From Big Medical Encyclopedia

PERMEABILITY — ability of cells and fabrics to absorb, allocate and transport chemicals, passing them through cellular membranes, walls of vessels and a cell of an epithelium. Living cells and fabrics are in a condition of continuous exchange of chemical substances with the environment. The main barrier (see. Barrier functions ) on the way of the movement of substances the cellular membrane is. Therefore historically mechanisms P. were investigated in parallel with studying of structure and function of biological membranes (see. Membranes biological ).

Distinguish the passive P., active transport of substances and special cases of P. connected with phagocytosis (see) and pinocytic (see).

According to the membrane theory of P. passive P. different types of diffusion of substance through cellular membranes are the cornerstone (see. Diffusion ). Diffusion rate of substance is described by Fick's equation:

where dm — amount of the substance diffusing during dt through the area of S; dc/dx - a gradient of concentration of substance; D — a diffusion coefficient.

Fig. 1. Molecular organization of an ionoforny antibiotic (valinomitsin): and — a constitutional formula of the molecule of a valinomitsin containing six dextrorotatory (D) and six left-handed (L) amino acids, all side groups [— SN 3 — CH (CH 3 ) 2 ] gidrofobna; — the diagrammatic representation of spatial configuration of a complex of a valinomitsin with a potassium ion (in the center). A part of carbonyl groups of a complex forms hydrogen bindings with nitrogen atoms, and others — coordinate bonds with a cation (potassium ion). Hydrophobic groups create the second hydrophobic sphere of a complex and provide its solubility in a hydrocarbon phase of a membrane; 1 — carbon atoms, 2 — oxygen atoms, 3 — a cation (potassium ion), 4 — nitrogen atoms, 5 — hydrogen bindings, 6 — coordinate bonds. The potassium ion «taken» by a molecule of a valinomitsin is transferred by this molecule through a cell membrane and released. With such way selective permeability of a cellular membrane for potassium ions is provided.

At a research P. of a cell for solute instead of a gradient of concentration use a concept of a difference of concentration of the diffusing substance on both sides of a membrane, and instead of a diffusion coefficient — the permeability coefficient (R) depending also on thickness of a membrane. One of possible ways of penetration of substances into a cell is their dissolution in lipids of cellular membranes that oil — water is confirmed by existence of direct proportionality between a permeability coefficient of a big class of chemical connections and a distribution coefficient of substance in system. At the same time water does not submit to this dependence, the speed of its penetration is much higher and is not proportional to a distribution coefficient in system oil — water. For water and low-molecular substances dissolved in it the most probable way P. is passing through a membrane time. Thus, diffusion of substances through a membrane can happen by dissolution of these substances in lipids of a membrane; by passing of molecules through the polar time formed by the polar, loaded groups of lipids and proteins and also by passing through not loaded time. Special types are the facilitated and exchange diffusions provided with proteins and fat-soluble substances carriers which are capable to connect transferable substance on one side of a membrane to diffuse with it through a membrane and to release it on other side of a membrane. Transport rate of substance through a membrane in case of the facilitated diffusion is much higher, than at simple diffusion. Some antibiotics (valinomitsin, nigeritsin, monensin and some other) which received the name ionoforny can carry out a role of specific carriers of ions (see. Ionophores ). The molecular organization of complexes of ionoforny antibiotics with cations is deciphered. In case of a valinomitsin (fig. 1) it is shown that after linkng with a cation of potassium the molecule of peptide changes conformation, taking a form of a bracelet with an internal diameter apprx. 0,8 nanometers, in Krom the potassium ion keeps as a result of ion-dipole interactions.

