Dear colleagues, in this part of my lecture, we shall discuss the onset of inflammation. As you remember through the major part of its duration, all three components of inflammation; alteration, exudation, and proliferation, they develop and go in parallels, but inflammation always starts with alteration. What does it mean? It means that in the beginning, there is always cell death or cell dying. Cell death is not a momentary process. It is not possible to convert a live cell into dead one in one moment. The dying is a process. Moreover, the dying can occur along different pathological processes, and the mechanisms of cell death and cell dying is a matter of my special lecture in maybe, my next course for you. Today, we shall just emphasize that every dying cell obligatory liberates or activates different mediators of inflammation. Some pathways of cell death, they produce a lot of inflammatory mediators like necrobiosis. Other pathways of cell death, they produce considerably less of inflammatory mediators, but nevertheless what we call alteration is, in fact, cell damage and progressive cell dying with liberation and activation of different inflammatory mediators. The most important thing is to put together the terminology and ideas of pathophysiology and the terminology and ideas of anatomic pathology. In anatomic pathology, pathologist works with the pictures, with the photographic moments of certain process, and pathophysiology is a cinema, all that photos in pathophysiology are a live movie. And in anatomic pathology, you have just pictures from that movie. The founder of pathology, Rudolf Virchow, introduced the term cell dystrophies to designate pictures, which can be observed in dying cell. The modern anatomic pathology uses the term cell degenerations, but you need to understand that cell degenerations are not separate typical pathological processes. These are just pictures from the movie named alteration or cell death. These are different patterns or different moments of either necrobiosis or apoptosis or other pathways of cell alteration and cell death. In other words, alteration in the beginning of inflammatory process always includes different patterns of hypoxic, either free radical mediated necrobiosis, and you can see the examples in these pictures. You can see reversed but deep hypoxic necrobiosis in hepatocytes and from the point of view of anatomic pathology, this is cell swelling or balloon-type dystrophy. But from the point of view of pathophysiology in dying cell, in hypoxic necrobiosis, we have a progressive deficit of energy and because of that, the greatest consumer of energy in living cell, which is sodium-potassium ATPase has not enough energy for its work, and it doesn't function properly. But because sodium-potassium pump doesn't function properly, there is excess of sodium and water within the cell. That's why we can see this swelling and this water droplets or balloon-type dystrophy. So, every anatomical picture has chemical and physiological process standing under it or behind it and from pathophysiological point of view, alteration is beginning of inflammation when cell is dying according to certain pattern of cell death and producing inflammatory mediators. In previous part of my lecture, I mentioned primary and secondary alteration. Here, you can see the example of secondary auto-alteration in active hepatitis. You can see self K-cells and T-killer lymphocytes and they attack hepatocyte. And you can see that hepatocyte under this attack is also dying. You can see signs of steatosis, which is subacute pattern of hypoxic necrobiosis in fatty acid consuming cells, like liver cells. Now, we shall discuss two main mechanisms of alteration. One is related to the action of free radicals or reactive oxygen-halogen species. They are potent mediators of cell injury or alteration. The problem is that, in fact, reactive oxygen species, ROS, is a weapon of cell against microbes, against bacteria. And in fact, their production is absolutely necessary during defensive process, but they are not selective. They are able to damage and even kill, not only bacteria, but also self cells around the [inaudible] of their production. That's why it is bilateral sword, which can hit your enemy, but also can hit yourself and the body defends its own cells from oxidative stress or ROS damage. The defense is related with hypoferremia, which is induced during acute inflammation and the infectious process. And also, there is a production of number of so-called positive acute phase globulins, part of these globulins possess with anti-oxidant potential and they protect tissues against. Oxidative stress but this protection is relative and of course, reactive oxygen and halogen species are very important mediators of alteration and outer alteration in the beginning of inflammatory process. Many cells are able to start their production very easy for example phagocytes and leukocytes. They can start the production of reactive oxygen radicals almost immediately after contact of the phagocytic receptors with phagocytosed object. For activation of reactive oxygen species production the cell needs to enhance pentose shunt biochemical reactions and the key enzyme is NADP Oxidase, an instrument of reactive oxygen species generation. Here you can see the chemical reactions which cause of the production of these substances and finally, we shall name them. These are very well known agents like hydrogen peroxide, singlet oxygen, hydroxyl radical, perchlorate anion which is most strong as regards to its anti-microbial effect. And also I shall mention, oxyiodide because leukocytes occupies second place in organism in consumption of iodine after thyroid gland. This is very strange but when you hit your finger or when you scratch your skin, you go to your home apothecary box and you take from this box, a bottle with hydrogen peroxide or a bottle with iodine. And you treat your damage with that universal disinfectants and the nature inside the inflammatory foci does the same because our leukocytes especially granulocytes, neutrophils. They are able to produce huge amounts of peroxide and iodine containing disinfectants. By the way, perchlorate is the same disinfectant which is used as bleaching in washing and for disinfection of sanitary items and perchlorate is also produced in inflammatory foci by neutrophil, leukocytes because of high activity of myeloperoxidase enzyme in them. Other leukocytes are not able to produce perchlorate. Perchlorate anion is strongest antibacterial but also a very strong agent of secondary self alteration. That's why the foci of pus inflammation with high activity of neutrophils and with great production of reactive oxygen species they also are foci of self alteration. You can see also Dr. Klibanoff who contributed greatly into the studies of free radicals and oxidative stress during inflammation. Another mechanism which is also essential for secondary alteration is non-oxygen depending. It is related to the function of lysosomes. Here you can see Christian de Duve, Belgian scientists, Nobel Prize-winner who discovered lysosomes. And he also named them figuratively, the bags of suicide or launch sites of inflammation, that is true because the content of lysosome. Lysosomes takes part in alteration in the onset of inflammatory process. The existence of lysosome was predicted long before Christian de Duve. The great Russian scientist, associate professor of my university, discoverer of phagocytosis, Élie Metchnikoff predicted that in order to digest the microbes, phagocytes should have special enzyme, cytase, he called this enzyme. And in fact, what Metchnikoff predicted as cytases are lysosomic hydrolysis. Lysosome is a source of hydrolysis and free radicals in the final stage of phagocytosis also it functions during so-called exocytosis and it contributes greatly into secondary alteration. Here you can see electronogram of pancreatocyte and you can see dark, round lysosomes which are abundant in this cell. Speaking about lysosomes and their role in inflammation, you need to understand three things. First thing, granules of polymorphonuclear leukocytes are modified lysosomes and peroxisomes, and in the course of inflammation these leukocytes undergo so-called degranulation. They liberate the content of granules into the foci of inflammation. The next thing lysosomal blockers like Delagil chloroquine, zinc salts and so on they are potent anti-inflammatory drugs and you can use it against inflammation. And the last thing, many microbes for example some molds, some pathogenic fungi, they produce special toxins so called lysosomal toxins. These toxins are able to destroy lysosomic membranes and by means of that toxins, fungi are able to cause the alteration and even death of leukocytes. An example is so-called alimentary toxic aleukia, the disease which occurs in consumers of outdated green and cereals. And now, another example is endemic disease in Northern China called Kashin-Beck's disease. In this disease, pathogenic fungi produce lysosomic toxin which causes the death of chondrocytes. So, lysosomes can be attacked by microbes, by fungi and it is the action of lysosomic toxin responsible for certain diseases.
