The mechanisms underlying the formation of keloid and hypertrophic scars

The lack of any components necessary for the implementation of "protective", physiological inflammation, can prolong this process and translate it into an "inadequate" level. In case secondary infection is associated with a trauma, the chronic inflammation occurs, which leads to a deregulation of the connective tissue of the dermis, an unbalanced accumulation of macromolecular components of the connective tissue with the formation of keloid and hypertrophic scars, which are often combined into a group of pathological scars. Deep injuries of a large area, especially after thermal and chemical burns, with partial destruction of the appendages of the skin - one of the most dangerous in terms of the appearance of pathological scars. The process of repair in this type of injury is difficult due to the absence of even fragments of the basal membrane with basal keratinocytes. Such injuries occur with burns of IIIa and IIIb degree: with deep operative dermabrasion, for example after removal of tattoos: with trauma. Received during military operations, at home, at work. In these cases, epithelialization proceeds slowly and. Mainly due to preserved epithelial cells of hair follicle residues or sebaceous and sweat glands. In addition, such trauma leads to a decrease in the overall reactivity of the organism, local immunity and is often accompanied by the attachment of a secondary infection. A normal inflammatory reaction turns into a prolonged alterative inflammation, with a deepening of the skin defect, the accumulation of decay products, free radicals in the wound. Similar processes occur in the skin with injuries deeper than the middle layer of the dermis, in which almost no hair follicles are even preserved. If the trauma has a large area, accompanied by a process of protracted inflammation due to the attachment of secondary infection and the presence of a large number of destroyed tissues, it heals always by secondary tension. Moreover, such traumas often do not heal on their own. Autodermoplasty is required. Healing of large wound surfaces is slow, accompanied by the formation of granulations and a long-existing inflammatory reaction that goes beyond adequate inflammation. Hypoxia and disturbance of microcirculation as a result of prolonged inflammatory process leads to the accumulation of cutaneous detritus, mediators of inflammation in the wound. Products of tissue decay (autoantigens) act as biological stimulators of fibrogenesis and lead to an imbalance of this system with the formation of a large number of cells of the fibroblastic series, which are characterized by a high metabolism. In addition, pericytes of the destroyed capillaries are transformed into fibroblasts. The accumulation of functionally active fibroblasts at the site of the pathological process and determines the nature of further changes in scar tissue. Because of the microcirculation disturbance, fresh macrophages cease to act in the inflammatory focus, they actively synthesize collagenase - preconditions for collagen accumulation are created .. All this leads to unbalanced growth and excessive formation of macromolecular components of connective tissue, in particular fibrillar collagen, fibronectin, hyaluronic acid and sulfated glycosaminoglycans . And an increased content of bound water. In addition, a change in the morphology of collagen fibers, the manifestation in it of trifunctional transverse pyridinoline cross-linking, characteristic of collagen type II cartilaginous tissue and for type I collagen bone tissue and tendons. Accompanying chronic inflammation of oxidative stress becomes an additional local trigger factor provoking stimulation of the synthetic and proliferative activity of fibroblasts with increased metabolism, causing the dermal connective tissue to degenerate with the formation of a keloid.

Thus, all of the above factors provoke and support an inadequate inflammatory reaction in the wound; pathological proliferation of connective tissue with predominance among cellular elements functionally active with high metabolism, undifferentiated, juvenile cells of the fibroblastic series, as well as giant functionally active pathological fibroblasts. With a high level of synthesis of atypical collagen and transforming growth factor-beta. In hypertrophic and keloid scars, the formation of collagen predominates over its disintegration due to a lack of collagenase, resulting in the development of powerful fibrosis. Deficiency of ascorbic acid, oligoelements (zinc, copper, iron, cobalt, potassium, magnesium), oxygen supplement unfavorable local background, maintain a long inflammatory process, which worsens the healing of wounds.

In addition to the above pathogenetic factors that explain the mechanism of the formation of pathological scars, there are still insufficiently studied, such, for example, as autoimmune processes. In recent years, with the help of a highly sensitive solid-phase enzyme-linked immunosorbent assay, natural autoantibodies have been found to mediators of inflammation and to various types of collagen, which can speak of the involvement of autoimmune processes in the rapid growth of scar tissue and the formation of pathological scars.

Summarizing the known local causes of the appearance of nonphysiological scars, we should dwell on general.

Common causes leading to the formation of keloids.

