Mechanisms underlying the formation of keloid and hypertrophic scars

Deficiency of any components necessary for the implementation of "protective", physiological inflammation can prolong this process and transfer it to an "inadequate" level. In case of secondary infection joining the injury against the background of reduced immunity, endocrinopathies and other predisposing factors, chronicity of the inflammation process occurs, which leads to dysregeneration of the connective tissue of the dermis, 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 skin appendages are among the most dangerous in terms of the appearance of pathological scars. The reparation process in this type of injury is complicated 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 surgical dermabrasion, for example, after tattoo removal: with injuries received during military actions, at home, at work. In these cases, epithelialization is slow and. mainly due to the preserved epithelial cells of the remains of hair follicles or sebaceous and sweat glands. In addition, such injuries lead to a decrease in the general reactivity of the body, local immunity and are often accompanied by the addition of a secondary infection. The normal inflammatory reaction turns into a protracted alterative inflammation, with a deepening of the skin defect, accumulation of decay products and free radicals in the wound. Similar processes occur in the skin with injuries deeper than the middle layer of the dermis, in which even hair follicles are practically not preserved. If the injury has a large area, is accompanied by a process of protracted inflammation due to the addition of a secondary infection and the presence of a large number of destroyed tissues, it always heals by secondary intention. Moreover, such injuries 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-term inflammatory reaction that goes beyond adequate inflammation. Hypoxia and impaired microcirculation as a result of a protracted inflammatory process leads to the accumulation of skin detritus and inflammation mediators in the wound. Tissue decay products (autoantigens) act as biological stimulators of fibrogenesis and lead to an imbalance in this system with the formation of a large number of fibroblastic cells, which are characterized by high metabolism. In addition, pericytes of destroyed capillaries are transformed into fibroblasts. The accumulation of functionally active fibroblasts at the site of the pathological process determines the nature of further changes in scar tissue. Due to impaired microcirculation, fresh macrophages stop entering the inflammation site,actively synthesizing collagenase - the prerequisites 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, to a change in the morphology of collagen fiber, the manifestation of trifunctional transverse pyridinoline cross-linking in it, characteristic of type II collagen of cartilage tissue and type I collagen of bone tissue and tendons. Oxidative stress accompanying chronic inflammation becomes an additional local trigger factor provoking stimulation of the synthetic and proliferative activity of fibroblasts with increased metabolism, causing dysregeneration of the connective tissue of the dermis with the formation of keloid.

Thus, all the above factors provoke and support an inadequate inflammatory reaction in the wound; pathological proliferation of connective tissue with prevalence among cellular elements of functionally active with high metabolism, undifferentiated, young cells of the fibroblast 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, collagen formation prevails over its decay due to a lack of collagenase, as a result of which powerful fibrosis develops. Deficiency of ascorbic acid, trace elements (zinc, copper, iron, cobalt, potassium, magnesium), oxygen complement the unfavorable local background, support a long-term inflammatory process, which worsens wound healing.

In addition to the above pathogenetic moments that explain the mechanism of formation of pathological scars, there are still insufficiently studied ones, such as, for example, autoimmune processes. In recent years, using highly sensitive solid-phase enzyme immunoassay, natural autoantibodies to inflammation mediators and to various types of collagen have been discovered, which may indicate the participation 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 non-physiological scars, we should also dwell on the general ones.

Common causes leading to the formation of keloids.

Dysfunction of the endocrine system. The functional state of the adrenal cortex is of primary importance. Keloid scars often occur due to stress. It is known that corticosteroids are stress hormones, they inhibit mitotic and synthetic activity of cells and fibroblasts in particular, but accelerate their differentiation, thereby inhibiting the process of scar tissue formation and prolonging the inflammatory reaction in the wound. Depletion of the adrenal cortex by prolonged stress leads to a deficiency 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 connective tissue, increase mitotic and proliferative activity of its cells, enhance collagen formation, formation of granulation tissue. Excess free testosterone in the blood under the influence of alpha-reductase is converted into dihydrotestosterone, which binds to receptors of epithelial cells of the 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.

Estrogen deficiency contributes to chronic inflammation due to the weakening of reparative processes and collagen formation.

Reduction of overall reactivity

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

Disruption of the regulatory functions of the central nervous system.

As a result, all common causes that contribute to prolonged inflammation lead to the development of unfavorable processes in the wound and give impetus to an increase in the number of fibroblastic cells, the emergence of different populations of fibroblasts with increased metabolism, synthetic and proliferative activity, and, consequently, to increased and prolonged fibrogenesis.

Biochemistry of keloid and hypertrophic scars

The main mass of a keloid scar consists of collagen fibers, which are built from fibrillar proteins - tropocollagen molecules. It is known that collagen synthesis 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 the same as in hypertrophic scars. The average content of pyridine cross-links in keloid collagen is 2 times higher than in hypertrophic scar collagen. In young hypertrophic scars, the increased content of collagen beta chains within 7 years after injury approaches the values of normal skin, in keloid scars such a decrease is not noted.

Keloid scars contain 4 times more calcium than normal skin, a large amount of hyaluronic acid and chondroitin sulfates, which is considered one of the signs of an immature state of connective tissue. Research in recent years has shown that keloid scars and the blood of patients with keloid scars contain a significant amount of transforming growth factor - TGF-beta, consisting of a number of molecules (TGF-beta 1, TGF-beta 2, TGF-beta 3), which activate cellular proliferation, differentiation and stimulate the production of extracellular matrix.

Since scar tissue is primarily composed of collagen fibers and collagen degradation is triggered by highly specialized enzymes called tissue collagenases, the appearance of a scar depends largely on collagenase activity and the collagen-collagenase ratio.

Collagenase produced by fibroblasts and macrophages breaks down collagen, but the resulting peptides stimulate new collagen synthesis in fibroblasts. As a result, the collagen-collagenase ratio changes in favor of collagen. In this case, if, as a result of microcirculation disorders, fresh macrophages stop entering the inflammation site, and old ones lose the ability to secrete collagenase, a real prerequisite for collagen accumulation arises. The formation of fibrous tissue in these cases follows a different path than in cases with normal scars. The activity of pathological, functionally active fibroblasts leads to excessive accumulation of macromolecular components of connective tissue, in particular, collagen, fibronectin, hyaluronic acid and sulfated glycosaminoglycans. The peculiarities of microcirculation in the resulting scar tissue contribute to the accumulation of a large amount of water associated with these molecules, which in combination gives the 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 types are characterized by excessive formation of fibrous tissue and arise as a result of microcirculation disorders, hypoxia, secondary infection, decreased local immunological reactivity, which ultimately leads to a prolonged inflammatory reaction and the transition of adequate physiological inflammation to inadequate. Some patients are found to have endocrinopathies. The clinical and morphological picture of these two types of scars has much in common, but there are also significant differences. The biochemistry of hypertrophic and keloid scars also differ, in particular, in collagen metabolism, which allows us to say that hypertrophic scars occupy an intermediate position in the classification of scars between keloid and physiological scars.