Oxidative stress and reactive oxygen species in burns

Overview¶

Burn injury is among the most powerful pro-oxidant insults in clinical medicine. The thermal wound and the systemic response it provokes trigger the release of reactive oxygen species (ROS), cytokines, and other inflammatory mediators ^[7]. Oxidative stress is the state that follows: a balance between oxidants and antioxidants shifted toward the oxidant side ^[1]. ROS are not merely a byproduct of this process; they are released in both acute and chronic burn wounds and play central roles in healing and regeneration, which makes them both a driver of injury and a participant in repair ^[3].

This dual character defines the clinical problem. The same oxidative chemistry that expands the wound, deepens the stasis zone, and damages distant organs is also woven into normal wound signaling, so the goal is restoration of balance rather than total radical suppression. Burns remain a major cause of death worldwide, with almost 300,000 deaths each year ^[16], and burn trauma still carries a 3% to 8% mortality even with modern care ^[17]. Oxidative injury is one of the threads that runs through the early shock phase, the hypermetabolic response, the immune dysfunction, and the organ failures that account for much of that mortality. This page synthesizes how oxidative stress arises after burns, how it is measured, how endogenous defenses are depleted, and what the antioxidant-therapy literature does and does not support.

Pathophysiology¶

The burn injury triggers the release of multiple mediators, including reactive oxygen species, cytokines, and other inflammatory mediators ^[7]. Several distinct sources feed the oxidant load. Hemolysis is one: after burn, ROS are released as a consequence of red-cell destruction, and the excess ROS cause oxidative stress that harms surrounding healthy tissue and expands the wound area ^[4]. Mitochondria are another, and an increasingly emphasized one. Severe burns provoke massive mitochondrial dysfunction not only in burned skin but also in muscle and internal organs, driven by the release of damage-associated molecular patterns and catecholamines ^[18]. Dysfunctional mitochondria are characterized by increased ROS production and release of mitochondrial DNA, which in turn enhance expression of proinflammatory cytokines ^[18]. This couples the oxidative and inflammatory responses into a self-reinforcing loop.

Neutrophils contribute a third source. In the shock stage of severe burns, neutrophils undergo targeted nuclear degranulation and release neutrophil extracellular traps, a process associated with subsequent lung injury when patients progress to the infection stage ^[9]. The net effect of these converging sources is to drive tissue-level oxidative damage. Oxidative damage induced by ROS leads to protein denaturation ^[19], and lipid peroxidation and ferroptosis contribute to extensive skin damage and delayed repair in thermal wounds ^[20]. At the level of the burn wound itself, oxidative stress and inflammation generate edema ^[21], one of the most clinically visible consequences of the process.

The systemic consequences track this mechanistic picture. Burn shock with its severe inflammatory response, oxidative stress, and hypermetabolic state is accompanied by extensive exudation, and the combination produces considerable loss of macro- and micronutrients, including essential trace elements ^[5]. The inflammatory and free-radical processes set in motion after injury drive the progression of oxidative stress, and the inhibition of that progression depends largely on an adequate supply of antioxidants and minerals ^[6] — a point that frames the entire therapeutic discussion below.

Biomarkers and Assessment¶

Oxidative stress in burns is assessed through markers of oxidative damage and markers of antioxidant capacity. The most widely used damage marker is malondialdehyde (MDA), an end-product of lipid peroxidation. Studies of severe burns measure MDA alongside total antioxidant capacity (T-AOC) and superoxide dismutase (SOD): serum T-AOC and SOD levels in burned patients run lower than controls while MDA runs higher ^[8]. The clinical interest in these markers comes from their correlation with outcome. The degree of wound healing is positively correlated with T-AOC and SOD and negatively correlated with MDA, and all three carry value in predicting the degree of postoperative wound healing ^[8].

A broader marker panel appears across the literature. Total antioxidant status, total oxidant status, vitamin E, the DNA-oxidation marker 8-hydroxy-deoxyguanosine, and coenzyme Q10 have all been analyzed in serum after burn ^[2]. Protein oxidation can be quantified by advanced oxidation protein products (AOPP); in one cohort, AOPP levels in second- and third-degree thermal burns fell significantly after treatment ^[22]. Trace-element status is also part of the assessment picture: serum concentrations of elements important for antioxidant protection (zinc, copper, selenium) decrease significantly after burn while toxic elements such as aluminum and nickel increase, changes that may aggravate burn shock ^[12].

