Neurohumoral reactions underlying reparative processes in skin injuries

It is known that the skin is a multifunctional organ that performs respiratory, nutritional, thermoregulatory, detoxifying, excretory, barrier-protective, vitamin-forming and other functions. Skin is an organ of immunogenesis and a limb of feelings, due to the presence of a large number of nerve endings, nerve receptors, specialized sensitive cells and bodies. The skin also contains biologically active zones and points, due to which the connection between the skin, nervous system and internal organs is carried out. Biochemical reactions that take place in the skin ensure a constant metabolism in it, which consists in balanced processes of synthesis and decomposition (oxidation) of various substrates, including specific ones, necessary to maintain the structure and function of skin cells. In it, chemical transformations occur in connection with the metabolic processes of other organs, and also specific processes are carried out: the formation of keratin, collagen, elastin, glycosaminoglycans. Melanin, sebum, sweat, etc. Through the dermal vasculature, skin metabolism is combined with the metabolism of the whole organism.

Functional activity of cellular elements of any organ and skin in particular is the basis of normal vital activity of the organism as a whole. The cell divides and functions using metabolites produced by blood and produced by neighboring cells. By producing their own compounds, isolating them into the blood or imagining them on the surface of their membrane, the cell communicates with its environment, organizing intercellular interactions that largely determine the nature of proliferation and differentiation, and also informs itself about all regulatory structures of the organism. The speed and direction of biochemical reactions depend on the presence and activity of enzymes, their activators and inhibitors, the amount of substrates, the level of final products, cofactors. Accordingly, a change in the structure of these cells leads to certain changes in the organ and in the organism as a whole and in the development of one or another pathology. Biochemical reactions in the skin are organized into biochemical processes, which are organically linked to each other in this way. As provided by the regulatory background, under the influence of which is a particular cell, a group of cells, a tissue site or the entire organ.

It is known that the neurohumoral regulation of the body functions is carried out through water-soluble receptor molecules - hormones, biologically active substances (mediators, cygokines, nitric oxide, micro-peptides). Which are secreted by the cells of the secreting organ and are perceived by the cells of the target organ. These same regulatory molecules affect growth and cellular regeneration.

Regulatory background is, first of all, the concentration of regulatory molecules: mediators, hormones, cytokines, whose products are under strict control of the central nervous system (CNS). And the central nervous system acts from the point of view of the needs of the organism, taking into account its functional and primarily adaptive capabilities. Biologically active substances and hormones act on intracellular metabolism through a system of secondary mediators and as a result of direct action on the genetic apparatus of cells.

Regulation of fibroplastic processes

Skin, being a superficially located organ, is often injured. Thus, it becomes clear that damage to the skin causes in the body a chain of general and local neurohumoral reactions, the purpose of which is to restore the body's homeostasis. The nervous system takes a direct part in the development of skin inflammation in response to trauma. The intensity, nature, duration and final result of the inflammatory reaction depend on her condition, since mesenchymal cells have a high sensitivity to neuropeptides - heterogeneous proteins. Playing the role of neuromodulators and neurohormones. They regulate cellular interactions, through which they can weaken or enhance inflammation. Among the agents that substantially modify the reactions of connective tissue in acute inflammation are betta-endorphins and substance R. Betta-endorphins have an anti-inflammatory effect, and substance P-potentiates inflammation.

The role of the nervous system. Stress, stress hormones

Any trauma to the skin - this is stress for the body, which has local and common manifestations. Depending on the adaptive abilities of the body. Local and general reactions caused by stress will go one way or the other. It was found that under stress, release of biologically active substances from the hypothalamus, pituitary gland, adrenal glands and sympathetic nervous system occurs. One of the main stress hormones is corticotropin-releasing hormone (corticotropin-releasing hormone or CRH). It stimulates the secretion of adrenocorticotropic hormone of the pituitary and cortisol. In addition, under its influence, the hormones of the sympathetic nervous system are released from the nervous ganglia and nerve endings. It is known that skin cells have receptors on their surface to all the hormones that are produced in the hypothalamic-pituitary-adrenal system.