Dysfunction of the endocrine system. The leading role belongs to the functional state of the adrenal cortex. Keloid scars often occur against a background of stress. It is known that corticosteroids are stress hormones, they inhibit the mitotic and synthetic activity of cells and fibroblasts in particular, but accelerate their differentiation than inhibit the formation of scar tissue and prolong the inflammatory reaction in the wound. Depletion of the adrenal cortex with prolonged stress leads to a lack of corticosteroids, adrenocorticotropic hormone of the pituitary gland, increased fibrogenesis and an increase in the volume of the scar.

Thyroid hormones, mineralocorticoids, androgens, somatotropic hormone, anabolic steroids stimulate the connective tissue, increase the mitotic and proliferative activity of its cells, enhance the formation of collagen, the formation of granulation tissue. Excess free testosterone blood under the influence of alpha-reductase is converted into dihydrotestosterone, which binds to receptors of epithelial cells of sebaceous glands, dermal fibroblasts, causing their proliferative, mitotic and synthetic activity. An increased amount of these hormones can serve as a predisposing factor for the growth of keloids.

The lack of estrogens promotes the chronic inflammation due to weakening of reparative processes and collagen formation.

Reduction of overall reactivity

Decrease in general and local immunity against a background of chronic diseases, stress leads to a worsening of the phagocytic function of leukocytes and macrophages, a decrease in the production of immunoglobulins. This leads to accumulation in the trauma zone of decay products, free radicals, infectious agents; deterioration of microcirculation, hypoxia, which play a major role in the development of a protracted inflammatory process.

Violation of regulatory functions of the central nervous system.

As a result, all the common causes contributing to prolonged inflammation lead to the unfolding of unfavorable processes in the wound and give the impulse to increase the number of cells of the fibroblastic series, the appearance of different populations of fibroblasts with enhanced metabolism, synthetic and proliferative activity, and consequently to enhanced and prolonged fibrogenesis.

Biochemistry of keloid and hypertrophic scars

The bulk of the keloid scar consists of collagen fibers, which are constructed from fibrillar proteins - tropocollagen molecules. It is known that the synthesis of collagen in keloids is approximately 20 times higher than in normal skin and 8 times higher than in hypertrophic scars. In young keloid scars, the content of type III collagen is reduced, in older scars this indicator is identical with that in hypertrophic scars. The average content of pyridine crosslinks in collagen keloids is 2 times greater than in the collagen of hypertrophic scars. In young hypertrophic scars, the increased content of beta-collagen chains within 7 years after injury is close to normal skin values, there is no such decrease in keloid scars.

In keloid scars, calcium is 4 times greater than in normal skin, a large amount of hyaluronic acid and chondroitin sulfate, which is considered. As one of the signs of immature condition of connective tissue. Studies of recent years have shown that a significant amount of the transforming growth factor-TGF-beta, consisting of a number of molecules (TGF-beta1, TGF-beta2, TGF-beta3), is detected in keloid scars and blood of patients with keloid scars, which activate cell proliferation, differentiation and stimulate the production of the extracellular matrix.

Due to the fact that scar tissue mainly consists of collagen fibers, and degradation of collagen is triggered by highly specialized enzymes called tissue collagenases, the type of scar is largely dependent on the activity of collagenase and the collagen-collagenase ratio.

Collagenase, produced by fibroblasts and macrophages, cleaves collagen, but the resulting peptides stimulate a new synthesis of collagen in fibroblasts. As a result, the collagen-collagenase ratio in the direction of collagen changes. At the same time, if as a result of disturbance of microcirculation into the focus of inflammation new macrophages cease to flow, and old ones lose the ability to secrete collagenase, a real prerequisite arises for collagen accumulation. The formation of fibrous tissue in these cases goes in a different way than in cases with normal scars. The activity of pathologically, functionally active fibroblasts leads to an excessive accumulation of macromolecular components of connective tissue, in particular, collagen, fibronectin, hyaluronic acid and sulfated glycosaminoglycans. Features of microcirculation in the resulting scar tissue contribute to the accumulation of a large amount of water associated with these molecules, which together provides a clinical picture of a keloid or hypertrophic scar.

Hypertrophic scars are often combined into a common group with keloid scars due to the fact that both species are characterized by excessive formation of fibrous tissue and result from disturbances in microcirculation, hypoxia, secondary infection, lower local immunological reactivity, resulting in a prolonged inflammatory response and the transition of adequate physiological inflammation to an inadequate one. Part of the patients are diagnosed with endocrinopathy. In the clinical and morphological picture of these two types of scars there is much in common, but there are also serious differences. Biochemistry of hypertrophic and keloid scars also differ, in particular, by the metabolism of collagen, which allows us to say that hypertrophic scars occupy an intermediate position in the classification of scars between keloid and physiological scars.