In this conclusive part of my lecture dedicated to mechanisms of acute inflammation, I would like to discuss the mediators of inflammation, their groups, and their effects in more details. First of all, about lipid mediators of inflammation. Why they are fused, because it is very easy to start their production. Well, plain damage of cell membrane in the oxygenated medium is enough to start so-called arachidonic cascade mutually in all cells except red blood cells, because red blood cells do not possess with the necessary enzymes. All other cells immediately after damage of plasma membrane in oxygenated environment start to produce new cause annoyance. It is a bridging from alteration to exudation because minor alteration of plasma membrane starts eukosanoid production, and eukosanoids are potent regulators of all facets of exudation process. Their major effects are increase of vascular permeability, arterial hyperemia, fever, anti ulcer effect. They are also essential in normal conditions out of any inflammation. For example, they are necessary for integrity of mucous membranes, for normal kidney function, and so on and so forth. But every event of inflammation increases greatly their production. You can see here the picture showing activation stimulus, membrane damage, and the phospholipid material of membranes is used for production of these inflammatory mediators. Here, neutrophil and platelet is shown. But many other cells are also able to produce them, except, I will repeat, except red blood cells. Here, you can see the general map of eukosanoid pathways, lipid mediators of inflammation. You can see that we need to the activity of several enzymes to establish the production. These are phospholipases, cyclooxigenase, and lipooxygenase. And modern medicine has many drugs able to inhibit these enzymes more or less selectively, and stop or diminish the production of eukosanoids which is used for anti-inflammatory and anti fever purposes. Look at the pathways. They are branching, and as final result, we can get several groups of the eukosanoids. These are prostaglandins, leukotrienes, lipoxins, hydroxy A cause apolienic acids, and thromboxanes. And every group is distinguished by its COXs, for example thromboxanes are produced in majority by platelets. Also, these groups differ by their effects. For example, well, some of them produce vasodilation, another group may produce vasoconstriction, and please look in details this map during self studies. In general, we may say that the effects of thromboxanes and leukotrienes mostly are pro-inflamatory and thrombogenic ones, but the effects of prostacyclin and lipoxanes are mostly anti inflammatory and anti thrombogenic. Let me also show you two scientists who contributed greatly in to this field. They discovered prostaglandins, prototype group of eukosanoid mediators. These are Swedish scientists from Carleen Sky Institute at Sune Bergstroem and Bengt Ingemar Sammueson. They were awarded by Nobel Prize for that. Well, this picture does not show that third scientist contributed into the discovery. It is just a bald person, who suffer from baldness, alopecia. Alopecia is eternal problem of mankind. And for a long time, medical doctors did not know the reasons and mechanisms of alopecia. But now, we definitely know that biosynthesis of prostaglandin D_2 which belongs to this group of eukosanoids. Biosynthesis of prostaglandin D_2 is androgen sensitive. That's why, in those males who have too much androgens in organism, and those who are too masculine, alopecia comes very early especially in the area of forehead. And this kind of alopecia is related to androgen depending excessive biosynthesis of prostaglandin D_2, which is able to stimulate skin sebum production. As a result, there is opturation of the orifices of the hair follicles, and these sad and poor result of complete baldness. So even alopecia is related in its pathogenesis to prostaglandins. Now, about next group of inflammatory mediators. This is a group of biogenic amines. Biogenic amines were described as chemical mediators of inflammation relatively early. Here, you can see a strange person who is sitting with his left leg immersed into some basin with water. This is famous pathophysiologist of Great Britain, Sir Thomas Lewis. By the way, he constructed the prototype of electrocardiograph. And here, you can see Sir Thomas Lewis during tests of his prototype of electrocardiograph device. He tested it on himself. Beside that contribution into cardiology, Mr. Thomas Lewis discovered the pro-inflammatory effect of histamine. Histamine which you can see here, is a derivative of amino-acid histidine, and it was discovered long ago, but it was not known that histamine is somehow related to inflammation. And Sir Thomas Lewis discovered, so called, Lewis triad which is rubor or redness, oedema, and pain, and all three elements can be equally produced by fluorogenic agent like mechanical injury and by simple injection of histamine. As soon as he demonstrated that this triad can be produced by that chemical substance, it was clear that histamine is potent mediator of exudation, partially responsible for early phase of increase of vascular permeability, partially responsible for oedema. Also, histamine is able to accelerate the cell movement within the inflammatory faculty so-called hemokinesis. You can see the major sources of histamine in inflammatory faculty. These are skin mastocytes or labrocytes, mast cells. They contain a lot of these mediator and liberated during the process of degranulation in inflammation and also in allergic reactions. In blood, basophils, basophilic granulocytes are huge sources of histamine. You can see in this table that histamine is not alone in this group. Besides histamine, the group of biogenic amines as inflammatory mediators includes also serotonin especially in rodents. Polyamines like spermine, spermidine, cadaverine, putrescine. These are Iodine inflammator and mediators. They put exudation down and they facilitate the activation of proliferation reparative process. And also, please remind that catecholamines, those of platelets origin, liberated from platelets during thrombi formation, they also belong to this group of biogenic amines. You can see in this table that major parts of this mediators is preformed, realized from granules. Some of them are synthesized De novo. For example, polyamines. All nucleated cells are able to produce polyamines, and for their production, the cells have special enzyme ornithindecarboxylase which is one of the most active enzymes in animal cells. Ornithindecarboxylase establishes the initial stage of polyamine production. You can see also that different biogenic amines, they have non-identical effects. Here is the scope of effects of histamine: pain, itching, fibrillation, mucus hyper secretion, bronchospasm, oedema, and so on and so forth. Please notice that H1 and H2 receptors of histamine are different in their expression and in their biological effects. And through H2 receptors, histamine is able to render certain anti-inflammatory effects. So the excitation of either H1 or H2 receptors in different organs in different permissive conditions can result in non-identical domain of histamine effects.
