The main functional units of the skin involved in the healing of a skin defect and scarring

There are many adhesive molecules - they all create a support grid through which cells move, linking to specific receptors on the surface of cell membranes, transmitting information to each other with the help of mediators: cytokines, growth factors, nitric oxide, etc.

Basal keratinocyte

Basal keratinocyte is not only the mother cell of the epidermis, which gives rise to all overlying cells, but is a mobile and powerful bioenergetic system. It produces a host of biologically active molecules such as epidermal growth factor (EGF), insulin-like growth factors (IGF, fibroblast growth factors (FGF), platelet growth factor (PDGF), macrophage growth factor (MDGF), vascular endothelial growth factor (VEGF) , transforming growth factor alpha (TGF-a), etc. After learning about the damage to the epidermis through information molecules, basal keratinocytes and cambial cells of sweat glands and hair follicles begin to actively proliferate and move along the bottom of the wound to epithelize it. Ulirovannye wound detritus, inflammatory mediators and fragments of destroyed cells, they actively synthesize growth factors that contribute to the acceleration of wound healing.

[1], [2], [3], [4], [5], [6]

Collagen

The main constructive component of connective and scar tissue is collagen. Collagen is the most abundant protein in mammals. It is synthesized in the skin by fibroblasts from free amino acids in the presence of cofactor - ascorbic acid and makes up almost a third of the total mass of human proteins. It contains in an insignificant amount proline, lysine, methionine, tyrosine. The share of glycine accounts for 35%, and 22% for hydroxyproline and hydroxylizine. About 40% of it is in the skin, where it is represented by collagen I, III, IV, V and VII types. Each type of collagen has its own structural features, preferential localization and, accordingly, performs various functions. Collagen type III consists of thin fibrils, in the skin it is called the reticular protein. In larger quantities, it is present in the upper part of the dermis. Collagen type I - the most common human collagen, it forms thicker fibrils of the deep layers of the dermis. Collagen type IV is a component of the basal membrane. Collagen type V is included in the blood vessels and all layers of the dermis, type VII collagen forms anchoring fibrils that connect the basal membranes to the papillary dermis.

The basic structure of collagen is a triplet polypeptide chain, which forms the structure of a triple helix, which consists of alpha chains of different types. There are 4 types of alpha chains, their combination and determines the type of collagen. Each chain has a molecular mass of about 120,000 kD. The ends of the chains are free and do not participate in the formation of the spiral, therefore, these points are sensitive to proteolytic enzymes, in particular to collagenase, which specifically breaks the bonds between glycine and hydroxyproline. In fibroblasts collagen is in the form of triplet helices procollagepa. After expression in the intercellular matrix, procollagen is converted to tropocollagen. Tropocollagen molecules are joined together with a shift of 1/4 length, are fixed by disulfide bridges, and thus striped striation is visible, visible in an electron microscope. After the release of collagen (tropocollagen) molecules into the extracellular environment, they are collected into collagen fibers and bundles that form dense networks, forming a durable frame in the dermis and hypodermis.

The smallest structural unit of mature collagen of human skin dermis is subfibrils. They have a diameter of 3-5 nm and are spirally located along the fibrils, which are considered as a structural element of collagen of the second order. Fibrils have a diameter of 60 to 110 nm. Collagen fibrils, grouped in bundles, form collagen fibers. The diameter of the collagen fiber is from 5-7 μm to 30 μm. Close-lying collagen fibers are formed into collagen beams. Because of the complexity of the structure of collagen, the presence of spiral triplet structures, connected by cross-links of various orders, the synthesis and catabolism of collagen takes a long period, up to 60 days

In the conditions of a skin trauma, which is always accompanied by hypoxia, the accumulation of decay products and free radicals in the wound, the proliferative and synthetic activity of fibroblasts increases and they react with enhanced collagen synthesis. It is known that the formation of collagen fibers requires certain conditions. So. Weakly acid medium, some electrolytes, chondroitin sulfate and other polysaccharides accelerate fibrillogenesis. Vitamin C, catecholamines, unsaturated fatty acids, especially linoleic, inhibit the polymerization of collagen. Self-regulation of the synthesis and decomposition of collagen is also regulated by amino acids in the intercellular environment. So polycation poly - L lysine inhibits the biosynthesis of collagen, and polyanion poly - L glutamate stimulates it. Due to the fact that the time of collagen synthesis prevails over the time of its degradation, there is a significant accumulation of collagen in the wound, which becomes the basis of the future scar. Collagen degradation is carried out with the help of fibrinolytic activity of special cells and specific enzymes.

