continued uptake of oxidatively modified LDL by the macrophage scavenger receptors with continuing foam cell formation. A few smooth muscle cells can also be seen apparently entering the subendothelial space and proliferating within the intima during this phase. The transitional phase of atherogenesis is characterized by necrosis of the foam cells and the formation of an extracellular lipid core. In this stage, there is an increase in both smooth muscle cells proliferation and collagen synthesis, and lesions continue to grow. As long as elevated low density lipoproteins are present in the circulation, the atherosclerosis process continues. Among the additional changes taking place is the influx of Tlymphocytes. The involvenment of an autoimmune inflammatory component becomes obvious in the late stages of lesion development and is reflected by a prominent lymphocytic infiltration of the adventitia.
atherogenesis –
plaque – атеросклеротическая бляшка
lymphocytic – лимфотический
inflammatory – воспалительный
low density lipoproteins – липопротеины низкой плотности
55. Advances in blood component separation and plasma treatment for therapeutics
The separation of blood cells from plasma is done routinely by centrifugal techniques.
Membranes for plasma separation.
Membrane modules vary in surface area from about 0,15 to 0,8 m2. Membrane plasma separation is a relatively simple process. At relatively low transmembrane pressure (generally less than 50 mm Hg), adequate plasma fluxes can be achieved. Equipment requirements are only minimal and the operation is much akin to that for other extracorporeal treatment technologies as hemodialysis, hemofiltration and hemoperfusion.
Membrane of on-line plasma treatment.
Plasma exchange whether by centrifugal or membrane techniques requires that the plasma discarded be replaced by physiological solution, which in most cases is en albumin solution. Because essential plasma components as well as pathological ones, are removed during plasma exchange, techniques designed to remove only the pathological components would be highly desirable. Review of the disease states treated by plasma exchange reveals that mane of the marker solutes ere of f molecular weight larger (generally greater than 100 000 daltons) than albumin, suggesting membrane filtration as physical separation techniques for their removal.
With presently available membranes, selective passage of albumin (near 70 000 daltons) and lower molecular weight solutes with complete retention of larger molecular weight solutes is difficult to achieve. However, such a complete separation may not be desirable since many higher molecular weight solutes are normal components of plasma To apply some selectivity in the separation of the marker solutes with a high return to the normal constituents of plasma and thus no requirement for plasma product infusion, the technique of cryofiltration was applied.
Cryofiltration is the on-line technique of plasma treatment consisting of plasma cooling followed by membrane filtration. By cooling the plasma, cryogel is deposited on the membrane during the Filtration process. The cryogel has been shown to contain concentrated quantities of the marker solutes. Response to therapy in the majority of patients with rheumatoid arthritis has been from good to excellent. In treatments, decreases in marker solutes have been noted coupled with improvement in clinical symptomology.
Membrane technology appears very promising in the separation and treatment of plasma on-line. Chronic treatment therapies appear safe and well tolerated by the patients.
centrifugal technique –
plasma exchange – плазмообмен
therapeutic – терапевтический
metabolic – метаболический
multiple – множественный
extracorporeal – экстракорпоральный
56. Artificial oxygen carries
Artificial oxygen (O2) carries aim at improving O2 delivery Artificial O2 carries thus may be used as alternative to allogeneic blood transfusions or to improve tissue oxygenation and function of organs with marginal O2 supply. Artificial O2 carries can be grouped into modified hemoglobin (Hb) solutions and perfluorocarbon (PFC) emulsions. The native human Hg molecule needs to be modified in order to decrease O2 affinity and to prevent rapid dissociation of the native tetramer into dimers. The O2 transport characteristics of modified Hb solutions and PFC emulsions are fundamentally different. The Hb solutions exhibit a sigmoidal O2 dissociation curve similar to blood. In contrast, the PFC emulsions are characterised by a linear relationship between O2 partial pressure and O2 content. Hb solutions thus provide O2 transport and unloading capacity similar to blood. This means that already at a relatively low arterial O2 partial pressure substantial amounts of O2 are being transported. In contrast, relatively high arterial O2 partial pressures are necessary to maximize the O2 transport capacity of PFC emulsions. Modified Hb solutions are very promising in improving O2 transport and tissure oxygenation to a physiologically relevant degree. Because cross-matching is unnecessary, these solutions hold great promise as alternative to allogeneic blood transfusions and as O2 therapeutics, which might be of great value also in the prehospital resuscitation of trauma victims or in specific situations in intensive care medicine. In patients with a reduced cardiac contractility and normal or elevated mean arterial pressure Hb infusion may increase systemic and pulmonary vascular resistances with consequent reduction in , cardiac output. In contrast, in a previously healthy trauma victim, suffering from severe hypovolaemia due to massive haemorrhage, the combined effects of volume replacement, added O2 transport capacity, and mild vasoconstriction due to the infusion of a modified Hb solution may be beneficial.