So CRH increases the inflammatory reaction of the skin, causing degranulation of mast cells and histamine release (there is itching, swelling, erythema).

ACTH, together with melanocyte-stimulating hormone (MSH), activate melanogenesis in the skin, and have an immunosuppressive effect.

Due to the action of glucocorticoids, there is a decrease in fibrogenesis, the synthesis of hyaluronic acid, a violation of wound healing.

Under stress, the concentration of androgenic hormones in the blood increases. Spasm of skin vessels in areas having a large number of receptors for testosterone worsens the local reactivity of tissues, which can lead to chronic inflammation and the appearance of keloid scars with even minor trauma or inflammation of the skin. These zones include: the shoulder region, the sternal region. To a lesser extent, the skin of the neck, face.

Skin cells also produce a number of hormones, in particular keratinocytes and melanocytes secrete CRH. Keratinocytes, melanocytes and Langerhans cells produce ACTH, MSH, sex hormones, catecholamines, endorphins, enkephalins, etc. Standing out in the intercellular fluid in skin injuries. They have not only a local, but also a general action.

Hormones of stress allow the skin to react quickly to a stressful situation. Short-term stress leads to an increase in the immune reactivity of the skin, a long-lasting (chronic inflammation) - has an opposite effect on the skin. Stressful situation in the body occurs with skin injuries, operative dermabrasion, deep peelings, mesotherapy. Local stress from skin injuries is exacerbated if the body is already in a state of chronic stress. Cytokines, neuropeptides, prostaglandins, secreted in the skin under local stress, cause inflammatory reaction in the skin, activation of keratinocytes, melanocytes, fibroblasts.

It should be remembered that procedures and operations performed against a background of chronic stress, against the background of a decrease in reactivity, can cause the appearance of long-term non-healing erosions, wound surfaces that can be accompanied by necrotizing nearby tissues and pathological scarring. Similarly, the treatment of physiological scars with operative dermabrasion on a background of stress can worsen the healing of erosive surfaces after grinding with the formation of pathological scars.

In addition to the central mechanisms that cause the appearance of stress hormones in the blood and in the focus of local stress, there are also local factors that trigger a chain of adaptive responses in response to trauma. These include free radicals, polyunsaturated fatty acids, micro-peptides and other biologically active molecules, appearing in large quantities when the skin is damaged by mechanical, radiation or chemical factors.

It is known that the composition of phospholipids of cell membranes includes polyunsaturated fatty acids, which are precursors of prostaglandins and leukotrienes. When the cell membrane is destroyed, they are the building material for synthesis in macrophages and other cells of the immune system of leukotrienes and prostaglandins, which potentiate the inflammatory response.

Free radicals - aggressive molecules (superoxide anion radical, hydroxyl radical, NO, etc.) constantly appear in the skin in the process of vital activity of the body, are formed also in inflammatory processes, immune reactions, against trauma. When free radicals are formed more than they can neutralize the natural antioxidant system, a condition called oxidative stress occurs in the body. In the early stages of oxidative stress, the primary target of free radicals are amino acids containing easily oxidizable groups (cysteine, serum, tyrosine, glutamate). With further accumulation of active forms of oxygen, cell membrane lipid peroxidation occurs, impairment of their permeability, damage to the genetic apparatus and premature apoptosis. Thus, oxidative stress exacerbates the damage to skin tissue.

Reorganization of the granulation tissue of the skin defect and growth of the scar is a complex process, which depends on the area, localization and depth of the lesion; the state of the immune and endocrine status; the degree of inflammatory reaction and the associated infection; the balance between the formation of collagen and its degradation and many other factors, not all of which are known to date. With the weakening of the nervous regulation, the proliferative, synthetic and functional activity of epidermal cells, leukocytes and connective tissue cells decreases. As a result, communicative, bactericidal, phagocytic properties of leukocytes are violated. Keratinocytes, macrophages, fibroblasts secrete fewer biologically active substances, growth factors; the differentiation of fibroblasts, etc. Is thus distorted, the reaction of physiological inflammation is distorted, the alterative reactions are intensified, the focus of destruction is deepened, which leads to the prolongation of adequate inflammation, its transition to an inadequate (prolonged) and as a result of these changes the appearance of pathological scars is possible.

