[MUSIC] Barrier function of inflammation was understood initially in the terms of mechanics, in the sense of mechanical barriers. And it was done long ago in previous century. But in the end of 20th century, part of physiology came to conclusion that barrier of inflammation should be understood, not only in the terms of mechanics, but also in the sense and terms of informatics. There are conclusive data on the development of classical acute inflammation is in isolated, denervated organs in chick embryo chorioallantoic membrane, which is devoid of neural elements. You can observe, for example placentitis, typical inflammation of placenta. But placenta is not innervated, neither from maternal nor from fetal side. So I already talked about that, but I will repeat. The nervous system is of some influence on inflammation, but of course, not decisive and not principal. It may exert a certain influence, especially in course of some inflammatory components such as vascular reaction. It provides also reception for the sense of pain and for the sense of itching, which may accompany inflammatory foci. And this is important for the overall picture of inflammatory manifestation, but especially important is normal reflex. Non-reflex paracrine activity of sensory neurons, because they are also endocrine cells, they are not only elements of relay in CNS. Sensory neurons are endocrinocytes, and they are able to secrete in impulsless mode via antidromal pathway. Some peptides or autacoids like neurokinins, for example, substance P and other neurokinins. And these neurokinins from sensory neurons, innervating the foci or areas of inflammation, they may influence the mechanisms of exudation. Moreover, sometimes the sensory neuropeptide action of sensory neurons may even elicit information. It would be so called neurogenic inflammation, but these neurogenic mechanisms are not reflectory. They are also humoral. Neuron works not as a source of neural impulse and neural transmitter. Neuron in that case works as a source of autacoid signal, like other cells of inflammatory focus. In other words, basically, the focus of inflammation is delimited in getting information from the neuroendocrine system. It is delimited with oedema, with slowing of blood flow, with functional sympatholysis, which was discussed in one of my previous lectures, and so on and so forth. Now I would like to give you very bright example of how local and systemic mechanisms interact through the acute inflammation.. Look at this picture. You can see unhappy person, who probably was ironing his trousers. And occasionally, he has got a burn with that hot iron, a burn of elbow area of his left arm. So this burned person, he has in that burned area typical zone of acute inflammation with strong and bright dynamics of this process, with a huge amount of inflammatory autacoids produced or activated. But at the same time, because of that accident, this person has stress. And stress goes in parallel as a systemic response for extraordinary stimulus. And because of stress, if you will measure the content of glucocorticoids like cortisol in systemic blood of that burned person, you can find it 6 times, 8 times, 10 times elevated. If you will measure the blood content of catecholamines in that person, it can be elevated 20 times, even 50 times. But listen, both glucocorticoids and catecholamines are potent and key inflammatory regulators. Glucocorticoids may inhibit virtually all facets of the acute inflammation. Catecholamines, well, if you have rhinitis, if you have cold in your nose, you take drops like Xymelin, Naftizin, and so and so forth, very many commercial means. But the acting ingredient is catecholamine. And by means of that catecholamine, dropping it into your inflamed nostril, you get inflammatory signs down. You decrease the intensity of hyperaemia, of oedema, and so on and so forth. How it is possible in one alive person, at the same time, locally, you have huge inflammation. But systemically, you have huge concentration of anti-inflammatory mediators. And they do not prevent the full local dynamic of inflammation. They do not stop local reactions. It means that local zone and systemic zone of regulation are somehow separated. They are delineated informationally. Informational isolation of the burn focus by means of stasis, by means of renal congestion, oedema, and other barrier functions. And these barriers, they establish non-sensitivity or decreased sensitivity of local targets to systemic and inflammatory signals. All that systemic signals can just to delineate inflammation, prevent its spread. But within that extraordinary damaged zone, there will be extraordinary situation and special laws, special laws of war. The constitution of organism is created for peaceful situation, it acts for peace. But in that area, another matter of regulation acts, extraordinary laws of emergency. They are dictated by local inflammatory mediators. And these inflammatory mediators, they overcome the anti-inflammatory systemic effects, but within the limited area only. That is very important. It means that the isolation in inflammatory barriers is bilateral. Not only organism is afraid to spread something out of the inflammatory focus into the whole organism. Body also prevents excessive systemic action on that zone of extraordinary laws. Not only germs should be delimited from spreading by the barrier function of inflammation. For many years, pathologists traditionally taught their students that, listen, there are barriers, and the barriers prevent the spread of infection beyond the borders of inflammatory focus in order to prevent sepsis. And it is the truth. There are different barriers, slowing of venous flow, complete stasis in the center of inflammation in microcirculatory band. Fibrin deposits leukocyte shaft, the formation of granular matter in so called delayed hypersensitivity. Pyogenic membranes of abscesses, sequestration of damaged area, for example, in osteomyelitis. All these are manifestations of physical barriers preventing from systemic spread of infection out of the focus of inflammation and to the neighboring tissues. I can remind that it includes also function of regional lymph nodes, filtering and inactivating dangerous components of fluid drained by the lymphatic vessels from the inflamed area. So all that above-mentioned mechanisms, they prevent the spread and generalization of infectious germs from the foci of inflammation. But what the body is afraid of in case of sterile aseptic inflammation? Inflammation can be aseptic very often. For example, auto-immune inflammation can be aseptic. But nevertheless, non-infectious cases of inflammation, they also create barriers and barrier function is also realized. So what the body is afraid of? Well, it surrounds with barriers foci of aseptic inflammation with no germs in them. Not only germs should be delimited from spreading. The most important thing is to delimit inflammatory mediators from systemic spreading. They should act within inflammatory foci. But if they will act too actively in systemic circulation on non-damaged organs, they may cause severe systemic complications. First of all, excessive systemic action of inflammatory mediators may cause shock. Here you can see the researchers, who first contributed into that idea of the bilateral character of inflammatory barriers. Not only inflammation does not let out, but it also does not let in. Some barriers prevent zone of inflammation from excessive systemic control. The person whom you see in the right picture is Polish pathologist of 19th century, Rudolf Klemensievicz. As early as in 1893, he said, in the development of inflammation, neurogenic factor in the time of maximum disappears, giving way to the phenomena of the vessels themselves. In that period, local autacoids driving the inflammation were not yet discovered. Much later, Soviet scientists Leon Orbeli and Alexandr Ginetsinskiy discovered so-called functional sympatholysis. They have shown that in inflammation, the blood vessels and smooth muscle cells within their wall become non-sensitive to systemic vasoconstrictive neural signals. Because they are under prevailing influence of antagonistic local vasodilatory mediators. So we may say that physical and informational barriers, they provide relative separation of the areas relevant predominantly to local control and predominantly to systemic regulation.