A widespread type of passive P. of cellular membranes for polar substances is P. through a time. Though direct observation of a time in a lipidic layer of a membrane represents a difficult task, experimental data confirm their real existence. In favor of real existence of a time confirm also this osmotic properties of cells. The size of osmotic pressure in solutions, pericellular, can be calculated by a formula:

π = σ CRT,

where π — osmotic pressure; With — concentration of solute; R — a gas characteristic; T — absolute temperature; σ — coefficient of reflection. If the speed of passing through a membrane of a molecule of solute is commensurable with a speed of passing of water molecules, then sizes of forces will be close to zero (osmotic change of volume of a cell is absent); if the cellular membrane is impenetrable for this substance, then size σ aims to 1 (osmotic change of volume of a cell as much as possible). Speed of penetration of molecules through a cellular membrane depends on molecular sizes and, thus, by selection of molecules of a certain size and overseeing it is possible to determine by change of volume of cells in solution of this substance the sizes of a cellular time. E.g., the membrane of an axon of a squid is low permeable for the molecules of glycerin having in a radius apprx. 0,3 nanometers, but a pronitsayem for substances with smaller sizes of molecules (tab). Similar experiments with other cells showed that pore sizes in cellular membranes, in particular in membranes of erythrocytes, colibacillus, cells of an epithelium of intestines, etc., rather precisely keep within within 0,6 — 0,8 nanometers.

Other way of penetration of substances into a cell and escaping it — active transport of substances also is characteristic of living cells and fabrics. Active transport is a transfer of substance through cellular (or intracellular) a membrane (transmembrane active transport) or through a layer of cells (transcellular active transport) proceeding against an electrochemical gradient (see. Gradient ). i.e. with expense of free energy of an organism (see. Metabolism and energy ). Molecular systems, in charge of active transport of substances, are in cellular (or intracellular) a membrane. In cytoplasmic membranes of the cells participating in active transport of ions — muscle cells, neurons, erythrocytes, cells of kidneys — in significant amounts there is a Na+ enzyme, Independent ATP-ase which is actively participating in mechanisms of transfer of ions (see. Transport of ions ). The mechanism of functioning of this enzyme is most studied on the erythrocytes and axons having yarkovyrazhenny ability to accumulate potassium ions and to delete (to pump out) ions of sodium. It is supposed that erythrocytes contain the molecular device — a potassium sodium pompe (potassium - a sodium pomp), the providing selective absorption of potassium ions and selective removal from a cell of ions of sodium, and a basic element of this pump is Na + , To + - ATP-ase. Studying of properties of enzyme showed that enzyme is active only in the presence of potassium ions and sodium, and ions of sodium activate enzyme from cytoplasm, and potassium ions — from surrounding solution. Specific inhibitor of enzyme is cardiac glycoside uabain. Also other transport ATP-ases, in particular, transporting ions of Sa are found +2 .

In membranes of mitochondrions the molecular system providing pumping of hydrogen ions — enzyme N is known + - ATP-ase, and in membranes of a sarcoplasmic reticulum — enzyme of Sa ++ - ATP-ase. P. Mitchell is the author of the hemiosmotichesky theory of oxidizing phosphorylation in mitochondrions (see. Phosphorylation ) — entered the concept «secondary transport of substances» which is carried out due to energy of membrane potential and (or) a gradient of pH. If for ionic ATP-ases antigradient movement of ions and utilization of ATP are provided with the same fermental system, then in case of secondary active transport these two events are provided with different systems and can be divided in time and space.

Penetration into cells of large macromolecules of protein, nucleinic to - t. cellular enzymes and the whole cells it is carried out on the mechanism of phagocytosis (capture and absorption by a cell of large solid particles) and a pinocytic (capture and absorption by a part of a cellular surface of surrounding liquid with the substances dissolved in it).

The item of cellular membranes matters more for functioning of cells and fabrics.

Active transport of ions and the absorption of water accompanying it in cells of a renal epithelium occurs in proximal tubules of a kidney (see. Kidneys ). Daily passes up to 1800 l of blood through kidneys of the adult. Proteins at the same time are filtered and remain in blood, 80% of salts and water, and also all glucose come back to a blood channel. It is considered that the prime cause of this process is the transcellular active transport of ions of sodium provided to Na + with K+ - the dependent ATP-ase localized in cellular membranes of a basal epithelium. If in line with a renal proximal tubule ion concentration of sodium makes apprx. 100 mmol/l, then in a cell it does not exceed 37 mmol/l; thereof the passive flow of ions of sodium is directed in a cell. Passive penetration of cations into cytoplasm is promoted also by existence of membrane potential (the inner surface of a membrane is loaded negatively). Thus in a cell ions of sodium get passively according to concentration and electric gradients (see. Gradient ). An exit of ions from a cell in a blood plasma is carried out against concentration and electric gradients. It is established that in a basal membrane and sodium - the potassium pump providing removal of ions of sodium is localized. It is supposed that anions of chlorine move after ions of sodium on intercellular space. As a result of it the osmotic pressure of a blood plasma increases, and water from a bed of a tubule begins to come to a blood plasma, providing a reabsorption of salt and water in renal tubules.