[7], [8], [9],

Collagenase

A specific enzyme for the cleavage of the most common type I and III collagen in the skin is collagenase. Auxiliary role in this play such enzymes as elastase, plasminogen and other enzymes. Collagenase regulates the amount of collagen in the skin and scar tissue. There is an opinion that the size of the scar that remains on the skin after wound healing, mainly depends on the activity of collagenase. It is produced by epidermal cells, fibroblasts, macrophages, eosinophils and refers to metalloproteases. Fibroblasts taking part in the destruction of collagen-containing structures are called fibroblasts. Some fibroblasts not only secrete collagenase, but absorb and utilize collagen. Depending on the specific situation in the wound, the state of the macroorganism, the rationality of therapeutic measures, the presence of concomitant flora, in the area of injury, either fibrinogenesis or fibroclase processes predominate, that is, the synthesis or destruction of collagen-containing structures. If fresh cells that produce collagenase cease to flow into the focus of inflammation, and the old ones lose this ability, a prerequisite arises for the accumulation of collagen. In addition, the high activity of collagenase in the focus of inflammation does not yet mean that it is the guarantee of optimization of reparative processes and the wound is insured against fibrotic changes. The activation of fibrotic processes is often regarded as an exacerbation of the inflammation and its chronization, while the prevalence of fibrogenesis is its calming down. Fibrogenesis, or the formation of scar tissue at the site of skin trauma, is carried out mainly with the participation of mast cells, lymphocytes, macrophages and fibroblasts. The starting vasoactive moment is carried out with the help of mast cells, biologically active substances, which help to attract lymphocytes to the lesion focus. Tissue decay products activate T-lymphocytes. Which through the lymphokines connect macrophages to the fibroblastic process or directly stimulate macrophages with proteases (necrohormones). Mononuclear cells not only stimulate the function of fibroblasts, but also inhibit them, acting as true regulators of fibrogenesis, releasing mediators of inflammation and other proteases.

[10], [11], [12], [13]

Mast cells

Mast cells are cells characterized by pleomorphism with large round or oval nuclei and hyperchromically stained basophilic granules in the cytoplasm. They are found in large quantities in the upper parts of the dermis and around the blood vessels. Being a source of biologically active substances (histamine, prostaglandin E2, chemotactic factors, heparin, serotonin, platelet growth factor, etc.). Mast cells, if damaged, excrete them into the extracellular environment, triggering an initial short-term vasodilator reaction in response to trauma. Histamine is a potent vasoactive drug, leading to vasodilation and increased permeability of the vascular wall, especially postcapillary venules. This reaction II Mechnikov in 1891 regarded as protective in order to facilitate access of leukocytes and other immunocompetent cells to the lesion focus. In addition, it stimulates the synthetic activity of melanocytes, which is often associated with post-traumatic pigmentation. It also stimulates the mitosis of epidermal cells, which is one of the key moments in wound healing. Heparin, in turn, reduces the permeability of the intercellular substance. Thus, mast cells are not only regulators of vascular reactions in the area of trauma, but also intercellular interactions, and therefore immunological, protective and reparative processes in the wound.

Macrophages

In the process of fibrogenesis, when repairing the wound, lymphocytes, macrophages and fibroblasts are given a decisive role. Other cells perform an auxiliary role, because through histamine and biogenic amines they can affect the function of the triad (lymphocytes, macrophages, fibroblasts). Cells interact with each other and with the extracellular matrix through membrane receptors, adhesive cell-cell and cell-matrix molecules, mediators. Stimulate the activity of lymphocytes, macrophages and fibroblasts, also tissue decay products, T-lymphocytes through lymphokines connect macrophages to the fibroblastic process or directly stimulate macrophages with proteases (necrohormones). Macrophages in turn not only stimulate the function of fibroblasts, but also inhibit them. Highlighting mediators of inflammation and other proteases. Thus, at the stage of wound healing, the main active cells are macrophages, which take an active part in cleansing the wound from cellular detritus, bacterial infection and promote wound healing.

