Dear listeners! Warning: this course contains shocking materials and is not recommended for viewing to persons with weak psyche, minors and pregnant women. The course describes subject and methods of Pathophysiology, its place within system of biomedical sciences and history. It includes General Nosology (concept of health and disease, general etiology and pathogenesis, pathological processes and states, role of causal factors, conditions, reactivity and somatotype in pathology). It gives systematic of locally and centrally driven typical pathological processes: arterial, venous and combined hyperemiae, stasis, inflammation, immunopathological processes (including allergy and autoimmune disorders) acute phase response, fever, stress, shock, etc. Course deals with functional, metabolic and informational aspects of typical pathologic processes, like disorders of signaling, reception, post – receptor translation, programming and program archiving, conflicts of programs in living systems. It contains the consequent analysis of the injury and defensive responses as regards separate cells, organs and tissues and the whole organism. The lectures based on author’s original three-volumed textbook and workshop in Pathophysiology republished in Russia many times.
6_8: "Mediators of Inflammation: Groups and Effects. Part 2"
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Из курса от партнера Saint Petersburg State University
General Pathophysiology
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Pathophysiology of inflammation. Part 2
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Churilov Leonid PavlovichAssociate Professor, Full Member of International Academy of Sciences (Health and Ecology)
Department of Pathology, Faculty of Medicine
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.
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