For passive and active P.'s studying various methods are used. Considerable distribution was gained by a tracer technique (see. Isotopes , Radioactive drugs , Radio isotope research ). For studying of cells by ionic P. isotopes are used 42 K, 22 Na and 24 Na, 45 Ca, 86 Rb, 137 Cs, 32 P, etc.; for P.'s studying waters — deyteriyevy or tritium water, and also water, marked on oxygen (18O); for P.'s studying sugars and amino acids — connections, marked on carbon 14 C or sulfur 35 S; for P.'s studying proteins — the iodated drugs, marked on 1 31 I.

Are widely applied at a research P. vital stains. The essence of a method consists in observation under a microscope of speed of penetration of molecules of dye in a cell. For the majority of vital stains (neutral red, methylene blue, rhodamine, etc.) observations are made in a visible part of a range. Also fluorescent connections, and among them flyuorestsein sodium, chlortetracyclin, purpuric acid ammonium salt, etc. are used. At a research of muscles it was shown that P. of molecules of dyes depends not only on properties of a cellular membrane, but also on the occluding ability of intracellular structures, most often proteins and nucleinic to - t, with to-rymi dyes communicate.

Water and substances dissolved in it apply an osmotic method to P.'s studying. At the same time by means of a microscope or measurement of light scattering of suspension of particles watch change of volume of cells depending on tonicity of surrounding solution. If the cell is in hypertensive solution, then water from it passes into solution and the cell contracts. The opposite effect is observed in hypotonic solution.

Even more often cellular membranes apply electrometric methods to P.'s studying (see. Microelectrode method of a research , Conductivity of biological systems ); a broad set of ionospetsifichny electrodes allows to investigate kinetics of transport of many inorganic ions (potassium, sodium, calcium, hydrogen, etc.), and also some organic ions (acetates, salicylates, etc.). All types of P. of cellular membranes are in a varying degree characteristic of multicellular fabric membrane systems — walls of blood vessels, an epithelium of kidneys, a mucous membrane of intestines and stomach. At the same time some features which are shown in vascular P.'s disturbance (see below) are characteristic of P. of vessels.

Pathological physiology of vascular permeability

used the Term «vascular permeability» for designation of gistogematichesky and transcapillary exchange, distribution of substances between blood and fabrics, fabric P., hemolymphatic transition of substances and other processes. Some researchers apply this term to designation of trophic function of kapillyaro-connective tissue structures. Ambiguity of use of the term was one of the reasons of inconsistency of the views on a number of questions which are especially concerning regulation of the 70th by vascular P. V of 20 century the term «vascular permeability» began to use hl. obr. for designation of selective permeability, or baryernotransportny function, walls of circulatory microvessels. It is tended to reference to vascular P. as well by P. of walls not only microvessels (circulatory and lymphatic), but also large vessels (up to an aorta).

Vascular P.'s changes are observed by hl. obr. in the form of selective P.'s increase for macromolecules and blood cells. A typical example of it is exudation (see). Vascular P.'s decrease is connected generally with proteinaceous treatment and the subsequent consolidation of vascular walls that is observed, e.g., at idiopathic hypertensia (see).

There is an opinion on a possibility of disturbance of P. of a vascular wall preferential in the direction of an interstitium or from an interstitium in blood. However the preferential movement of substances in this or that party of rather vascular wall does not prove its communication with a condition of barrier and transport function of a vascular wall yet.