These tools have limits that the literature names directly. Antioxidant-capacity assays have shown poor sensitivity: in one study of severely burned patients, total antioxidant capacity did not correlate with burned surface area or clinical evolution, suggesting the method is poorly suited to studying this condition ^[23]. High-dose ascorbic acid therapy, discussed below as a treatment, also interferes with point-of-care glucose monitoring and tight glycemic control ^[24], a measurement caveat with direct clinical consequences.

Antioxidant Defense and Its Depletion¶

The body counters oxidants with enzymatic defenses (superoxide dismutase, catalase, glutathione peroxidase), small-molecule antioxidants (glutathione, vitamins C and E), and plasma scavenger proteins. Burn injury depletes all of these. Plasma scavenger proteins such as haptoglobin, hemopexin, and transferrin normally neutralize ROS by binding free hemoglobin, heme, and iron respectively ^[4], but in severe burns endogenous levels of these scavenging proteins may be insufficient to keep pace with the hemolytic byproducts generated ^[4].

The trace-element substrate for enzymatic defense is also lost. The severe inflammatory response, oxidative stress, hypermetabolic state, and extensive exudation of burns produce a considerable loss of essential trace elements ^[5]. Many trace elements involved in immune function, gene-expression regulation, and antioxidant defense have not been properly investigated in the clinical setting ^[5], and the depletion leads to complications including more frequent infections and impaired wound healing ^[5]. Because the inhibition of oxidative-stress progression depends on an adequate supply of antioxidants and minerals ^[6], this depletion is the rationale that underlies supplementation strategies. The antioxidant-depletion picture also intersects with burn immune dysfunction: burn shock can produce immunosuppression with increased susceptibility to fatal infections ^[25], and that immunosuppression includes apoptosis-induced lymphopenia, decreased IL-2 secretion, a neutrophil storm, impaired phagocytosis, and decreased monocyte HLA-DR ^[25].

Organ-Specific Oxidative Injury¶

Oxidative injury is not confined to the wound; it reaches distant organs and contributes to the organ failures that complicate severe burns. The lung is a prominent target. Neutrophil extracellular trap release in the burn shock stage is associated with acute lung injury when patients progress to infection ^[9], and experimental insults that amplify oxidative stress, such as seawater immersion, aggravate burn-associated lung injury and inflammatory and oxidative-stress responses ^[26]. Smoke inhalation, which carries its own oxidant burden, increases overall burn mortality by up to 20-fold ^[27].

The kidney is a second target. Burn-induced acute kidney injury involves inflammatory programmed cell-death pathways including PANoptosis ^[28], and in a rat burn-AKI model renal oxidative stress peaked at 48 hours alongside renal dysfunction and injury ^[28]. High-voltage electrical burns produce AKI in which neutrophils and inflammation drive the damage ^[10]. The liver is a third: aged burn animals exhibit severe liver damage from heightened lipid peroxidation and an inadequate antioxidative response ^[11]. Across these organs the common thread is the same oxidant-antioxidant imbalance described in the wound, which makes systemic oxidative stress a unifying mechanism behind multi-organ involvement after burns.

Antioxidant Therapy¶

Antioxidant supplementation is the principal therapeutic application of this biology, and the literature on it is large, mechanistically coherent, and clinically unsettled. High-dose intravenous vitamin C has the most developed clinical rationale. Vitamin C is a scavenger of oxygen free radicals in the endothelium and can limit the inflammatory response and ischemia-reperfusion injury while promoting wound healing ^[29]. Several animal studies and clinical trials have shown that high-dose intravenous vitamin C may reduce fluid requirements, body-weight gain, and wound edema while improving gas exchange and renal function in the acute phase after burn injury ^[29]. The evidence-strength characterization in the literature, however, is cautious; the utility of antioxidants in burn treatment remains unclear ^[14].

