Now, about next group of inflammatory mediators, polypeptide mediators of inflammation. They can be joined into contact system of blood plasma because the precursors for activation of these mediators, they exist in blood plasma and they are activated after contact of these blood plasma to collagen, to basement membrane of damaged blood vessels or to activated platelets or to negatively charged biopolymeric molecules, like DNA or to negatively charged surfaces, like for example surface on which blood is split. So, contact activation is characteristic for that system. So, after this contact to activating surfaces or activated molecules, which physically occurs after damage of blood vessel, blood plasma is involved in these stepwise proteolysis and precursors are converted into active molecules and their self assembly results in activation of this contact system. Contact system is like a dragon with four heads, one body but four heads, four subsystems. Every one is based on that stepwise proteolysis and on that contact principle. And these four systems are blood coagulation system depending on Hageman's factor and thrombin and fibrinogen. The final result of this system action is fibrin formation and fibrin stabilization, which is important in blood coagulation and blood clotting. Another head of that dragon is fibrinolytic system. It is also activated in parallels and pro-fibrinogen or plasminogen is converted into fibrinogen or plasmin, and the final result of activation is fibrinolysis. The third head of that dragon of contact system of blood plasma is kinin cascade. Because as a result of plasma contact to inflammatory area, high molecular weight kininogens precursors are proteolytically converted into active kinins and among them, most famous is bradykinin, potent mediator responsible for late phase of increase in vascular wall permeability and contributing into edema formation and vascular dynamic of inflammation. And the fourth component of this polysystem is complement. Complement, very close and very familiar to immunologists, but also tightly related to other three components of contact system. Because in complement system, you also have stepwise proteolysis, self assembly, and as a result of complement activation, you have final complex of membrane attack, which is responsible for lytic effect of complement, and side products of complement activation are so-called anaphylatoxins, very potent non-lytic peptides able to drive the cell behavior and exudation process. Now, let me show you those who originated our current knowledge about these four components of plasma contact system. Blood coagulation was discovered and its multi-step mechanism was described by two persons, Alexander Schmidt and Paul Morawitz, both were born in Russian Empire, but both were Germans. Alexander Schmidt described two steps of fibrin formation and discovered the enzymatic proteolytic mechanism for that system and Paul Morawitz added third step. Now, we have three-step model for blood coagulation process after Schmidt and Morawitz. This is a great French pathophysiologist, Albert Dastre, who discovered fibrinolysis, and described the proteolytic nature of multi-step fibrinolytic process. And the kinin system was described by Brazilian scholar, Mauricio Oscar da Rocha-e-Silva, and he described that in the venom of some Brazilian spiders and Brazilian poisonous snakes which use kinins in order to produce edematous effect of their bite. And the complement system was first discovered by a German biochemist, Hans Buchner and described in details in immunological reactions by Belgian scientist, pupil of Élie Metchnikoff, Jules Bordet, whom you can see in that portrait. Complement as well as other parts of contact polysystem is based on stepwise limited proteolysis. In some kind, it is way of biological amplification of reaction because in initial stage of complement activation, only a few molecules enter into reaction. On next step of cascade, we have dozens of molecules, then hundreds of molecules, thousands of molecules. So, step by step, the overall effect is enhanced like in snow avalanche. And, this is a way of biological amplification of reaction. It is characteristic for compliment system, for coagulation system, for fibrinolysis, and to a certain degree for kinins also. And end product of this complement system is cytolytic. It is able to make a hole in the membrane of target cell. For example, self cell in allergic reaction or bacterial cell in infectious inflammation. And in fact, the side products of this activation, cleavage peptides, they are responsible for various effects regulating exudation, chemotaxis, switch of immunoglobulin classes and so on and so forth. Finally, in the end of my lecture, I will show you the typical pathways of complement activation. Complement is mediator of inflammation. Final product membrane attacking complex is responsible for lysis of target cell and the byproducts, so-called anaphylatoxins are side fragments of compliment, short peptides with known cytolytic bio-regulating action. For example, they increase exudation and vascular permeability is increased by them. You can see three pathways of activation for this system. Classic pathway, by the way, it is realized if the complement is activated by antibodies in course of immune response. And the so-called alternative pathway, which can be activated directly without antibody participants by components of microorganisms, and also relatively, recently discovered lectin pathway or mannose-depending pathway, which is also activated outside of immunological interactions, even without antibodies. But generally speaking, compliment is a blind dog, and compliment needs some guide, which can indicate a target and the guide which indicates a target for that blind dog is antibody. Complement is assembled on the surface of a cell matched by antibodies. Please, in conclusion look our cartoon. This cartoon will show you the process of complement activation, step by step in dynamics. We'll show you the classical pathway of complement activation. You can see that complement is a responsible for complement-dependent cytotoxicity. It means the activation of complement system via classical pathway is able to cause lysis of a cell on the surface of which the membrane attacking complex, C five, C nine is assembled. At the same time, fragments of complement factors arising from stepwise proteolysis are important mediators of accompanying inflammatory events. First of all, they are essential in exudation. As a result of this activation, target cell dies and this complement depending cytotoxicity is broadly involved in immune and non-immune inflammation as a mechanism of secondary alteration. Thank you for attention.