The principles of studying of disturbances of vascular permeability

Assessment of a condition of vascular P. needs to be carried out taking into account that the vascular wall provides differentiation and a functional linkage of two adjacent environments (blood and the interstitial environment) which are the main components internal environment of an organism (see). Exchange between these adjacent environments in general is carried out due to microhaemo circulation (see. Mikrotsirkulyation ), and the vascular wall with its barrier and transport function acts only as a basis of organ specialization of gistogematichesky exchange. Therefore the method of studying of a condition of vascular P. can be considered adequate only when he allows to estimate qualitative parameters of gistogematichesky exchange taking into account their organospetsifichnost and irrespective of a condition of organ microhaemo circulation and the nature of the exchange processes forming out of a vascular wall. From this point of view the most adequate of the existing methods is the electronic and microscopic method of studying of vascular P. allowing in the direct way to observe ways and mechanisms of penetration of substances through a vascular wall. Especially fruitful was a combination of a submicroscopy to so-called tracer indicators, or the treytser marking ways of the movement through a vascular wall. As such indicators any nontoxic substances revealed by means of a submicroscopy or special receptions can be used (histochemical, autoradiographic, immunocytochemistry, etc.). For this purpose ferritin, various enzymes with peroksidazny activity, colloid coal (the purified china ink) etc. apply ferriferous protein.

From indirect methods of studying of a condition of barrier and transport function of walls of blood vessels the most wide spread occurance was received by registration of penetration through a vascular wall of natural or artificial indicators, poorly or at all not getting through a wall in the conditions of norm. At disturbance of microhaemo circulation that is often observed at vascular P.'s disturbance, these methods can be low-informative, and then it is necessary to combine them with control methods of a condition of microhaemo circulation, e.g. by means of biomicroscopy or the easily diffusing indicators which gistogematichesky exchange does not depend on vascular P.'s condition and fabric metabolism. Lack of all indirect methods based on registration of accumulation of indicator substances outside a vascular bed is need of the accounting of mass of the factors capable it is essential to influence the level of the indicator in the studied site. Besides, these methods are quite inertial and do not allow to study short-term and reversible changes of vascular P., especially in combination with change of microhaemo circulation. These difficulties manage to be overcome partially by means of the method of marked vessels based on definition of penetration into a vascular wall of the slabodiffundiruyushchy indicator collecting in a wall and painting it. The painted (marked) sites come to light by means of a light microscope and are the proof of disturbance of P. of an endothelium. As the indicator the colloid coal forming easily revealed dark accumulations in places of gross violation of an endothelial barrier can be used. Changes of activity of microvesicular transport by this method are not registered and it is necessary to use other indicators transferred through an endothelium by microvesicles.

Possibilities of studying of disturbances of vascular P. in the conditions of clinic are more limited since the majority of the methods based on use of the micromolecular easily diffusing indicators (including and radioisotopes), is not allowed to judge a condition of barrier and transport function of walls of blood vessels unambiguously.

Rather widely apply the method based on definition of quantitative distinctions in protein content in the tests of an arterial and venous blood taken at the same time (see. Landis test ). At calculation of percent of loss of protein blood in the course of its transition from an arterial bed in venous it is necessary to know percent of loss of water which is determined by a difference in a hematocrit of an arterial and venous blood. In the researches on healthy people V.P. Kaznacheev and A. A. Dzizinsky (1975) as normal P.'s indicators of vessels of an upper extremity removed the following sizes: for water on average 2,4 — 2,6%, for protein 4 — 4,5%, i.e. during the passing on a vascular bed of 100 ml of blood in limf. the bed arrives apprx. 2,5 ml of water and 0,15 — 0,16 g of protein. Therefore, per day in a human body not less than 200 l of a lymph shall be formed that in tens of times exceeds the actual size of a daily limfoproduktion in an organism of the adult. It is obvious that a lack of a method is the assumption, according to Krom of distinction in a hematocrit of an arterial and venous blood are explained only by change of content in blood of water at the expense of its exit out of limits of a vascular bed.

In a wedge. to practice about a state regional vascular P. quite often judge by existence of interstitial or band accumulations of the free liquid rich with protein. However at assessment of a condition of vascular P., e.g. in an abdominal cavity, the wrong conclusion as exchange microvessels of these bodies and fabrics normal are characterized by high P. for macromolecules thanks to intermittence or porosity of their endothelium can be made. Increase in filtrational pressure in such cases leads to formation of an exudate rich with protein. Especially pronitsayema for proteinaceous molecules venous sine and sinusoids.