The function of macrophages in the epidermis is also performed by Langerhans cells, which are also found in the dermis. In case of damage to the skin, Langerhans cells are also damaged, releasing mediators of inflammation, such as lysosome enzymes. Tissue macrophages or histiocytes make up about 25% of the cellular elements of connective tissue. They synthesize a number of mediators, enzymes, interferons, growth factors, complement proteins, tumor necrosis factor, have high phagocytic and bactericidal activity, etc. When a skin injury in histiocytes, metabolism increases dramatically, their bactericidal, phagocytic and synthetic activity increases , due to which a large number of biologically active molecules enter the wound.

Adopted that fibroblast growth factor. Epidermal growth factor and insulin-like factor secreted by macrophages accelerate wound healing, transforming growth factor-beta (TGF-B) stimulates the formation of scar tissue. By activating the activity of macrophages or blocking certain receptors of cell membranes, it is possible to regulate the process of skin repair. For example, using immunostimulants, it is possible to activate macrophages, increasing nonspecific immunity. It is known that the macrophage has receptors that recognize mannose-containing and glucose-containing polysaccharides (mannans and glucans). Which are contained in Aloe Vera, hence the mechanism of action of drugs from scarlet, used for long-term non-healing wounds, ulcers and acne.

Fibroblasts

The basis and the most common cellular form of connective tissue is fibroblast. The function of fibroblasts includes the production of carbohydrate-protein complexes (proteoglycans and glycoproteins), the formation of collagen, reticulin, elastic fibers. Fibroblasts regulate metabolism and structural stability of these elements, including their catabolism, modeling of their "microenvironment" and epithelial-mesenchymal interactions. Fibroblasts produce glycosaminoglycans, of which the most important is hyaluronic acid. In combination with fibrous components of fibroblasts, the spatial structure (architectonics) of the connective tissue is also determined. The fibroblast population is not homogeneous. Fibroblasts of different degrees of maturity are divided into slightly differentiated, young, mature and inactive. Mature forms include fibroblasts, in which the lysis process of collagen predominates over the function of its production.

In recent years, the heterogeneity of the "fibroblastic system" has been specified. Three mitogically active fibroblast precursors - the cellular types of MFI, MFII, MFIII and three postmitotic fibroblasts - PMFIV, PMFV, PMFVI, were found. By cell division, MFI is sequentially differentiated in MFII, MFIII and PMMV, PMFV, PMFVI, PMFVI is characterized by the ability to synthesize collagen I. III and V types, progeoglycans and other components of the intercellular matrix. After a period of high metabolic activity, PMFVI degenerates and undergoes apoptosis. The optimal ratio between fibroblasts and fibroblasts is 2: 1. As fibroblasts accumulate, their growth is inhibited by stopping the division of mature cells that have converted to biosynthesis of collagen. Collagen degradation products stimulate its synthesis by the feedback principle. New cells cease to form from their predecessors due to the depletion of growth factors, as well as the production of growth inhibitors by the fibroblasts themselves - the Keylones.

The connective tissue is rich in cellular elements, but the range of cellular forms is especially wide for chronic inflammation and fibrotic processes. So. In keloid scars appear atypical, giant, pathological fibroblasts. Size (from 10x45 to 12x65 microns), which are the pathognomonic sign of the keloid. Fibroblasts obtained from hypertrophic scars, some authors call myofibroblasts due to highly developed bundles of actinic filaments, the formation of which is associated with the elongation of the shape of fibroblasts. However, this statement can be objected to, since all fibroblasts are in vivo, especially in the scars. Have an elongated shape, and their processes sometimes have a length exceeding more than 10 times the size of the body of the cell. This is explained by the density of scar tissue and the mobility of fibroblasts. Moving along the bundles of collagen fibers in a dense mass of the rumen in an insignificant amount of interstitial substance. They stretch along their axis and sometimes turn into thin spindle-like cells that have very long processes.

