Stages and course of the wound process

When speaking about local reactions, various authors agree that three main stages of the wound healing process should be distinguished. Thus, Chernukh AM (1979) distinguished the stage of damage, the stage of inflammation and the stage of recovery. Serov VV and Shekhter AB (1981) divided the wound healing process into stages: traumatic inflammation, proliferation and regeneration, and scar formation.

From our point of view, the allocation of these stages is conditional, since in the depths of the previous stage, conditions are created for the formation of the subsequent one. In addition, the healing process of a skin wound depends, and quite radically, on many factors. In particular, on the nature of the damaging agent; the location, depth and area of damage: contamination with pyogenic flora; adaptive abilities and immunity; age and concomitant diseases. Therefore, the course of the wound process with the same injury in different people can go differently and, ultimately, lead to a completely different outcome - scars of group No. 1 or keloid and hypertrophic.

The most severe injuries in terms of consequences are associated with:

• with the impact of physical (thermal, cold, radiation) and chemical (acids, alkalis) factors on the skin;
• with crushing of soft tissues;
• with wound infection;
• with contamination of wounds with soil;
• with stress-related injuries;
• with impaired neurohumoral and endocrine regulation in patients.

As a rule, such injuries result in a protracted process of tissue reparation and, as a consequence, keloid or hypertrophic scars, cicatricial deformities and contractures.

Inflammation

Inflammation is a stereotypical protective and adaptive local vascular tissue reaction of living systems to the action of pathogenic irritants that caused damage that arose during evolution.

As its main components, it includes changes in blood circulation, mainly the microcirculatory bed, increased vascular permeability, migration of leukocytes, eosinophils, macrophages, fibroblasts to the damage zone and their active activity in it, aimed at eliminating the damaging factor and restoring (or replacing) damaged tissues. Thus, inflammation in its biological essence is a protective reaction of the body. Skin inflammation is conventionally divided into immune and non-immune. Skin injuries cause the development of non-immune inflammation. Since any injury to the skin is accompanied by an inflammatory reaction, the stages of the wound process can be equated to the stages of inflammation. According to the form of the inflammatory reaction, such inflammation is classified as alterative, since it is characterized by acute damage to the skin.

Stages of inflammation

According to many researchers, the most accurate reflection of the course of the wound process and inflammatory reaction is provided by the classification of Strukov A.I. (1990), who identified 3 phases of inflammation:

1. Damage or alteration phase.
2. Exudation phase (vascular reaction).
3. Recovery or proliferation phase

The first phase of damage or alteration is characterized by a destructive process accompanied by the death of cells, vessels and the release of a large number of inflammatory mediators and blood into the wound. Inflammatory mediators are a widespread group of biologically active substances, which include such substances as serotonin, histamine, interleukins, lysosomal enzymes, prostaglandins, the Hageman factor, etc. Their most important representatives are eicosanoids, the precursor of which is arachidonic acid - an essential fatty acid that is part of the phospholipids of cell walls. Injury causes the destruction of cell membranes with the appearance of a large amount of "raw material" for the formation of inflammatory mediators. Eicosanoids have extremely high biological activity. Such types of eicosanoids as prostaglandins type E, prostacyclin (prostaglandin I), thromboxanes, leukotrienes participate in the development of inflammation. They promote vascular dilation and thrombus formation; increase the permeability of the vascular wall, enhance the migration of leukocytes, etc.

Damage to the capillary endothelium causes the appearance of substances that stimulate polymorphonuclear leukocytes, which in turn increase the damage to the vascular wall. All this leads to a slowdown in blood flow, and then to its complete cessation.

The second phase or exudation phase is characterized mainly by the reaction of the vascular bed and cells, the release of formed elements and the liquid part of the blood and lymph into the extravascular area. Leukocytes, erythrocytes, lymphocytes appear in the wound along with cellular detritus and connective tissue cellular and structural elements. Cellular clusters represent an inflammatory infiltrate consisting mainly of polymorphonuclear leukocytes, lymphocytes, macrophages, mast cells. In the wound, there is active reproduction of cells participating in the inflammatory process - mesenchymal, adventitial, endothelial, lymphocytes, fibroblasts, etc. The wound continues to be cleansed of tissue detritus and bacterial flora. New formation of vessels occurs, which are the basis of granulation tissue.

In more detail, this phase can be divided into several stages:

Vascular stage. Characterized by short-term spasm (up to 5 min.) and subsequent dilation of skin capillaries, which is accompanied by increased permeability of capillaries and postcapillary venules of the affected area. Stasis in the vessels, occurring after the slowdown of blood circulation, leads to marginal standing of leukocytes, formation of aggregates, their adhesion to the endothelium and release of leukokinins into the contact zone with the endothelium, increasing the permeability of microvessels and creating conditions for the filtration of plasma chemotaxins and the release of blood cells into the inflammation site. Neutrophils themselves release pseudopodia (cytoplasmic processes) and get out of the vessel, helping themselves with enzymes (cathepsin, elastase, etc.). Clinically, this stage is manifested by edema.