It should be noted that the raised exit of plasma proteins in fabric and development of fabric hypostasis (see) not always accompany vascular P. Mikrososuda's increase (capillaries and venules) which endothelium is normal low permeable for macromolecules, gain endothelial defects; through these defects easily there are in subendothelial space indicators entered into a blood stream — macromolecules and microparticles. However symptoms of fabric hypostasis at the same time are absent — a so-called bezotekovy form of disturbance of vascular permeability. The similar phenomenon is observed, e.g., in muscles of animals at development in them the neurodystrophic process connected with section of a motor nerve. Similar changes in tissues of the person are described, e.g., during the aging and a diabetes mellitus when so-called atsellyulyarny capillaries are formed, i.e. exchange to a mikrosos dy with partially or completely desquamated endothelial cells (symptoms of fabric hypostasis at the same time are also absent). All these facts speak, on the one hand, about relativity of communication of fabric hypostases with vascular P.'s increase, and with another — about existence of the extravasated mechanisms responsible for distribution of water and substances between blood and fabrics.

Factors of disturbance of vascular permeability

conditionally divide Factors of disturbance of vascular permeability into two groups: exogenous and endogenous. Exogenous factors of disturbance of various nature by vascular P. (physical, chemical, etc.) in turn are divided into the factors which are directly influencing a vascular wall and its barrier and transport function e.g., the histamine entered into a vascular bed, various toxins, etc.), and factors of disturbance of P. of indirect action which effect is mediated through internal causes.

A large number of others began to carry to already known internal causes of disturbance of vascular P. (a histamine, serotonin, kinina), in particular prostaglandins (see), and the last not only raise vascular P., but also strengthen action of other factors; many of internal causes are produced by various fermental systems of blood (system of a factor of Hageman, system of a complement, etc.).

Raise vascular P. and cell-bound immune complexes. From the factor responsible for the «delayed» vascular P.'s increase at development of a phenomenon of Artyus, Yosinaga (1966) emitted pseudoglobulin; Kuroyanag (1974) were opened by the new factor of P. designated by it as Ig-PF. On the properties it significantly differs from a histamine, kinin, anaphylatoxin and kallikrein, works longer, than the histamine and bradikinin, is oppressed by K1 and K2 vitamins.

Many factors of disturbance of vascular P. are produced by leukocytes. So, the protease forming the neutral peptide mediator raising soudisty the Item of proteins of plasma is connected with a surface of neutrophils. Proteinaceous substrate of protease has a pier. the weight (weight) 90 000 also differs from a kininogen.

Lysosomes and specific granules of blood cells contain the cationic proteins capable to violate vascular the Item. Their action is mediated by a histamine of mast cells.

Various internal causes of disturbance of vascular P. work in fabrics at the same time or consistently, causing century of vascular P. phase shifts. In this regard allocate early, delayed and pozd ny changes vascular to the Item. An early phase — a phase of action histamine (see) and serotonin (see). The second phase develops after the period of imaginary wellbeing, later 1 — 3 hour after primary damage the phase which — is slowed down, or delayed; its development is caused by action kinin (see) or prostaglandins. Development of these two phases depends on the level of a complement and is oppressed by anticomplementary immune serum. In a day after damage the third phase connected with action cyto - and the proteolytic enzymes which are released from lysosomes of leukocytes and lymphocytes develops. Depending on the nature of primary damaging agent the quantity of phases can be a miscellaneous. In an early phase vascular P. is broken by hl. obr. at the level of venules, in the subsequent phases process extends to a capillary bed and arterioles.

Reception of factors of permeability vascular wall. Internal causes of disturbance of P. represent the most important group of causes of infringement of vascular P. Otdelnye of them are in fabrics in finished form (a histamine, serotonin) and under the influence of various pathogenic influences are released from depots as which mast cells and blood cells act (basophiles, thrombocytes). Other factors are a product of different biochemical systems both in the place of primary damage, and at distance from it.