N-acetylcysteine (NAC), a glutathione precursor, has been tested directly in severe burns. In a controlled study, NAC treatment increased glutathione levels on days 4–5 and protein-sulfhydryl levels on days 2–6 compared with controls ^[21]; plasma IL-6 was lower in the NAC group on days 4–5, and IL-8 and IL-10 were lower on days 4–6 ^[21]; and the NAC group required fewer catecholamines from day 4, although without a significant difference in multiple-organ-dysfunction score ^[21]. The authors concluded that NAC is associated with diminished oxidative stress, lower inflammation, and less vasopressor requirement ^[21]. Vitamin E has a parallel literature: one review concluded that enteral or parenteral vitamin E supplementation can prevent, mitigate, and even reverse the effects of thermal burn injury, infection, and sepsis ^[30], while noting that a large-scale prospective study is warranted before practice changes ^[30].

Trace-element and combination strategies round out the field. A randomized, double-blind, placebo-controlled pilot in burned children found that supplementation with vitamins E and C and zinc decreased lipid peroxidation and increased vitamin E concentrations ^[31] and shortened healing time, apparently by enhancing antioxidant protection against oxidative stress ^[31]. Selenium repletion is supported on the rationale that early administration of a consistent selenium amount can improve glutathione-peroxidase activity and help prevent impairment of antioxidant status ^[32]. In critical illness more broadly, two meta-analyses suggested a trend toward reduced mortality with selenium supplementation ^[13], and selenium may be associated with reduced mortality through its support of antioxidant function ^[13]. Beyond systemic supplementation, antioxidant chemistry also shapes topical-agent behavior: silver sulfadiazine, while effective at reducing oxidative stress, was less successful at promoting wound healing and appeared to delay granulation and fibrosis in an experimental comparison ^[2].

Special Considerations¶

Age modifies the oxidative response to burns. Aged burn animals show heightened hepatic damage driven by greater lipid peroxidation and an inadequate antioxidative response ^[11], and burn-induced oxidative stress in lung tissue is significantly higher in elderly than in adult animals ^[15]; in that model pentoxifylline reduced the augmented injury ^[15]. These findings suggest the antioxidant-defense reserve that younger hosts draw on is diminished with age.

Diabetes is a second modifying condition, where impaired healing and excess oxidative stress compound each other; atmospheric-plasma treatment that controlled inflammation and oxidative stress accelerated tissue healing in diabetes-induced burn wounds in one model ^[33]. Chemical and ocular burns form a distinct injury context dominated by oxidative mechanisms: the cornea is injured by alkali-induced oxidative disturbances and an inflammatory response ^[34], and corneal alkali-burn-induced neovascularization, which can lead to blindness, is driven by pro-inflammatory and pro-angiogenic factors after ocular surface damage ^[35]. Electrical burns behave differently from thermal burns with respect to antioxidant response, a distinction taken up in the controversies below.

Controversies and Evidence Gaps¶

The central unresolved question is whether the strong mechanistic rationale for antioxidant therapy translates into patient benefit. The position stated plainly in the critical-care literature is that the utility of antioxidants in burn treatment remains unclear ^[14]. The mortality question is the sharpest version of this gap: no trial has demonstrated a statistically significant improvement in mortality with antioxidant micronutrient therapy, even as meta-analyses hint at a trend ^[13]. Early evidence for specific agents is repeatedly described as promising but requiring confirmation from larger trials ^[36]. The vitamin C literature carries an additional definitional problem: future research is urged to distinguish therapeutic high-dose ascorbic acid antioxidant therapy from nutritional parenteral-nutrition requirements ^[37], because the two are easily conflated.

Burn etiology may matter. Antioxidant treatment may be advantageous in minimizing injury in thermal burns but not always in electrical burns ^[38], cautioning against a uniform approach across burn types. The wound-progression question is also long-standing and unsettled: it remains controversial whether free-radical scavengers can prevent the progressive dermal ischemia of the postburn stasis zone ^[39]. Measurement is a further gap; antioxidant-capacity assays have shown poor sensitivity for studying this pathology ^[23], which complicates trial design that depends on such endpoints. The overall state of the field was anticipated decades ago and has not fully resolved: the available information indicates oxidants may well play a key role and antioxidants may be of clinical therapeutic use ^[40], a hypothesis that remains mechanistically robust and clinically contested.

References¶

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