The role of the endocrine system

In addition to nervous regulation, the skin is greatly influenced by the hormonal background. From the endocrine status of a person depends on the appearance of the skin, metabolism, proliferative and synthetic activity of cellular elements, the state and functional activity of the vascular bed, fibroplastic processes. In turn, the production of hormones depends on the state of the nervous system, the level of endorphins released, mediators, trace element composition of the blood. One of the indispensable elements for the normal functioning of the endocrine system is zinc. Zinc-dependent are such vital hormones as insulin, corticotropin, somatotropin, gonadotropin

Functional activity of the pituitary gland, thyroid gland, gonads, adrenals directly affects fibrogenesis, the general regulation of which is provided through neurohumoral mechanisms with the help of a number of hormones. The condition of connective tissue, proliferative and synthetic activity of skin cells is influenced by all classical hormones such as cortisol, ACTH, insulin, somatropin, thyroid hormones, estrogens, testosterone.

Corticosteroids and adrenocorticotropic hormone of the pituitary gland inhibit the mitotic activity of fibroblasts, but accelerate their differentiation. Mineralocorticoids intensify the inflammatory reaction, stimulate the development of all elements of connective tissue, accelerate epithelization.

The growth hormone of the pituitary gland enhances the proliferation of cells, the formation of collagen, the formation of granulation tissue. Thyroid hormones stimulate the metabolism of connective tissue cells and their proliferation, the development of granulation tissue, collagen formation and wound healing. The lack of estrogen slows the reparative processes, androgens activates the activity of fibroblasts.

Due to the fact that an increased level of androgenic hormones is noted in the majority of patients with acne-keloid, in the initial admission of patients, special attention should be paid to the presence of other clinical signs of hyperandrogenemia. Such patients need to determine the level of sex hormones in the blood. When identifying dysfunction - to connect to the treatment of doctors of related specialties: endocrinologists, gynecologists, etc. It must be remembered that the physiological hyperandrogenic syndrome occurs in the post-puerperal period: in women in the construction period due to the elevated level of luteinizing hormone and in the postmenopausal period.

In addition to the classical hormones influencing the growth of cells, cellular regeneration and hyperplasia are regulated by polypeptide growth factors of the cellular origin of several species, also called cytokines: epidermal growth factors, platelet growth factor, fibroblast growth factor, insulin-like growth factors, nerve growth factor and transforming growth factor. They bind to certain receptors on the surface of cells, thus transmitting information about the mechanisms of cell division and differentiation. Interaction between cells is also carried out through them. An important role is played also by the peptide "parahormones", which are released by the cells that make up the so-called diffuse endocrine system (ARUD system). They are scattered over many organs and tissues (CNS, epithelium of the gastrointestinal tract and respiratory tract).

Growth Factors

Growth factors are highly specialized biologically active proteins, recognized by today as powerful mediators of many biological processes that take place in the body. Growth factors bind to specific receptors on the cell membrane, conduct a signal inside the cell and include mechanisms of cell division and differentiation.

