Skin Burns: Review of Molecular Mechanisms and Therapeutic Approaches

Ahad Ferdowsi Khosroshahi, PhD; Jafar Soleimani Rad, PhD; Raziyeh Kheirjou, PhD student; Mohammad Reza Ranjkesh, MD; Leila Roshangar, PhD

Disclosures

Wounds. 2019;31(12):308-315. 

In This Article

Factors Affecting Burn Wounds

Wound healing starts with the expression of various chemokines that initiate a topical response to constrict the impaired area. This topical response is associated with inflammation and local infection, which starts with sympathetic stimulation and may lead to hypovolemia, renal failure, and myocardial dysfunction. Progressive organ dysfunction is accompanied by a high mortality rate.[11,12] Patient-dependent factors such as nutrition, resuscitation, aging, oxygen therapy, and stress can play a crucial role in the systemic response. When the topical pathways become insufficient for a therapeutic response, a systemic response is induced.

Local Factors and Responses in Burn Injuries

Cytokines. Cytokines are a broad category of proteins, which are secreted by certain cells of the immune system and interact with cell signaling. They include ILs, lymphokines, and signaling molecules (eg, interferons and TNF-α). Chemokines or chemotactic cytokines are small cytokines that can induce direct migration of leukocytes to the wound area (chemotaxis). For example, IL-1α, IL-1β, IL-6, and TNF-α may control various processes in the wound area, including keratinocyte and fibroblast proliferation and differentiation, synthesis and destruction of extracellular matrix (ECM) proteins, and immune response regulation. In the inflammatory phase of wound healing, macrophages and neutrophils are the major sources of these cytokines.[6,13,14]

Growth Factors. Growth factors are several classes of endogenous signaling molecules that regulate cellular responses to wound healing processes. They consist of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), transforming growth factor beta (TGF-β), granulocyte-macrophage colony-stimulating factor (GM-CSF), and amnion-derived cellular cytokine solution (ACCS). Growth factors play a role in many biological processes, such as proliferation, migration, chemotaxis of fibroblasts and inflammatory cells, stimulation of endothelial cells, and angiogenesis. They interact with the production of the ECM, which inhibits apoptosis, and mediate synthesis of other cytokines and growth factors (Table 1[6,15]). Growth factors and cytokines have therapeutic importance in burn wounds to accelerate wound healing; however, they may not be effective in healing extensive and/or deeper burn wounds. While not well understood, it seems the use of these factors applied with skin grafts may be helpful in severe burn wounds.[6,13,15]

Oxidative Stresses. A severe burn is associated with the secretion of free radicals (ROS and RNS) that cause local and systemic pathophysiological responses in burns. Research has shown released ROS and RNS could protect the wound area against infection.[16,17] On the other hand, increased ROS secretion is associated with immunosuppression, systemic inflammatory response syndrome (SIRS), infection, sepsis, tissue damage, and multiple organ failure.[17] Thus, burn wound improvement depends on the balance between secretion and excretion of free radicals. Particularly, lipid peroxidation of cell membrane polyunsaturated fatty acids with free radicals activates the accumulation of cytotoxic products, such as lipid-derived aldehydes (LDAs). Hydroxynonenal, malondialdehyde, and acrolein are toxic LDAs that interact with normal cell functions such as cell signal transduction, DNA synthesis, and enzyme activities. They cause severe damage to DNA, resulting in genotoxic and mutagenic alternation. Therefore, oxidative stress is an important mechanism in the development of burns. Some studies[18–20] also suggest proinflammatory cytokines (IL-6 and TNF-α) release chemokines, (IL-8), leading to a continuous cascade of ROS and producing severe cellular injuries.

Inflammation. Within the burn area, inflammatory mediators increase the vascular hydrostatic pressure, leading to vessel dilation and systemic edema. As a response to inflammation, the endothelial cell junctions are disjointed and the cell membrane barrier functions are disrupted. It has been shown that thermal injury alters reorganization and contraction of endothelial cell actin and induces general vascular hyperpermeability. It also causes the formation of stress fibers in endothelial cells as well as disruption of integrity of the endothelial barrier.[21] Furthermore, kinins, specifically bradykinin released from mast cells, cause vasodilation, smooth muscle contraction, and increased microvascular permeability.[22] Not surprisingly, in the first week following a burn injury, bacteria can grow within the wound area and infections of the skin and soft tissue commonly occur early in hospitalization.[23] This can cause a prolonged inflammatory phase associated with increased levels of matrix metalloproteases (MMPs) and the breakdown of collagen and ECM. If the inflammatory phase takes longer, the wound may enter a chronic state that fails to heal (Figure).[24]

