Now, we shall discuss some details as regards to Cell Adhesion Molecules and all other mediators of inflammation. In everyday life, in the rule of micro-circulatory vessels is not sticky, and the blood cells in streaming blood also are not sticky. That's why the friction in the stream of blood is minimal. That real logical properties of blood are optimal and blood does not produce sludge, thrombin, fibrin, and cell adhesion. But within the cells of endothelium and within the blood cells, first of all within mucosite and platelets, we have free-formed prepared ready, although not active, cell adhesion molecules. Cell Adhesion Molecules are heteropolymers. Heteropolymers which are sticky and they are produced from standard building blocks like in a Lego toy. And these standard building blocks are sticky to each other. They can recognize each other like key and keyhole. Look at this picture. Here, we can see four major families of Cell Adhesion Molecules, C-A-Ms, and they are ligands, or they are adhesion receptors. Right to left these, are selectins, integrins, immunoglobulin like superfamily of adhesion molecules, and cadherins. And you can see in all over part of picture, the ligands of that molecules various glycoproteins, sugars, fibronectin of connective tissue. Also, these molecules are able to recognize and bind each other. Again, look at this picture, and again, I remind that these are heteropolymers, and they are made from a ready standard blocks complementary to each other like in a Lego building toy. This can be mucin-like units, immunoglobulin-like units, PG-core protein homologue, and some other Lego blocks. And initially, these Lego constructor blocks are ready. They are kept in granules within the cells like these granules in this photo, and they are activated by the mediators of inflammation and expressed on cell surface. For example, you can see here integrins. Integrins is a glue for connective tissue. They recognize so-called RGD tripeptide. And because of that, they establish the aggregation, the homing of cells, the diapedesis of cells, and many other phenomena. But initially, these Cell Adhesion Molecules are in granules and they should be actuated by the mediators of inflammation. These are selectins, P-selectin peculiar to platelets, E-selectin peculiar to endothelial cells, and L-selectin expressed by leukocytes. And every time we discussed the mechanisms of cell margination, cell migration, cell adhesion, platelet block formation, we refer to these integrins, selectins in the interaction. But look at this initially, adhesion molecules are within granules. For example, in endothelial cell, these are so-called Weibel Palade Bodies. And under the influence of histamine, thrombin, and other mediators of inflammation, the content of the granules is liberated and expressed on cell surface. Another example is, well, the action of interleukin first, human necrosis factor, and other potent pro-inflammatory mediators. They cause the expression of sticky mutually adhesive molecules or neutrophil and on endothelial cell. And because of that, neutrophil attach to vascular rule in inflammatory facts. But outside the focus, there is no inflammatory mediators. At least, there is no considerable concentration of these rapidly decaying molecules. And outside inflammatory focus, endothelial cell is still not sticky and blood still keeps its normal real logical properties. Since the initial observations of Henrido Troshi, which I discussed earlier, a lot of time elapsed and many new discoveries were made in this field. It was very essential to have a model of acute inflammation, model by Juluis Cohnheim, and in that particular model, all the discoveries are related to Cell Adhesion Molecules were made. Now, I would like to show you three scholars who made the greatest contribution into cell adhesion molecules doctrine. These are Erkki Ruoslahti from Finland, Richard Hynes from United States, and Masatoshi Takeichi from Japan. I will hope that one day these three guys will share Nobel Prize for their discoveries in cell adhesion molecules and their function because this is crucial for understanding of margination of leukocytes during inflammation. Now, we shall discuss other mediators of inflammation. Let me remind you that there are four main chemical groups of inflammatory autacoids. These are: peptides and proteins, biogenic amines, lipids and part of the eicosanoids, and finally polysaccharides. Of course some scientists, they insist that there is a fifth group, gazelle mediators of inflammation like nitric oxide, H2S, and other gazelle substances able to influence cell behavior. Moreover, now we understand that not only provocation and development of inflammation depends on mediators. To quench it down, to finish it, we also need special mediators, so-called anti-inflammatory mediators, among them polyamines, lipoxins, transforming growth factor beta and other growth factors, lipomodulin, and other eosinophilic proteins from eosinophilic leukocytes, major part of polysaccharides mediators like heparin or chondroitin sulfate are also anti-inflammatory. So, the whole bulk of events related to development of inflammation as well as related to stop of inflammation, everything is controlled by local chemical mediators. Let me show you the person who initiated the doctrine of inflammatory mediators, and his pioneering experiments will have proven that inflammatory dynamic depends on local humoral chemical agents. This is Valy Menkin, he was born in Russia, educated in Switzerland but spent a major part of his scholarly career in United States. Valy Menkin, the discoverer of the inflammatory mediators and their dynamics. You see when we speak about inflammatory autacoids or inflammatory mediators, you need to bear in mind several most important moments. Stop of inflammation also is not just a result of discharge or exhaustion of some supply. It is a result of active separation of alteration, active suppression of exsudation mechanism, and active stimulation of proliferative process. So, the stop of inflammation also requires active autacoid signals. The humoral signals driving inflammation, they can result from some pre-formed substances kept until the moment of inflammation in secretary granules like cell adhesion molecules for example. Also some inflammatory mediators are newly synthesized. They elicit in you during inflammatory process. Of course, this first of all is refer to eicosanoids because they can easily and rapidly be synthesized from the phospholipid material of damage cell membranes. These are prostaglandins, leukotrienes, platelet activating factors, also reactive oxygen species, nitric oxide, and several cytokines related to inflammasome. They all are newly synthesized by the participants of inflammation. Some of the inflammatory mediators are activated. It means that we have precursor as well with this peptide or protein, and activation occurs by means of stepwise proteolysis. Several systems of inflammatory mediators are based on that stepwise proteolysis principle. These are blood coagulation system with its Hageman's factor activation, fibrinolysis or fibrinolytic system, complement system with its stepwise proteolytic activation, and also kinin system which depends on activation of precursors, kininogens by proteolysis into acting mediators kinins. So, the method of putting in function, this autacoid machinery method can be different. It can be preformation and expression, it can be synthesis De Novo, and it can be activation. And the sources of mediators are also extremely versatile: mast cells, basophils, platelets, neutrophils, macrophages, endotheliocytes, lymphocytes, many cells of blood and connective tissue are important sources of driving signals. This is self-assembly and self-ruling of inflammation process.
