So, within the foci of inflammation, cells exchange with chemical signals which they produce themselves. It is self regulation. And this self regulation is based on several groups of autacoids, eukosanoids, cytokines, cell adhesion molecules, step proteolytic activators, stepwise proteolytic activators like compliments, like fibrinolysis and so on, biogenic amines and polysaccharide mediators. Step by step, in our next lectures we'll talk about each group of them. But, in general, let me emphasize that these regulators are ruling inside that limited zone, inside inflammatory focus. In typical, normergic cause of acute inflammation or arthrophlogosis. The inflammatory autacoids act within the foci of inflammation, but only very small amounts of them spread across the inflammatory barriers into systemic circulation. As a result of that, normergic inflammation is accompanied by minimal manifestations of systemic action of inflammatory autacoids. These are leukocytosis because some cytokines spread to bone marrow and stimulate their buccal poiesis. This can be fever because some inflammatory mediators influence hypothalamus and change the body temperature regulation. These can be also so-called acute phase response or change of blood plasma protein fractions with increase of erythrocyte sedimentation rate and all that belongs to normergic cause of events. But sometimes, very large amounts of inflammatory mediators may transgress the barrier and spread into systemic circulation. In severe multiple foci of inflammation, for example, in very, very big percentage of skin burns, the total area, the total border of inflame to resume is so huge that the border guardians can not execute properly these barrier function. If you just burned your finger or two fingers, that is not dangerous for your life, but if, for example, 35% of total skin surface are burned, in that case, the border is so huge that very large amount of inflammatory autacoids are spread systemically. This may cause systemic action of inflammatory mediators over respiration, circulation, systemic blood clotting and other vitally important functions, and organs and tissues which are not primarily damaged would be involved in that, let me say, why Fyfield of inflammatory programs. No one never use the word organismitis to designate to this complication. We designate the complication of severe excessive systemic action of inflammatory mediators, we designate that with the word shock. It causes acute circulatory failure, acute circulatory insufficiency and the hypoxia of many different organs because of hyperperfusion. So, the consequence of these transgressing of barriers, for the organism as a whole, is very, very harmful. Person may enter into various kinds of shock as a result of excessive systemic action of inflammatory mediators. Depending on situation, doctor will call that infectious shock, allergic shock, pseudoallergic shock, or, for example, traumatic shock. But nevertheless, regardless of the primary reason of tissue damage, if the barrier mechanisms of inflammation did not function properly, if they did not keep this huge storm of autacoids inside the inflammatory area, this would destroy the systemic vitally important functions and this would cause shock, which may result in huge lethality. So, two very important conclusions. Conclusion one: systemic excessive action of inflammatory mediators may cause shock, traumatic, burn, allergic, septic, toxic and many other kinds of these severe disorder. But it means that inflammation per se, as far as it is able to keep barriers, is anti-shock mechanism. Not every inflammation results in shock, only those cases which violate the barrier function. And another conclusion is that In damaged or diseased organism, we have not one pathologic process. We have several pathological processes of different level developing in parallels and influencing each other. In trauma, locally, inflammation starts and at the same time, systemically, stress starts, and these pathological processes are interacting. And look at these scheme. When damaging agent acts on organism, it can produce several lines of effects. Non-specific effect resulted in stress. Phlogogenic effect and apoptogenic effect resulted in liberation and activation of inflammatory autacoids and inflammatory process. And at the same time, every agent has its specific side, its specific action. For example, if it is a toxin, it may cause poisoning, if it is a, for example, some immune ligand like outer antibody, it may cause outer immune disorder. It may block some receptor or glycerols are stimulated. If the damaging agent was a germ, it has its own biological life living organism with some consequences, and the mosaic of all that constitutes the whole picture of disease. So arthrophlogosis or normal allergic inflammation and ill stress, which means non-excessive, properly regulated acute stress, they both are two natural mutually sustaining anti-shock mechanisms. It means that inflammation is bad but as soon as you have normal allergic inflammation keeping its barrier function, you would not have shock. Stress is also unpleasant, but as soon as you have properly regulated stress, you would not have shock. Without the barrier or function of inflammation and without ill stress, every serious damage would cause systemic circulator insufficiency, would cause shock with all its severe consequences. The balance between stress and inflammation with its barrier function, this balance does not allow after local damage to steady multiorgan hypoxia. That is very essential. If the rule is violated, it means if barrier or function of inflammation is insufficient, if stress mechanisms are insufficient in that case, organism develops multiorgan hypoxia insufficiency, and this is a very serious complication of shock. The worst thing about the mechanisms of INT shock and INT inflammation reaction of stress, look at this picture. Glucocorticoids, the main hormones of stress, they both suppress the components of inflammation and at the same time, they are applied in a resuscitation in INT shock surgery, and they serve in emergency medicine as potent anti-shock drugs. So this same drug, adrenocortical hormones, glucocorticoids, the same drugs are both potent anti-inflammatory and potent anti-shock. This is very essential detail. Please notice it. It means that inflammation and stress interact and mutually balance each other in order to prevent shock. Informational influences of hormones in the foci of inflammation are limited. They are limited by slowing of blood flow, by slowing of hormone delivery into the four signs of inflammation. But moreover, we may remember that many inflammatory autacoids can partially block their transmission of hormonal signals. A good example is tumor necrosis factor alpha, which is a potent antagonist of insulin on the post receptor level. So because of that, permissive interaction within the inflammatory foci, there is a predominance of local regulators, and beyond the inflammatory foci , in normal allergic inflammation, in auto-flogosis, we have predominance of stress and other systemic anti-inflammatory drivers. Look at this picture. These are two persons who understood the anti-shock and anti- inflammatory role of stress hormones. These are Hans Selye, who discovered stress, and Fred Hench, who introduced glucocorticoids into broad medical practice. Selye non-occasionally compared in his books the inflammation and stress, although they contradict each other. Stress hormones are anti-inflammatory. Inflammation mediators can elicit and increase stress. But nevertheless, Selye, he even called inflammation a "local stress" in one of his papers of 1959. Of course it was just figurative expression but in fact, both of these non-specific responses to injury, they are united in their final goal to avoid that shock. If we regulate inflammation properly, we avoid the shock after trauma. If we regulate stress properly, we avoid the shock after trauma. And in fact, both inflammation and stress serve as natural anti-shock barriers balancing each other. Thank you for attention. My next lecture will be about mediators of inflammation.
