Reticuloendothelial system, removal

Red blood cells are amongst the most numerous of the human cell lines an average healthy 70 kg male having a total of approximately 25 x cells in his 51 of blood. A typical red cell contains in excess of 600 million haemoglobin molecules which equates to a total of about 300 g of haemoglobin, an amount that is far greater than for any other protein in the body. The lack of a nucleus clearly indicates that red cells cannot divide and at the end of their life, worn out RBCs are removed by the cells of the reticuloendothelial system. Approximately 2% (5 x 1011) of the red cell number are removed and replaced by new ones each day. Haem synthesis is outlined later in this chapter and its catabolism is discussed in Chapter 6. 

Physiologically, body stores are maintained by extracting approximately 10% of the iron provided in a balanced diet and this corresponds to 1.5 mg each day for males and slightly more for females to compensate for pregnancy and menses. The trace element is derived from food by peptic digestion and after reduction the ferrous form crosses the enterocyte to be released at the serosal pole via the ferroportin-hepcidin mechanism to be transported, by plasma transferrin, to developing red cells in the marrow for haemoglobin synthesis. At the end of their life span effete erythrocytes are removed by the reticuloendothelial system in the spleen, bone marrow and the liver. 

Physiologically red cells are removed from circulation at the end of their lifespan by the reticuloendothelial system. This is thought to occur as the genetic machinery required to maintain intracellular mechanisms for defence from oxidative stress ceases to function and membrane integrity is lost. 

Antithymocyte globulin binds to circulating T lymphocytes in the blood, which are subsequently removed from the circulation by the reticuloendothelial system. This globulin also reduces the number of T lymphocytes in the thymus-dependent areas of the spleen and lymph nodes. 

Pharmacokinetics Well absorbed following subcutaneous administration. Protein binding Very high. Metabolized in the liver. Removed from the circulation via uptake by the reticuloendothelial system. Primarily excreted in urine. Not removedby hemodialysis. Half-life i-6hr. 

It is well established that size, charge, and chemical composition of liposomes affect their fate in vivo [306], To manipulate their biodistribution and/or drug release, liposomes of different structures have been prepared, including those sensitive to changes in pH [307, 308] or temperature [309,310]. Compared to soluble polymers discussed in previous chapters, liposomes, when applied i.v., are captured by a substantially greater extent by the specialized cells (macrophages) of the reticuloendothelial system (RES) [311]. The removal of liposomes from the bloodstream takes place by nonspecific endocytosis (phagocytosis) [312],... 

In plasma, the drug-carrier complex is exposed to normal clearance mechanisms by the liver, the kidney, and the reticuloendothelial system. The success of avoiding these nonspecific clearance mechanisms depends on the affinity of carriers for their target receptors and on their plasma concentrations. An excess of conjugate in plasma caused by saturation of its cellular uptake by means of the target receptors renders the conjugate present in plasma more susceptible to nonspecific removal. 

Particles introduced into the bloodstream are covered rapidly by components of the circulation, such as plasma proteins, in a process called opsonization. Opsonization makes the particles recognizable to the body s major defense system, the reticuloendothelial system (RES). The RES comprises a diffuse system of phagocytic cells (which engulf inert material) that are primarily associated with the connective tissues in the liver, spleen, and lymph nodes. Macrophage (Kupffer) cells in the liver and macrophages of the spleen and circulation are important in removing particles identified by opsonization. A significant fraction of nanoparticles can be cleared from the circulation system in as little as 15 minutes [48, 49],... 

There is evidence that lipid emulsion, which is cleared by the Kupffer cells of the reticuloendothelial system, can adversely affect reticuloendothelial function by reducing its ability to remove blood-borne bacteria. In a study of the blood clearance and organ localization of viable S-radiolabelled Escherichia coli after slow intraperito-neal and more rapid intravenous administration of 20% fat emulsion in Sprague-Dawley rats, although there was... 

All of the colloid solutions available currently are removed from the circulation by the reticuloendothelial system, resulting in colloid-containing vacuoles, which may persist for years (Sirtl et al 1999, Thompson et al 1970). The presence of these vacuoles does not appear to interfere with the function of the reticuloendothelial system (Lenz et al 1986). 

Precipitation. When a soluble antigen reacts with an Ab. it may form an insoluble particulate precipitate.. Such a complex cannot remain in the bloodstream in its insoluble. state. These. species must be removed by the spleen or through the reticuloendothelial system by phagocytosis. 

C4b and C3b are important for solubilization of immune complexes (by disrupting lattice formation) and their removal by the reticuloendothelial system. 

Inflammation is a local protective response to infection or injury whereby cells and proteins in the blood enter to remove the pathogens and repair the damaged tissue. Edema, redness, pain, and heat are the four cardinal symptoms of inflammation. Extent of reactions is determined by inflammatory mechanisms mediated by serum protein or cellular systems. Serum protein systems include complement, coagulation, fibrinolysis, and kinin cellular systems include PMN cells, mast cells, platelets, eosinophils, lymphocytes, macrophages, and reticuloendothelial system. Insufficient responses result in immunodeficiency leading to cancer and infections excessive responses are the cause of a number of chronic diseases like diabetes, cardiovascular disease, rheumatoid arthritis, multiple sclerosis, and Alzheimer s disease (Tracey, 2002). 

Inactivation or removal of plasma enzymes may be accomplished by several processes denaturation of the enzyme due to dilution in plasma or separation from its natural substrate or coenzyme presence of enzyme inhibitors (e.g., falsely decreased activity of amylase in acute pancreatitis with hyperlipemia) removal by the reticuloendothelial system digestion by circulating proteinases uptake by tissues and subsequent degradation by tissue proteinases and clearance by the kidneys of enzymes of low molecular mass (amylase and lysozyme). 

Overall, however, the reason that only some patients develop autoantibodies, and that only some of those have hemolytic disease, is not known. In an effort to explain why patients may have a positive result from a Coombs test and no hemolysis, Kelton demonstrated that methyldopa impairs the abihty of these patients to remove antibody-sensitized cells. In Coombs-positive patients receiving methyldopa, patients with impairment of the reticuloendothelial system could not clear the RBCs coated with autoantibodies from their bloodstream, and therefore hemolysis did not occur. Patients with hemolysis had no impairment of the reticuloendothelial system. Procainamide has also been reported to cause a positive result on the direct anti-human globulin test and hemolytic anemia. Other drugs that have been reported to cause autoimmune hemolytic anemia include levodopa, mefenamic acid, and diclofenac. ... 

The issue of targeting is far more complex than simply showing a specific affinity of a particular carrier complex with a specific cell or even the ability of the cell to take up the complex and have the drug or peptide activity expressed. Here we must seek to understand how the complex reaches the site of action from the site of administration. Except for cases where this involves local or topical administration, it invariably implies the circulation or blood stream as a pathway and therefore the endothelial cell membrane or layer as an important barrier. A second important obstacle is really a negative barrier, i.e., the reticuloendothelial system (RES), including macrophages, whose function it is to remove unfamiliar... 

Kll. Klein, R. I., and Levinsohn, S. A., Removal of bromsulphalein from the blood stream by the reticuloendothelial system. Proe. Soc. Exptl. Biol. Med. 31,179-181 (1933). 

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