1. Epidermal growth factor (EGF). Stimulates the division and migration of epithelial cells during wound healing, epithelization of wounds, regulates regeneration, suppresses differentiation and apoptosis. It plays a leading role in regeneration processes in the epidermis. It is synthesized by macrophages, fibroblasts, keratinocytes.
2. Vascular endothelial growth factor (VEGF). It belongs to the same family and is produced by keratinocytes, macrophages and fibroblasts. It is produced in three varieties and is a powerful mitogen for endothelial cells. It supports angiogenesis during tissue repair.
3. The transforming growth factor is alpha (TGF-a). A polypeptide, also related to the epidermal growth factor, stimulates vascular growth. Recent studies have shown that this factor is synthesized by the culture of normal human keratinocytes. It is also synthesized in neoplasmic cells, during the early development of the fetus and in the primary culture of human keratinocytes. It is considered an embryonic growth factor.
4. Insulin-like factors (IGF). They are polypeptides homologous to proinsulin. They increase the production of elements of the extracellular matrix and thus play a vital role in the normal growth, development and restoration of tissues.
5. Factors of fibroblast growth (FGF). Relate to the family of monomeric peptides, are also a factor of neoangiogenesis. They cause the migration of epithelial cells and accelerate wound healing. Operate in conjunction with heparin-sulfate compounds and proteoglycans, modulating cellular migration, angiogenesis and epithelial-mesenchymal integration. FGF stimulate the proliferation of endothelial cells, fibroblasts, play a significant role in stimulating the formation of new capillary vessels, stimulate the production of extracellular matrix. Stimulate the production of proteases and chemotaxis of not only fibroblasts, but also keratinocytes. They are synthesized by keratinocytes, fibroblasts, macrophages, platelets.
6. A family of platelet-derived growth factors (PDGF). It is produced not only by platelets, but by macrophages, fibroblasts and endothelial cells. They are strong mitogens for mesenchymal cells and an important chemotactic factor. Activating the proliferation of glial, smooth muscle cells and fibroblasts, play a major role in stimulating wound healing. Stimulants for their synthesis are thrombin, tumor growth factor and hypoxia. (PDGF) provides the chemotaxis of fibroblasts, macrophages and smooth muscle cells, triggers a number of processes involved in wound healing, stimulates the production of other different wound cytokines, increases collagen synthesis
7. Transforming growth factor - beta (TGF-beta). Represents a group of protein signaling molecules, which includes inhibins, stimulants, bone morphogenetic factor. Stimulates the synthesis of connective tissue matrix and the formation of scar tissue. It is produced by many types of cells and, above all, by fibroblasts, endothelial cells, platelets and bone tissue. Stimulates the migration of fibroblasts and monocytes, the formation of granulation tissue, the formation of collagen fibers, the synthesis of fibronectin, cell proliferation, differentiation and production of the extracellular matrix. Plasmin activates the latent TGF-beta. Studies Livingston van De Water at all. It was established that when a activated factor is introduced into intact skin a scar is formed; when fibroblasts are added to the culture, the synthesis of collagen, proteoglycans, fibronectin increases; when inoculated into the collagen gel, its contraction occurs. It is believed that TGF-cells modulate the functional activity of fibroblasts of pathological scars.
8. Polyergin or tumor growth factor - beta. Refers to nonspecific inhibitors. Along with stimulators of cell growth (growth factors), growth inhibitors play an important role in the realization of regeneration and hyperplasia, among which prostaglandins, cyclic nucleotides and Ceylones are of particular importance. Polyergin inhibits the proliferation of epithelial, mesenchymal and hematopoietic cells, but increases their synthetic activity. As a result, the synthesis of fibroblast proteins by extracellular matrix proteins - collagen, fibronectin, cell adhesion proteins, whose presence is a prerequisite for the repair of wound sites. Thus, polyergin is an important factor in regulating the restoration of tissue integrity.

From the foregoing it follows that in response to trauma in the entire body and in the skin in particular, dramatic events that are invisible to the eye develop, the purpose of which is to preserve the homeostasis of the macrosystem by closing the defect. The pain reflex from the skin along the afferent pathways reaches the central nervous system, then through the complex of biologically active substances and neurotransmitters signals go to the brain stem structures, the pituitary gland, the endocrine glands and through the liquid medium of the body through hormones, cytokines and mediators enter the injury site. Instantaneous vascular reaction in case of trauma in the form of short-term spasm and subsequent vasodilation - is a graphic illustration of the connection of the central adaptation mechanisms and the lesion focus. Thus, local reactions are connected by a single chain with general neurohumoral processes in the body, aimed at eliminating the consequences of skin trauma.

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