The increased mitotic and synthetic activity of fibroblasts after skin trauma is first stimulated by tissue decay products, free radicals, followed by growth factors: (PDGF) -generous platelet factor, fibroblast growth factor (FGF), and then iMDGF-growth factor of macrophages. The fibroblasts themselves synthesize proteases (collagenase, hyaluronidase, elastase), platelet growth factor, transforming growth factor - beta. Epidermal growth factor, collagen, elastin, etc. The reorganization of the granulation tissue into the scar is a complex process, which is based on the ever-changing balance between the synthesis of collagen and its destruction by collagenase. Depending on the specific situation, fibroblasts then produce collagen, then secrete collagenase under the influence of proteases and, above all, the activator of plasminogen. Presence of young, undifferentiated forms of fibroblasts; giant, pathological, functionally active fibroblasts in conjunction with excess collagen biosynthesis, provides a constant growth of keloid scars.

[14], [15],

Hyaluronic acid

It is a natural polysaccharide, a large molecular weight (1,000,000 daltons), which is contained in the interstitial substance. Hyaluronic acid is non-specific, hydrophilic. An important physical property of hyaluronic acid is its high viscosity, due to which it plays the role of a cementing substance that binds collagen beams and fibrils to each other and to cells. The space between collagen fibrils, small vessels, cells is occupied by a solution of hyaluronic acid. Hyaluronic acid, enveloping small vessels, strengthens their wall, prevents the sweat of the liquid part of the blood in the surrounding tissues. It performs in many respects a supporting function, supporting the resistance of tissues and skin to mechanical factors. Hyaluronic is a strong cation that actively binds anions in the interstitial space, thus the exchange processes between the aunt and the extracellular space, the proliferative processes in the skin depend on the state of glycosaminoglycans and hyaluronic acid. One molecule of hyaluronic acid has the ability to keep near to itself about 500 water molecules, which is the basis of hydrophilicity and moisture capacity of the interstitial space.

Hyaluronic acid is found in the papillary layer of the dermis, the granular layer of the epidermis, and also along the vessels and appendages of the skin. Due to the numerous carboxyl groups, the hyaluronic acid molecule is negatively charged and can move in the electric field. Depolymerization of the acid is carried out by the enzyme hyaluronidase (lidase), which acts in two stages. First, the enzyme depolymerizes the molecule, and then splits it into small fragments. As a result, the viscosity of the gels formed by the acid is sharply reduced, and the permeability of the skin structures is increased. Due to these properties, bacteria synthesizing hyaluronidase can easily overcome the skin barrier. Hyaluronic acid has a stimulating effect on fibroblasts, enhancing their migration and activating the synthesis of collagen, has a disinfectant, anti-inflammatory and wound-healing effect. In addition, it has antioxidant, immunostimulating properties, does not form complexes with proteins. Being in the intercellular space of connective tissue in the form of a stable gel with water, provides the output of metabolic products through the skin.

Fibronectin

In the process of arresting the inflammatory reaction, the matrix of connective tissue is restored. One of the main structural components of the extracellular matrix is the fibronectin glycoprotein. Fibroblasts and macrophages of the wound actively secrete fibronectically to accelerate contraction of the wound and restore the basal membrane. With electron microscopic examination of fibroblasts, wounds in them. A large number of paralleled beams of filaments of cellular fibronectin are detected in a large number, which allowed a number of researchers to call the fibroblasts of the wound myofibroblasts. Being an adhesive molecule and existing in two types - cellular and plasma, fibronectin in the intercellular matrix plays the role of "rafters" and provides a strong adhesion of fibroblasts to the matrix of connective tissue. Molecules of cellular fibronectin bind to each other with disulfide bonds and together with collagen, elastin, glycosaminoglycans fill the intercellular matrix. When wound healing, fibronectin plays the role of a primary framework that creates a certain orientation of fibroblasts and collagen fibers in the repair zone. It binds collagen fibers to fibroblasts through actinic bundles of fibroblast filaments. Thus, fibronectin can act as a regulator of the balance of fibroblastic processes, causing attraction of fibroblasts, binding to fibrils of collagen and inhibiting their growth. It can be said that due to fibronectin, the phase of inflammatory infiltration in the wound itself passes to the granulomatous-fibrous stage.

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