Cellular stage. Characterized by diapedesis, through the widened intercellular gaps of capillaries, into the wound of neutrophilic leukocytes, the process of accumulation of which in the skin defect begins already 2-3 hours after the injury. Polymorphonuclear leukocytes have an extremely high phlogogenic potential, manifested by hyperproduction and hypersecretion of lysosomal hydrolases (prostaglandins), leukotrienes, active forms of oxygen, causing additional damage to the endothelium and microcirculation disorder. Along with this, neutrophils are a source of factors with the help of which other cells, including platelets, mast cells, eosinophils, mononuclear cells join the inflammation process. They also have special receptors for IgG and C, due to which at this stage of exudative-destructive inflammation cooperative connections are formed between polymorphonuclear leukocytes-effectors and humoral mediators and, first of all, the complement system. This occurs due to the autoactivation of factor XII or Hageman factor (HF), inducing blood coagulation processes, fibrinolysis, activation of the kallikrein-kinin system. Of all the plasma mediator systems that are included in the event of endothelial damage, the complement system is of primary importance. Its activation occurs when C binds to IgG, after which C becomes an active serine proteinase. However, complement activation can also be plasmin, C-reactive protein, crystals of monosodium urate, and some bacterial glycolipids. Binding and activation of C leads to the formation of C1 esterase (CI _s ), which cleaves the second protein of the cascade - C into C4a and C4b. The third protein involved in complement activation is C2. It is also cleaved by activated C1, attaching to the C4b fragment. The resulting fragment C2a, connecting with C4b, acquires enzymatic activity (C3 convertase) and cleaves C3 into 2 fragments - C3a and C3b.

СЗb combines with the complement component C5 _, which disintegrates into С5а and С5b. С5а, like СЗb, passes into the liquid phase. Thus, fragments of С5а and СЗb are formed, which have chemotactic properties, which become plasma mediators of inflammation. Mast cells, secreting histamine, serotonin, and chemotaxin for eosinophils, are connected to the inflammation via С5а and СЗа. С5а causes an increase in vascular permeability, initiates chemotaxis of neutrophils and monocytes, aggregation of neutrophils and attachment to the walls of capillaries. Phlogogens secreted by polymorphonuclear leukocytes, including thrombogenic factors, contribute to thrombosis of microvessels, which leads to rapid necrosis of perivascular tissues and the formation of reactive polynuclear infiltrates. Tissue decay products, auto- and xenoantigens in turn activate polymorphonuclear leukocytes, monocytes, macrophages and mast cells, which causes neutrophil degranulation, secretion of biologically active substances by monocytes, macrophages and polymorphonuclear leukocytes. Protein kinases accumulate in the wound, causing further degranulation of mast cells, activation of complement, platelet activating factor, interleukins, interferons alpha and beta, prostaglandins, leukotrienes. The entire cascade of biologically active molecules activate fibroblasts, T and B lymphocytes, neutrophils, macrophages, which leads to stimulation of enzymatic and antibacterial activity in the wound. While promoting tissue necrosis to some extent, neutrophils at the same time clear the damaged area of infection and decay products of autolytic cells. When the inflammation process is prolonged, possibly at the level of a genetically determined defect, the inflammation site takes a torpid course, it becomes “chronic”, the neutrophilic period of the cellular stage is extended and the fibroplastic process is inhibited.

The predominance of neutrophils in the wound is replaced by the predominance of macrophages, the migration of which into the wound is provoked by neutrophils.

Mononuclear phagocytes, or macrophages, provide largely nonspecific protection of the body due to their phagocytic function. They regulate the activity of lymphocytes and fibroblasts. They secrete nitric oxide (NO), without which epithelial cells cannot begin migration, despite the presence of growth factors in the medium. The wound contains a large number of growth factors. Platelet-derived growth factor stimulates proliferation of cells of mesenchymal origin, such as fibroblasts. Transforming growth factor-beta stimulates chemotaxis of fibroblasts and their production of collagen. Epidermal growth factor enhances proliferation and migration of keratinocytes, transforming growth factor-alpha affects angiogenesis, keratinocyte growth factor stimulates wound healing. Basic fibroblast growth factor - has a positive effect on the growth of all cell types, stimulates the production of proteases, chemotaxis of fibroblasts and keratinocytes, and the production of extracellular matrix components. Cytokines secreted by cells in the wound, activated by proteases and other biologically active molecules, perform effector and regulatory functions. In particular, interleukin-1 promotes the activation of T-lymphocytes, affects the production of proteoglycans and collagen by fibroblasts. The activated T-lymphocyte produces and secretes interleukin-2, stimulating the T-lymphocyte. In turn, the T-lymphocyte produces interferon-alpha, activating the function of macrophages and the production of interleukin-1.

Recovery or proliferation phase

This phase is also called reparative, since cell proliferation and collagen secretion continue at the site of injury, aimed at restoring homeostasis and closing the wound defect. The emphasis of the cellular spectrum in this phase shifts towards proliferation, differentiation and transformation of fibroblasts and proliferation of keratinocytes. It is known that the faster the inflammation is stopped as a response of the body to damage to the integrity of the skin and the wound defect is closed by fibrous and cellular structures of connective tissue with subsequent epithelialization, the more favorable the scar will look. Granulation tissue, which formed at the site of the former skin defect, healing by secondary intention, is loops of newly formed vessels surrounded by glycosaminoglycans and cellular elements. In the process of completing inflammation and as a result of fibrous transformations, it is organized into scar tissue.

The less deep the injury, the faster the inflammation is stopped as a response of the body to the damage, the faster the epithelialization of the wound defect occurs, the more favorable the scar looks. In infected, long-term non-healing wounds, as well as in the presence of predisposing factors, the inflammatory reaction becomes chronic and adequate inflammation turns into inadequate. Local immune shifts in the body of such patients are manifested in a decrease in the number of mast, plasma and lymphoid cells in the granulating wound. Inadequate inflammation does not limit itself, has a protracted course, is characterized by excessive formation of inflammation mediators, hypoxia, decreased phagocytic activity of cells, proliferation of certain populations of fibroblasts, which are distinguished by high metabolism and collagen synthesis. As a result, such inflammation ends with the formation of keloid or hypertrophic scars.

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