Questions of an origin of factors of P. in itself are important for the solution of practical problems of prevention and treatment of disturbances of vascular P. Odnako emergence of a factor of P. not enough for disturbance vascular the Item. In order that P.'s factor became really a factor of disturbance of vascular P., it shall be noticed», i.e. retseptirovan, a vascular wall (if only it has no destrukturiruyushchy ability like cytolytic agents). It is known, e.g., that the histamine entered into the general blood stream breaks vascular P. only in certain bodies and fabrics whereas in other fabrics (a brain, pulmonary fabric, endonevry, etc.) it is not effective. Introduction to a vascular bed of serotonin and bradikinin does not cause disturbance of the reason for inefficiency of a histamine by vascular P. Odnako in both cases in frogs at all are various.

According to modern data, the endothelium of exchange microvessels of hematothermal animals and the person has sensitivity to a large number of various agents, i.e. is characterized by high receptor ability. As for a histamine — one of major factors of P. causing acute and considerable (though short-term) vascular P.'s disturbance, experimental data speak about existence in an endothelium of two types of histamine receptors of H1 and H2 playing a different role in the mechanism of action of a histamine. Stimulation of H1 receptors leads to the vascular P.'s disturbance characteristic of action of a histamine.

At action of some internal causes of P., in particular a histamine, it is observed tachyphylaxis (see) and repeated use (in 30 min.) the agent does not violate vascular the Item any more. Similar temporary nonsensitivity of an endothelium of micro vessels is not explained by temporary blockade of the corresponding receptors though in certain cases it and can be. In a case with a histamine the mechanism of a tachyphylaxis, on a nek-eye to the data, has extra receptor localization. It is proved, in particular, by the fact of development of a cross tachyphylaxis when use of a histamine leads to development of stability of an endothelium not only to the histamine, but also to the salts of lanthanum circumventing receptors. Emergence of a cross tachyphylaxis can be one of the reasons of inefficiency of separate factors of P. operating at the same time or consistently.

Ultrastructural bases and effector mechanisms of disturbance of vascular permeability

Fig. 2. Ways and mechanisms of a transcapillary metabolism in the conditions of norm (a) and pathology: 1 — transcellular diffusion; 2 — diffusion and ultrafiltration in the field of tight intercellular joints; 3 — diffusion and ultrafiltration in the field of simple intercellular connections; 4 — microvesicular transport bypassing tight intercellular joints; 3a and 4a — pathological intercellular «channels of histamine cracks»; 5 — microvesicular transport; 6 — formation of the transcellular channel by merge of microvesicles; 7 — phagocytal vacuoles in pericytes; 8 — microparticles of the indicator of vascular permeability (BM — a basal membrane, EN1, EN2, EN3 — endotheliocytes, PTs — pericytes).

By electronic microscopic examinations it is revealed that morfol. a basis of increase in vascular P. is formation of wide channels in the field of intercellular connections in an endothelium (fig. 2). Such channels, or «leaks», often call histamine cracks since their education is typical for action on a vascular wall of a histamine and is for the first time in detail studied at its action. Histamine cracks are formed by hl. obr. in walls of venules of those bodies and fabrics where there are no low-permeable gistogematichesky barriers of type hematoencephalic, etc. Local discrepancies of intercellular contacts are found at neuroregulatory frustration, mechanical, thermal, chemical and other types of damages of fabrics, at operation of various bioregulators (serotonin, bradikinin, E1 and E2 prostaglandins etc.). Disturbance of intercellular contacts arises, though with great difficulty, in capillaries and arterioles and even in larger vessels. Ease of formation of histamine cracks is directly proportional to initial structural weakness of intercellular connections, edges increases upon transition from arterioles to capillaries and from capillaries to venules, reaching a maximum at the level of post-capillary (peritsitarny) venules.

Inefficiency of a histamine in disturbance of some bodies by vascular P. well speaks from the point of view of development of tight joints in an endothelium of microvessels of these bodies, e.g. a brain.

