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. The skin is an organ of immunogenesis and an organ of senses, 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 occurring in the skin provide a constant metabolism in it, which consists of balanced processes of synthesis and decay (oxidation) of various substrates, including specific ones, necessary for maintaining the structure and function of skin cells. Chemical transformations occur in it, which are related to the metabolic processes of other organs, and processes specific to it are also carried out: the formation of keratin, collagen, elastin, glycosaminoglycans. melanin, sebum, sweat, etc. Through the dermal vascular network, the metabolism of the skin is connected with the metabolism of the whole body.

The 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 brought by blood and produced by neighboring cells. Producing its own compounds, releasing them into the blood or presenting them on the surface of its membrane, the cell communicates with its environment, organizing intercellular interactions that largely determine the nature of proliferation and differentiation, and also communicates information about itself to 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 end 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 to the development of a particular pathology. Biochemical reactions in the skin are organized into biochemical processes that are organically linked to each other as provided by the regulatory background under the influence of which a specific cell, group of cells, tissue area or the entire organ is.

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

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

Regulation of fibroplastic processes

The skin, being a superficial organ, is often subject to injury. Thus, it becomes clear that skin damage causes a chain of general and local neurohumoral reactions in the body, the purpose of which is to restore the body's homeostasis. The nervous system takes direct part in the development of skin inflammation in response to injury. The intensity, nature, duration and final result of the inflammatory reaction depend on its condition, since mesenchymal cells have high sensitivity to neuropeptides - heterogeneous proteins that play the role of neuromodulators and neurohormones. They regulate cellular interactions, through which they can weaken or strengthen inflammation. Beta-endorphins and substance P are among the agents that significantly modify the reactions of connective tissue in acute inflammation. Beta-endorphins have an anti-inflammatory effect, and substance P potentiates inflammation.

The Role of the Nervous System. Stress, Stress Hormones

Any skin injury is stress for the body, which has local and general manifestations. Depending on the adaptive capacity of the body, local and general reactions caused by stress will follow one or the other path. It has been established that stress causes the release of biologically active substances from the hypothalamus, pituitary gland, adrenal glands and sympathetic nervous system. 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 gland and cortisol. In addition, under its influence, hormones of the sympathetic nervous system are released from nerve ganglia and nerve endings. It is known that skin cells have receptors on their surface for all hormones that are produced in the hypothalamic-pituitary-adrenal system.

Thus, CRH enhances the inflammatory reaction of the skin, causing degranulation of mast cells and the release of histamine (itching, swelling, erythema appear).

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, synthesis of hyaluronic acid, and disruption of wound healing.

During stress, the concentration of androgen hormones in the blood increases. Spasm of skin vessels in areas with a large number of testosterone receptors worsens local tissue reactivity, which, even with minor trauma or inflammation of the skin, can lead to chronic inflammation and the appearance of keloid scars. Such areas include: the shoulder girdle, sternal area. To a lesser extent, the skin of the neck and 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. Being released into the intercellular fluid during skin injuries, they have not only a local but also a general effect.

Stress hormones allow the skin to quickly react to a stressful situation. Short-term stress leads to increased immune reactivity of the skin, long-term stress (chronic inflammation) has the opposite effect on the skin. A stressful situation in the body also occurs with skin injuries, surgical dermabrasion, deep peeling, mesotherapy. Local stress from skin injuries is aggravated if the body has already been in a state of chronic stress. Cytokines, neuropeptides, prostaglandins released in the skin during local stress cause an inflammatory reaction in the skin, activation of keratinocytes, melanocytes, fibroblasts.

It is necessary to remember that procedures and operations performed against the background of chronic stress, against the background of decreased reactivity, can cause the appearance of long-term non-healing erosions, wound surfaces, which can be accompanied by necrosis of nearby tissues and pathological scarring. In the same way, the treatment of physiological scars with surgical dermabrasion against the 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 local stress area, there are also local factors that trigger a chain of adaptive reactions in response to trauma. These include free radicals, polyunsaturated fatty acids, micropeptides and other biologically active molecules that appear 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 become building material for the synthesis of leukotrienes and prostaglandins in macrophages and other cells of the immune system, which potentiate the inflammatory reaction.

Free radicals are aggressive molecules (superoxide anion radical, hydroxyl radical, NO, etc.) that constantly appear in the skin during the life of the body, and are also formed during inflammatory processes, immune reactions, and against the background of trauma. When more free radicals are formed than the natural antioxidant system can neutralize, 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 oxidized groups (cysteine, serine, tyrosine, glutamate). With further accumulation of active oxygen forms, lipid peroxidation of cell membranes, disruption of their permeability, damage to the genetic apparatus, and premature apoptosis occur. Thus, oxidative stress aggravates damage to skin tissue.

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

The role of the endocrine system

In addition to nervous regulation, the hormonal background has a huge impact on the skin. The appearance of the skin, metabolism, proliferative and synthetic activity of cellular elements, the state and functional activity of the vascular bed, fibroplastic processes depend on the endocrine status of a person. In turn, the production of hormones depends on the state of the nervous system, the level of secreted endorphins, mediators, and the microelement composition of the blood. One of the essential elements for the normal functioning of the endocrine system is zinc. Such vital hormones as insulin, corticotropin, somatotropin, gonadotropin are zinc-dependent.

The functional activity of the pituitary gland, thyroid gland, sex glands, and adrenal glands 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 are affected by all classical hormones, such as cortisol, ACTH, insulin, somatropin, thyroid hormones, estrogens, and testosterone.

