لخّصلي

The current understanding of burn wounds includes three zones of injury: zone of coagulation, zone of stasis, and zone of hyperemia.3 The region of coagulation represents tissue that was destroyed at the time of injury. This is surrounded by a zone of stasis, with inflammation and low levels of perfusion.4 Outside the zone of stasis is a zone of hyperemia, where microvascular perfusion is not impaired.4 Often the area of stasis will progress and become necrotic within the first 48 hours following thermal injury.4 As a result, the initial burn expands in area and depth. Thermal injury induces an immunosuppressed state that predisposes patients to sepsis and multiple organ failure.5

In assessing an approach to treat burn wounds, one must attempt to understand the numerous mechanisms behind the resulting microvascular dysfunction. Three main categories are commonly discussed in the literature. They include thrombosis of vessels due to vascular damage, upregulation of inflammatory mediators, and proapoptotic factors.

Nuclear factor κB (NF-κB), a transcription activator protein, is activated immediately following severe burn injury (SBI) and is thought to regulate the induction of several inflammatory mediators, including tumor necrosis factor (TNF-α).6 Sequestered leukocytes in injured tissues are also thought to be a major source of proinflammatory mediators that cause microvascular damage.4 The products released by tissue injury result in a biphasic response.

The first phase is the predominant proinflammatory phenomena known as systemic inflammatory response syndrome.7 The central element is the macrophage cell and the biochemical cytokines TNF-α and interleukin-6 (IL-6).7 Macrophages are major producers of proinflammatory mediators (ie, prostaglandin E2, reactive nitrogen intermediates, IL-6, TNF-α).5 Furthermore, thermal injury increases the production of these mediators by macrophages.5 Thermal injury also results in prolonged and profound hypermetabolism that involves increased production of proinflammatory cytokines, as well as the formation of reactive oxygen species (ROS), such as superoxide anion, hydroxyl radical, hydrogen peroxide, and reactive nitrogen species, such as nitric oxide (NO) and peroxynitrite.8 TNF-α is responsible in part for inducing apoptosis of various cell elements.7 In addition, proapoptotic factors show increased expression including Bax, Bcl-xl, and caspase-3 activity. Furthermore, epidermal burn injury often triggers significant apoptosis of organ cells, which may be caused by a severe burn-induced systemic inflammatory reaction.TNF-α also involves the antimicrobial defenses by activation of neutrophils and monocytes and also has the capacity to induce the secretion of other proinflammatory mediators, including IL-1 and IL-6.7 However, of these proinflammatory cytokines, only IL-6 has consistently been shown to be elevated systemically post-burn.5 In experimental animal models with third degree burns of either 20 or 40%, serum IL-6 levels peaked during the first hours after injury and were proportionate to the size of area burned.9 During this early stage of burn injury, the inflammatory response can lead to organ failure, called early organ failure.

The second phase of a burn injury is predominantly anti-inflammatory.7 This phase depends on T lymphocytes of helper Th-2 and three principal mediators: the cytokines IL-4/IL-10 and TGF.7 This phase has become known as the counter anti-inflammatory response syndrome.7These previously discussed inflammatory mediators along with the increase of vascular hydrostatic pressure caused by vessel dilation are the major reasons for systemic microvascular leakage observed in burns.10 As a response to inflammation, the endothelial cell junctions widen and gaps form, resulting in compromised barrier functions.11 One known mechanism behind these vascular changes involves actomyosin-dependent actin rearrangement.11 Recently, it was discovered that thermal injury induces generalized venular hyperpermeability and that serum from burned rats induces endothelial cell actin rearrangement, contraction, as well as tight junction damage.12 Studies show that exposure to burn serum results in a significant increase in endothelial permeability in a time-dependent manner, which is paralleled by a rapid and persistent activation of the p38 mitogen-activated protein kinase.13 Inhibition of p38 mitogen-activated protein kinase largely ameliorates resulting vascular dysfunction.11,13 The maintenance of normal vascular permeability depends on the integrity of endothelial barrier function regulated by the interaction of intracellular junctions, cell–matrix adhesion, and the cytoskeleton contractile force.10 Furthermore, kinins, specifically bradykinin, are produced at the burn injury site.6 Bradykinin is a powerful vasoactive mediator that causes venular dilation, increased microvascular permeability, smooth muscle contraction, and pain.6

After thermal injury, tissue adenosine triphosphate levels gradually fall, and increased adenosine monophosphate is converted to hypoxanthine, providing substrate for xanthine oxidase.14 These complex reactions lead to deleterious free radicals, such as superoxide and hydrogen peroxide.14 In addition to xanthine oxidase-related free radical generation in burn trauma, adherent-activated neutrophils produce additional free radicals.14 Free radicals have been found to have beneficial effects on antimicrobial action and wound healing. However following a burn, there is an enormous production of ROS which is harmful and implicated in inflammation, systemic inflammatory response syndrome, immunosuppression, infection and sepsis, tissue damage, and multiple organ failure.15Thus clinical response to burn is dependent on the balance between production of free radicals and their detoxification.15 Enhanced free radical production is paralleled by impaired antioxidant mechanisms, as indicated by burn-related decrease in superoxide dismutase, catalase, glutathione, α-tocopherol, and ascorbic acid levels.15 Burn-related upregulation of inducible NO synthase may produce peripheral vasodilatation, upregulate the transcription factor NF-κB, and promote transcription and translation of numerous inflammatory cytokines.14 NO may also interact with the superoxide radical to yield peroxynitrite, a highly reactive mediator of tissue injury.14 Free radical-mediated cell injury has been supported by post burn increases in systemic and tissue levels of lipid peroxidation products, such as conjugated dienes, thiobarbituric acid reaction products, or malondialdehyde (MDA) levels.14

Burn injury has recently been shown to result in a significant increase of hydrogen sulfide level (P < .01) by 1.31-fold in the plasma.16 This is due to the significant increase in hydrogen sulfide formed in liver after burn injury, which was enhanced by 1.23-fold compared with a control group (P < .01).16 This is significant due to new data supporting the proinflammatory role of hydrogen sulfide.16 Injection of exogenous sodium hydrogen sulfide at the time of burn injury has been shown to significantly aggravate the systemic inflammatory response and increase multiple organ damage.16

Lipid mediators, including eicanosoids and recently discovered “specialized proresolution lipid mediators,” are key signaling molecules in the resolution of inflammation, playing a pivotal role in regulating the inflammatory profile and promoting return to homeostasis following burn.17 Their dysregulation may lead to chronic inflammation and increased tissue damage.17 Furthermore, these molecules have been shown to provide an ancillary treatment to antibiotics by increasing mucosal production of bactericidal peptides and enhancing bacterial phagocytosis by polymorphonuclear cells and macrophages.17