[MUSIC] Dear colleagues, This lecture is devoted to the mechanisms of inflammation. And first of all, we shall talk about etiology of inflammation and early events of inflammatory process. We shall speak about acute inflammation. Acute inflammation, which you can see in these pictures, Has some specifics. First of all, it is relatively short. It may occupy few dozens of minutes, or days, or weeks. And besides, it has some characteristic signs. It is, as a rule, rather intensive, and there is a prevail of some component. Typically, it can be prevail of exudation with obvious edema. Or it can be prevail of alteration with obvious necrosis and cell death. As a rule, during acute inflammation, you can easily notice and follow hyperemia, stasis, edema, leukocyte emigration out of microcirculatory blood vessels. And these leukocytes in acute inflammation are mostly, and firstly, neutrophils, neutrophilic granulocytes. Acute inflammation has pretty good chance for spontaneous termination as soon as the causal agent of inflammation will be abolished or extinguished. As soon as the cells will generate a set of so-called anti-inflammatory mediators, acute inflammation resume and quenched out. And it may have several outcomes. There can be full restitution ad integrum. There can be also fibroplasia or cicatrix formation. Also as a result of acute inflammation, you may have a transition into chronic form, sometimes with abscesses formation, sometimes without that. The next thing we shall discuss is the typical sequence of early events and later events in acute inflammation. Here you can see acute tracheitis in diphtheria. And with that picture in mind, I should say that inflammation starts with the events of alteration. First of all, within seconds or first minutes, it would be primary alteration caused by inflammatory agent itself. But later occurs second wave of cell death and tissue deterioration. And we call that second wave or second phase of alteration, secondary alteration. The fundamental difference is that secondary alteration is caused by inflammatory mediators, inflammatory autacoids, those able to kill the cells and destroy the intracellular matrix. It means primary alteration is caused by phlogogenic agent, bacteria or virus or high temperature or frostbite or something else. But secondary alteration, in fact, is self-alteration, self-damage caused by organism itself striving to defend. The next process, which is obvious during acute inflammation from the very beginning, is a process of exudation. Exudation is not just outflow of liquid out of blood vessels into tissue. This is much more multifaceted process. Exudation includes vascular reactions, among them, short initial ischemia of damaged vessels, active hyperemia, combined hyperemia, passive hyperemia or venous congestion, and finally, combined stasis. All that we discussed in one of my previous lectures. And all that occurs in any area of acute inflammation, and all that belong to exudation. But exudation is also cellular behavior, white blood cell margination, white blood cell emigration out of blood vessels into tissue. These are also elements of exudation. And also, even on the background of complete stasis within the microcirculatory bed, extravascular processes continues. We may observe chemotaxis of leukocytes, phagocytosis. And these reactions also belong to exudation, although to its extravascular phase. In the end of acute inflammation, proliferative processes prevail. It doesn't mean they started late. They can be registered from the very beginning of process. But they became obvious because the exudative manifestations to that moment, to that period, they get down, under the influence of anti-inflammatory autacoids. And you may observe the action of these anti-inflammatory mediators like polyamines, spermine, spermidine, cadaverine, putrescine, eosinophilic proteins, serpin and kunin proteolytic inhibitors, and so on. They establish the decrease of exudation and the obvious manifestation of proliferative process. Growth factors regulate these proliferative processes, among them, several cytokines like interleukin-23 and many others. These proliferative processes driven by growth factors will result in restore of tissue structure. Or in fibroplasia, which is substitution of parenchymal tissue for connective stromal one. Also, we can absorb neoangiogenesis, restore of microcirculatory bed. And finally, complete or incomplete, a reparation of tissue structure and function. So the consequence of the early and late events in acute inflammation is very complicated and multifaceted, although the question of inflammation etiology is very simple. Everything may cause inflammation. It can be caused by any agent which is able to produce tissue damage or primary alteration. It can be biological agent, like a microbe or parasite. It can be mechanical agent like, well, mechanical trauma. It can be thermal agent, like frostbite or burn. It can be radiation, because we have inflammation caused by free radicals produced by radiation. It can be chemical agent, like acid or alkaline, producing tissue death and starting inflammatory process. So we call every agent able to start inflammation phlogogenic agent, regardless of its nature. In many instances, the process of inflammation does not require any microbes, it can be aseptic. Etiological factor of inflammation can be exogenous, like in hay fever, for example, where the etiological agent is allergen inhaled into bronchi. But the inflammation can also have endogenous origin, like in many autoimmune diseases. Like in gout, where the etiologic agent is a crystal of uric acid. Also, for example, if person has stone-borne cholecystopancreatitis. It is also inflammation, but it is caused by bile stones, endogenous factors. Regardless of the properties of the damaging agent, with their great variety, the response of tissue or response of organ, in general terms, is similar for acute inflammation. It has much common, regardless of the etiology. Although, in pathology, especially in diagnostic pathology, we need to distinguish between different etiological factors, for example, between different viruses, different bacteria. And in some times, we look for some specific manifestations. Although, of course, etiologically different cases of acute inflammation have much common in their manifestation. And intensity and duration of inflammation is determined by the extent, and by location of the primary injury, as well as by the reactivity of the body. If you look at this scheme, you can see that phlogogenic agent, let's say, microbe, may cause primary alteration. And after that, humoral mediators of inflammation will cause secondary alteration. To observe this in general, we may say that primary alteration is resulting in cell necrobiosis and in cell degenerations. It can be fibrinoid and mucoid swelling. It can be various manifestation of cell apoptosis or cell necrobiosis. And it is always related to activation and release of primary inflammatory mediators. Which mediators are earliest in their start in their action? They are numerous. Eukosanoids are activated very early, as soon as cell membrane will be damaged. Contact system of blood plasma is activated very early, just after the contact of the blood from the damaged vessels to certain surfaces or to certain molecules. If you will analyze the mechanisms of secondary alteration, we may say that there are different agents able to cause secondary alterations. Some of them are of cellular origin, some of them are of humoral origin. Cellular factors of secondary alterations are all mechanisms when one cell in organism is able to kill another cell. These are phagocytosis, K-cell effect, antibody-depending cell mediated cytotoxicity, natural killers and their NK-killing effect, T-killing effect of T-lymphocytes. In every case, one cell kills, by different mechanisms, another self cell, and all that is self-alteration or secondary alteration. Also, many mediators of secondary alterations are humoral agents in soluble form, in tissue fluid, in blood, in inflammatory pus. Besides cellular agents of secondary alteration, when one cells kills another self cell, there are humoral soluble agents, able to destroy tissue or cause cell death by kind of signalling. And humoral agents of secondary alteration are also numerous. They work in parallel levels. These are, first of all, reactive oxygen and halogen species. They are produced by many cells participating in inflammation, first of all, by granulocytes. Complement system is also agent of humoral secondary alteration. Because its end product, C5-C9 complex of proteins, in fact, is an enzyme able to make a hole in the cell membrane and destroy the cell which is attacked by antibody and complement. Another very potent agent of secondary alterations are lysosomal hydrolases. They take part in any kind of acute inflammation. We may also list as a humoral agent of secondary alteration tumor necrosis factor alpha. Because as soon as this humoral mediator will interact with a cellular receptor, the target cell may enter apoptosis. Defensins and other natural peptide antibiotics produced by our cells during inflammation also belong to the agent of secondary alterations. And finally, I must say that autoantibodies generated during the inflammatory process, they also may serve as the agents of secondary alterations. You can see that secondary alteration is very huge process, and as a rule, it is much stronger than primary one. Primary could be just a bite of mosquito. And secondary alteration could cause a focus of necrosis.