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

Somatotropic hormone of the pituitary gland enhances cell proliferation, collagen formation, and formation of granulation tissue. Thyroid hormones stimulate the metabolism of connective tissue cells and their proliferation, development of granulation tissue, collagen formation, and wound healing. Estrogen deficiency slows down reparative processes, androgens activate fibroblast activity.

Since elevated levels of androgen hormones are observed in most patients with acne keloid, special attention should be paid to the presence of other clinical signs of hyperandrogenemia during the initial consultation with patients. Such patients should have their blood levels of sex hormones determined. If dysfunction is detected, doctors of related specialties should be involved in the treatment: endocrinologists, gynecologists, etc. It is necessary to remember that physiological hyperandrogen syndrome occurs in the post-pubertal period: in women in the postpartum period due to elevated levels of luteinizing hormone and in the postmenopausal period.

In addition to classical hormones that affect cell growth, cell regeneration and hyperplasia are regulated by polypeptide growth factors of cellular origin of several types, 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 cell surface, thus transmitting information about the mechanisms of cell division and differentiation. Interaction between cells is also carried out through them. A significant role is also played by peptide "parahormones" secreted by cells that are part of the so-called diffuse endocrine system (APUD system). They are scattered throughout many organs and tissues (CNS, epithelium of the gastrointestinal tract and respiratory tract).

Growth factors

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

1. Epidermal growth factor (EGF). Stimulates division and migration of epithelial cells during wound healing, wound epithelialization, regulates regeneration, suppresses differentiation and apoptosis. Plays a leading role in regeneration processes in the epidermis. Synthesized by macrophages, fibroblasts, keratinocytes.
2. Vascular endothelial growth factor (VEGF). 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. Transforming growth factor - 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 a culture of normal human keratinocytes. It is also synthesized in neoplasm cells, during early fetal development and in the primary culture of human keratinocytes. It is considered an embryonic growth factor.
4. Insulin-like factors (IGFs) are polypeptides homologous to proinsulin. They enhance the production of extracellular matrix elements and thus play a vital role in normal tissue growth, development, and repair.
5. Fibroblast growth factors (FGF). Belong to the family of monomeric peptides, are also a factor of neoangiogenesis. They cause migration of epithelial cells and accelerate wound healing. They act in collaboration with heparin sulfate compounds and proteoglycans, modulating cell migration, angiogenesis and epithelial-mesenchymal integration. FGF stimulates proliferation of endothelial cells, fibroblasts, play a significant role in stimulating formation of new capillary vessels, stimulate production of extracellular matrix. Stimulates production of proteases and chemotaxis not only of fibroblasts, but also of keratinocytes. Synthesized by keratinocytes, fibroblasts, macrophages, thrombocytes.
6. Platelet-derived growth factor (PDGF) family. Produced not only by platelets, but also by macrophages, fibroblasts, and endothelial cells. They are strong mitogens for mesenchymal cells and an important chemotactic factor. They activate the proliferation of glial, smooth muscle cells, and fibroblasts, and play a major role in stimulating wound healing. The stimuli for their synthesis are thrombin, tumor growth factor, and hypoxia. (PDGF) provides chemotaxis of fibroblasts, macrophages, and smooth muscle cells, triggers a number of processes involved in wound healing, stimulates the production of other various wound cytokines, and increases collagen synthesis.
7. Transforming growth factor - beta (TGF-beta). Represents a group of protein signaling molecules, including inhibins, stimulins, bone morphogenetic factor. Stimulates synthesis of connective tissue matrix and formation of scar tissue. It is produced by many types of cells and, above all, fibroblasts, endothelial cells, platelets and bone tissue. Stimulates migration of fibroblasts and monocytes, formation of granulation tissue, formation of collagen fibers, synthesis of fibronectin, cell proliferation, differentiation and production of extracellular matrix. Plasmin activates latent TGF-beta. Studies by Livingston van De Water at all. have established that when activated factor is introduced into intact skin, a scar is formed; when added to fibroblast culture, synthesis of collagen, proteoglycans, fibronectin increases; when inoculated into collagen gel, its contraction occurs. TGF-beta is believed to modulate the functional activity of fibroblasts in pathological scars.
8. Polyergin or tumor growth factor - beta. Refers to non-specific inhibitors. Along with cell growth stimulators (growth factors), growth inhibitors play an important role in the implementation of regeneration and hyperplasia processes, among which prostaglandins, cyclic nucleotides and chalones are of particular importance. Polyergin suppresses the proliferation of epithelial, mesenchymal and hematopoietic cells, but increases their synthetic activity. As a result, the synthesis of extracellular matrix proteins by fibroblasts increases - collagen, fibronectin, cell adhesion proteins, the presence of which is a prerequisite for the reparation of wound areas. Thus, polyergin is an important factor in regulating the restoration of tissue integrity.

It follows from the above that in response to trauma, dramatic events invisible to the eye develop throughout the body and in the skin in particular, the purpose of which is to maintain 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 a complex of biologically active substances and neurotransmitters, signals go to the brain stem structures, the pituitary gland, the endocrine glands and through the body's fluid medium by means of hormones, cytokines and mediators enter the site of injury. An instantaneous vascular reaction to trauma in the form of a short-term spasm and subsequent vasodilation is a clear illustration of the connection between the central adaptation mechanisms and the lesion. Thus, local reactions are connected in a single chain with general neurohumoral processes in the body aimed at eliminating the consequences of skin injury.

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