Infection. The skin acts as a barrier from the external environment to maintain homeostasis and body temperature. Any type of damage to this barrier can disrupt the immune system and increase its susceptibility to bacterial infection. Infection leads to delayed wound treatment, prolonged hospitalization, and increased costs and mortality rate.[25] In vitro research has demonstrated bacterial infection in burn wounds can colonize to other tissues after 5 to 7 days and exacerbate to sepsis and death.[26] Burn wound infections have been widely investigated in the literature. The rate of systemic infections and mortalities have decreased since the development of topical antibiotics (eg, silver sulfadiazine).[27] Moreover, bacterial culture also has helped identify appropriate antibiotics for the invasive bacterial species.[28] However, fungi are a culprit for infections with high mortality rates in severe burn wounds.[29]

Systemic Factors in Burn Injuries

Systemic Inflammatory Response Syndrome. This syndrome is a common inflammatory condition associated with various injuries, such as infection, trauma, and burns. The probability of SIRS increases 3-fold in patients with burns with a total body surface area (TBSA) of more than 30% and is characterized by elevated levels of IL-6, IL-2, and IL-8. The released cytokines induce the synthesis of prostaglandin E2 (PGE2), IL-6, and platelet-activating factor by endothelial cells and macrophages in cutaneous burns. Expression of PGE2 suppresses the lymphocyte reactivity and provokes TH cells to differentiation to T suppressor. Therefore, this alternation in lymphocyte population inhibits pro-inflammatory cytokines such as IL-2 and IL-1β.[30,31]

Patient-dependent Factors in Burn Injuries

Oxygen Supply. Oxygen is essential for cell metabolism, adenosine triphosphate production, and wound healing. In the early phases (hemostasis and inflammatory phase), the oxygen supply to burned tissue is important for neutrophilic function because it produces ROS required to inhibit bacterial colonization and wound infection. Furthermore, ROS, such as superoxide and hydrogen peroxide, act as free radicals that help wound healing via PDGF signal transduction, angiogenesis, and cell migration. Because of vascular impairment and high oxygen demand, the microenvironment of the burn wound is susceptible to hypoxia. Some cytokine and growth factors (eg, VEGF, TNF-α, PDGF, TGF-β, and endothelin-1) are generated through hypoxia from macrophages, fibroblasts, and keratinocytes, which are important in the development of chemotaxis and proliferation of cells in burn wound healing.[11,32,33]

Nutrition. Severe burns cause hypermetabolism, which is also a consequence of several hormonal changes. Burn trauma stimulates major increases in catabolic hormones (eg, epinephrine, cortisol, and glucagon) and accelerates gluconeogenesis, glycogenolysis, and muscle proteolysis. Catabolic hormones neutralize the effect of insulin and raise blood sugar levels; protein synthesis and lipogenesis are inhibited. Similarly, growth hormone is antagonized and less effective.[34] Therefore, in burn wound healing, prevention of hypermetabolic conditions and good nutritional support are determinant factors.[35]

Nutritional support in burn injuries is complicated and includes several nutritional possibilities. For example, excessive utilization of carbohydrates may cause hyperglycemia, which causes systemic inflammation and muscle damage. Also, excessive intake of fatty acids results in immunosuppression that can impose serious risks of infection and sepsis. It has been shown vitamins and insulin administration reduce protein catabolism, increase protein synthesis, and consequently, improve healing time.[36,37] Insulin also can be replaced with other recombinant growth factors (EGF and TGF) in wound healing, however, the use of such factors is still controversial and expensive.[38,39]

Resuscitation. Severe thermal wounds (> 20% TBSA) require fluid resuscitation. The purpose of fluid resuscitation is to maintain the perfusion of all organs with a minimal volume of liquid. Traditional resuscitation fluid includes modified Brock and Park formulations, crystalloid solutions (lactate ranger containing sodium, chloride, calcium, potassium, and lactate), and colloid solutions (fresh frozen plasma, albumin).[40]

Aging. Aging is recognized as a common cause of a temporary interruption in wound healing, but it does not seriously endanger wound healing. Aging leads to a change in the inflammatory reaction, such as lower macrophage phagocytic capacity, T-cell infiltration into the wound site, and chemokine production. In addition, reduction of collagen synthesis and reassembly, wound angiogenesis, and re-epithelialization were observed in aged mice.[41,42]

Stress. Stress impacts human health in different ways as seen in many diseases and impaired wound healing. Stress reduces the level of pro-inflammatory cytokines and decreases the expression of chemoattractant factors such as IL-1α and IL-8 at the wound site, which are important for the initiation of the inflammatory phase of wound healing.[43]

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