Dear friends, the main topic of our today's talk is relative adequacy and potential pathogenicity of the defensive mechanisms in our body. The main idea we shall discuss is that the defense can be pathogenic itself and defense can be too expensive for our body. First of all, I would like to remind you so-called condemned questions of pathology. These are main controversies of our science. First controversy is between local regulating mechanisms and systemic ones. In health state, local and systemic regulation are pretty good balanced and they are in accordance with each other but under pathological conditions they can contradict to each other and even enter into deep conflict. The next controversy is that of specific and non-specific reactions. Every disease have both specific and non-specific responses and they are combined in a kind of mosaic. The next controversy of pathophysiology is that of acute versus chronic responses. What determines the character of response? Will it be acute or chronic? Will chronic illness give exacerbation? Will acute illness became chronic with time or not? And the last major controversy of our science is between pathogenic and sanogenic effect. Sometimes the same mechanism can establish both pathogenic and sanogenic consequences. Now, please look at this person. It is not pathophysiologists and not medical doctor. It is former prime minister of Russia Victor Stepanovich Chernomyrdin. He was not medical doctor, he was oilman and statesman but he coined very important statement. I will quotate his phrase, "We wanted to make better but it turned in a usual way!" It was said not about health and disease, it was said about state administration but the whole phrase sounds pretty pathophysiologically, because medical doctor in pathology observes very similar situation. Our organism always wants to make better, our body strives to defend but defense causes secondary lesion and sometimes this secondary lesion is much more vicious for the body than the first attack against which body is defending. Our body always wants to make better, our organism strives to defend against attack of certain vicious factors but defense causes secondary lesion and the harm of that secondary self-injury, self-lesion sometimes is much greater than the harm of primary attack. That's the problem, the problem of costs of defense. But why does the defense inevitably causes secondary self-injury? There are several variants of answers. The first answer was given by this person, German biologist, August Weismann. He was the first who suggested the explanation of this paradox, and it was long ago. Weismann insisted that evolution has programmed only those mechanisms which helped to achieve two tasks. First task give birth to your posterity and the second task equally important to give way and space and to liberate some resources for your posterity, and because of that all compensatory reactions programmed in our organism for chronic diseases are principally long-time harmful, they are short-time defensive. But in a long perspective, all of them are too costly and all of them cause harm in organism. So as a result, we have many minds with postponed explosion and which is defensive in short perspective, is vicious in long perspective and death is evolutionary necessary. The second later explanation which does not exclude the first one was given by Canadian Hans Selye, the discoverer of stress. Selye have noticed that sometimes our body has to use acute defensive mechanism in prolonged manner for chronic situations because of lack of choice, but the reaction which can save in acute situation may be too costly, too expensive as regards to resources. So to prolong its application can be vicious for organism and after a certain moment, instead of defensive effect which was in acute situation, you will get harmful effect, adverse effects which is characteristic for prolongation of acute mechanism in the chronic perspective. And the third explanation is rather simple. For the first time it was noticed and clearly articulated by Roger Guillemin. We have inherited many automatic mechanisms from very, very simple organisms, our evolutionary ancestors. But what was absolutely good for them is not absolutely good for much more complicated organism. Good example is phagocytosis, it is inherited from unicellular organisms but if for amoeba it is almost perfect kind of defense. For a multicellular organism, it is not so perfect because decay products and reactive oxygen species created by phagocytes, they cannot fly to the moon, they will be excreted and they will harm the neighboring cells of multicellular organisms. So archetypic mechanism may be pretty effective in simple ancestors but it is always a little bit vicious for more complicated multicellular organisms. Roger Guillemin call that evolutionary opportunism. For a long time, medical doctors insisted that every disease has two sides. One side is injury and another side is defense. For the first time, probably, it was coined by English Dr. Thomas Sydenham. Famous Russian physiologist, Ivan Pavlov, was absolutely agreeing with siding him. He said, "Every disease has two sides, injury and defense and physicians must divide injury and defense in course of every disease. Support, by all means, defense and attack the factors which cause harm". But, is it really always possible to distinguish between vicious and defensive side of disease, and does it really make sense to delineate clearly defense and harm? Because sometimes, both defense and harm are concentrated within the same reaction, within the same response of the body. Look at this picture, you can see Johann Wolfgang Von Goethe the whole world knows him as a poet but also, he had a diploma of anatomist and that person said, "To be generous in one respect, nature must scrooge in another respect." Another poet apostle of American transcendentalism, Ralph Waldo Emerson, and he said, "Nature does not give nothing gratis just trades." And the third example from this sphere of arts, Russian poet Alexander Pushkin, he said, "There is no truth on the earth but neither on Heavens." All of them in that famous expressions, they knew that two sides of disease, lesion and defense can be unseparable. They can be concentrated in the same element, in the same reaction of disease, and I will give you few examples of that. But first, look at this person. That is my teacher, professor Albert Zaichik, he said, "There is no 'kind uncle' inside the body, moreover - the same 'uncle' maybe both friend or foe." Like here, where you have two faces in one face, Dr. Jekyll and Mr. Hyde, in the same time, in one body, in one reaction. It is not enough to recognize that disease elicit defensive reactions which can cause secondary harm for self. More subtle but not less important for medicine is that both defensive effect and self alteration are brought in by the same program by the same mechanism. First example I would like to give is fever. Everyone knows that fever is defensive process, it increases the antibacterial and antiviral immunity. It accelerates the course of phagocytosis, inflammation, and other defensive reactions. But listen, at the same time, every case of fever is obligatorily companied by decrease of iron content in blood. Decrease of iron in blood is not good for bone marrow. It is not good for red blood cells. It is very bad for hematopoiesis, and if you have attacks of fever frequently, or if you have prolonged fever, it may cause iron deficiency and even iron deficient anemia in such a person. Like in those children who are frequently ill. So every fever has defensive side and every fever has vicious harmful side: hypoferremia, lack of iron in blood. Let us try to separate good and bad side. Let us inject additional iron to an animal which is in a status of fever. You will be very surprised. If you will correct the level of iron, if you will normalize the level of iron in experimental animals staying in the process of fever. The defensive effects of fever will vanish, they will disappear. It seems that, it is not high temperature which is important for defense. It is a low level of iron in blood which is important for defense. And if you will try to correct the nature, you will loss the positive side of fever. Why low iron is good for the organism in status of infectious process? Because bacteria also need iron and organism intentionally produces a hormone named hepcidin in liver and that hormone decreases the absorption of iron in feverish person. In order to diminish the level of iron, to diminish the possibilities of bacteria to proliferate, and another thing, iron is an agent which activates the reactive oxygen species production. So to prevent self oxidation, self damage during struggle against infection, organism intentionally makes the level of iron lower. It is bad and you will pay for that with the problems related to poor erythropoiesis and even iron deficient anemia. But it is the cost of your defense. You are defending against infection by the cost of temporarily iron deficiency and you can not separate good from bad.