In the theoretical and practical relation the question of the effector mechanisms which are the cornerstone of formation of structural defects like histamine cracks is important. These ultrastructural shifts are typical for an initial phase of acute inflammations (see) when, by data I. I. Mechnikova (1891), vascular P.'s increase is biologically reasonable since thanks to it the raised exit of phagocytes to the center of damage is provided. It is possible to add that the raised exit of plasma in such cases is also reasonable since at the same time in the center antibodies and means of nonspecific protection are delivered. Thus, vascular P.'s increase in the center of an inflammation can be considered as the specific condition of barrier and transport function of walls of micro vessels adequate to new living conditions of fabric, and vascular P.'s change at an inflammation and similar situations — not as disturbance, and as the new functional state promoting recovery of the broken fabric homeostasis. It is necessary to consider that in some bodies (a liver, a spleen, marrow) where according to features of organ functions there is a continuous exchange stream of cells and macromolecules, intercellular «leaks» are the normal and continuous educations representing the exaggerated histamine cracks, but unlike true histamine cracks are capable to long existence. True histamine cracks are formed in the first seconds after impact on an endothelium of mediators of an acute inflammation and in the majority in 10 — 15 min. are closed. The mechanism of formation of histamine cracks has the protective, phylogenetic caused character and is connected with the stereotypic reaction at the cellular level started by stimulation of different types of receptors.

The nature of this stereotypic reaction long remained not studied. I. I. Mechnikov considered that vascular P.'s increase at an inflammation is connected with reduction of endothelial cells. However it was established later that endotheliocytes in vessels hematothermal do not belong to the category of the cells which are actively changing the form it is similar to muscular. Rowley (D. A. Rowley, 1964) suggested that discrepancy of endotheliocytes is a consequence of increase in intravascular pressure and the restretching of an endothelium connected with it. Direct measurements proved unacceptability of this hypothesis concerning venules and capillaries, however for arterial vessels it has a certain value since at disturbance of tonic activity of a muscular coat high intravascular pressure is really capable to cause restretching of an endothelium and damage of intercellular contacts. But also in this case emergence of histamine cracks in an intima is not always connected with action of transmural pressure. Robertson and Kayrallakh (A. L. Robertson, P. A. Khairallah, 1972) in experiences on the isolated segment of a ventral aorta of a rabbit showed that wide cracks in an endothelium are formed under the influence of angiotensin II in places of rounding and shortening of endotheliocytes. Similar morfol. shifts are found also in an endothelium of exchange microvessels of skin at topical administration of angiotensin II, E1 prostaglandin and serumal triglycerides.

O. V. Alekseev and A. M. Chernukh (1977) found in endotheliocytes of exchange microvessels ability, to bystry increase in content in cytoplasm of the microfibrillar structures similar on the morfol. to signs with octynic microthreads. This reversible phenomenon (a so-called phenomenon of an operational strukturalization of the microfibrillar device) develops under the influence of the factors causing formation of wide intercellular cracks. Reversibility of a phenomenon in case of use of a histamine complicates its identification and well explains short duration and reversibility of existence of histamine cracks. With the help tsitokhalazina-B, blocking formation of octynic microfibrils, pathogenetic value of this phenomenon in the mechanism of formation of intercellular histamine cracks comes to light. These facts speak about existence at endotheliocytes of the hidden ability to reduction which is implemented in conditions when the previous level of vascular P. is inadequate and rather fast and its reversible changing is required. Vascular P.'s change acts, thus, as the special act biol. regulation, providing adaptation of barrier and transport function of a vascular endothelium according to the new local requirements which sharply arose in connection with change of conditions of life activity of fabric.

Existence in fabrics of the mechanism of change of vascular P. can be referred to so-called risk factors since operation of this mechanism in inadequate conditions can become a cause of infringement of a fabric homeostasis and organ function, but not manifestation of operation of adaptation and protective mechanisms. The main ways of disturbance of vascular P. are presented on the scheme. Vascular P.'s changes are the cornerstone the mechanisms not only leading to formation of intercellular channels (histamine cracks), but also influencing activity of a cellular surface (i.e. on microvesiculation and microvesicular transport, vacuolation and a mikropuzyreobrazovaniye). Perforation of endotheliocytes with formation of more or less extensive and long-term transcellular channels can be result.

The great value in mechanisms of disturbance of vascular P. is attached to local changes of surface-bound electric charge, especially on the membranes closing a time in fenestrirovanny capillaries (e.g., renal balls). On a nek-eye to data, only one change of a charge can be a basis of increase in an exit of proteins from glomerular capillaries. Thus limitation of the theory of a time is proved, according to P.'s cut depends only on the size and a ratio of a hypothetical large and small time in walls of vessels. In the conditions of pathology the effect of increase in porosity of an endothelium can be reached in the different ways: formation of intercellular channels like histamine cracks; strengthening of microvesicular and intravakuolyarny transport; perforation of endotheliocytes on the basis of strengthening of microvesiculation, vacuolation or mikropuzyreob a razovaniye in an endothelium; microfocal destruction of endotheliocytes; exfoliating of endotheliocytes; change physical. - chemical properties of a surface of endotheliocytes, etc. (see. Mikrotsirkulyation ]]). The same effect can be reached also at the expense of vnestenochny mechanisms, in particular due to change of svyazyvatelny ability of macromolecules of blood, with to-rymi almost all known indicators used for assessment of a state vascular by the Item interact. In the conditions of pathology most often at the same time or consistently work different of the listed mechanisms. So, e.g., the histamine increases porosity of a vascular wall due to formation of histamine cracks in an endothelium of venules, and also by influence on a surface of endotheliocytes and the transport processes and ultrastructural transformations connected with its activity (formation of a transcellular time, fenestr, microtubules, etc.). It is necessary to consider that at the same time thickness of endotheliocytes and depth of intercellular cracks often changes that can have significant effect on permeability of a vascular wall as diffusion barrier. The question of behavior in the conditions of pathology of the biochemical mechanisms interfering or, on the contrary, the substances promoting penetration through a vascular wall, especially biologically active is not studied at all. It is known, e.g., that endotheliocytes of brain capillaries normal have the enzymatic activity destroying serotonin and by that interfering its penetration as from blood in a brain, and in the opposite direction. The endothelium of pulmonary capillaries contains a kininaza of II, localizable in mikropinotsitozny vesicles and providing destruction of bradikinin and at the same time transformation of angiotensin I into angiotensin II (hypertensia). Thus, the endothelium exercises a peculiar control of balance of humoral bioregulators, actively influences gistogematichesky exchange of these agents.

Scheme of the main ways of disturbance of vascular permeability: And, B, In — levels of therapeutic intervention.

Etiopatogenetichesky bases of prevention and treatment of disturbances of vascular permeability

the Directed intervention is carried out at three levels (see the scheme). The first level — impact on process of formation of causative (retseptiruyemy) factors — is practically not used though there are separate medicamentous means capable to operate on this level. E.g., Reserpinum influences deposition of factors of disturbance of P. in the mast cells representing the main source of mediators of an acute inflammation (a histamine and serotonin); antiprostaglandinovy means oppress synthesis of prostaglandins — acetylsalicylic acid, etc.

The second level is the basic in practice of development of prophylactics and treatment of disturbances vascular the Item. It corresponds to process of reception of a causative factor. The considerable number of the anti-histamine, antiserotoninovy and antibradikininovy drugs preventing the vascular P.'s disturbances caused by the corresponding mediators is used. The advantage and at the same time a lack of these drugs operating by blockade of specific receptors is their high specificity. Such specificity does them inefficient in the conditions of plurality etiol. the factors operating at the same time or consistently that is usually observed in a wedge. to practice. Important and the fact that the exception of action of one factor or several, one phase of disturbance of vascular P. defining development, does not exclude development of the subsequent phases. These shortcomings can be overcome by intervention at the third level.

The third level — impact on intracellular (subcellular) effector mechanisms via which action of factors of P., and uniform for action of various pathogenic agents directly is implemented. The reality and efficiency of such approach manage to be shown in an experiment by use of the substance (tsitokhalazina-B) oppressing a phenomenon of an operational strukturalization of the microfibrillar device in endotheliocytes (formation of octynic gel and octynic microfibrils).

In a wedge. to practice for the purpose of normalization the raised vascular P. use citrin (see. Bioflavonoida ) and salts of calcium. However these drugs cannot be considered as specific to lay down. means at vascular P.'s disturbance though they also exert fortifying impact on gistogematichesky barriers, membranes and a wall of vessels in particular.

For vascular P.'s increase various internal causes of P., e.g. a histamine, or the substances releasing them from fabric depots can be used.

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B. F. Antonov; O. V. Alekseev (stalemate. physical.).