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Severity of thermal burn injury is associated with systemic neutrophil activation

ABSTRACT: Burn injuries elicit a unique and dynamic stress response which can lead to burn injury progression. Though neutrophils represent crucial players in the burn-induced immunological events, the dynamic secretion pattern and systemic levels of neutrophil-derived factors have not been investigated in detail so far. Serum levels of neutrophil elastase (NE), myeloperoxidase (MPO), citrullinated histone H3 (CitH3), and complement factor C3a were quantified in burn victims over 4 weeks post injury. Furthermore, the potential association with mortality, degree of burn injury, and inhalation trauma was evaluated. In addition, leukocyte, platelet, neutrophil, and lymphocyte counts were assessed. Lastly, we analyzed the association of neutrophil-derived factors with clinical severity scoring systems. Serum levels of NE, MPO, CitH3, and C3a were remarkably elevated in burn victims compared to healthy controls. Leukocyte and neutrophil counts were significantly increased on admission day and day 1, while relative lymphocytes were decreased in the first 7 days post burn trauma. Though neutrophil-derived factors did not predict mortality, patients suffering from 3rd degree burn injuries displayed increased CitH3 and NE levels. Accordingly, CitH3 and NE were elevated in cases with higher abbreviated burn severity indices (ABSI). Taken together, our data suggest a role for neutrophil activation and NETosis in burn injuries and burn injury progression. Targeting exacerbated neutrophil activation might represent a new therapeutic option for severe cases of burn injury.

SUBMITTER: Laggner M

PROVIDER: S-EPMC8803945 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleMitochondria have important roles in intracellular energy generation, modulation of apoptosis, and redox-dependent intracellular signaling. Although reactive oxygen species (ROS) participate in the regulation of intracellular signaling pathways, including activation of nuclear factor (NF)-kappaB, there is only limited information concerning the role of mitochondrially derived ROS in modulating cellular activation and tissue injury associated with acute inflammatory processes.ObjectivesTo examine involvement of the mitochondrial electron transport chain complex I on LPS-mediated NF-kappaB activation in neutrophils and neutrophil-dependent acute lung injury.MethodsNeutrophils incubated with rotenone or metformin were treated with bacterial lipopolysaccharide (LPS) to determine the effects of mitochondrial complex I inhibition on intracellular concentrations of reactive oxygen species, NF-kappaB activation, and proinflammatory cytokine expression. Acute lung injury was produced by intratracheal injection of LPS into control, metformin, or rotenone-treated mice.Measurements and main resultsInhibition of complex I with either rotenone or the antihyperglycemic agent metformin was associated with increased intracellular levels of both superoxide and hydrogen peroxide, as well as inhibition of LPS-induced I kappaB-alpha degradation, NF-kappaB nuclear accumulation, and proinflammatory cytokine production. Treatment of LPS-exposed mice with rotenone or metformin resulted in inhibition of complex I in the lungs, as well as diminished severity of lung injury.ConclusionsThese results demonstrate that mitochondrial complex I plays an important role in modulating Toll-like receptor 4-mediated neutrophil activation and suggest that metformin, as well as other agents that inhibit mitochondrial complex I, may be useful in the prevention or treatment of acute inflammatory processes in which activated neutrophils play a major role, such as acute lung injury.

Project description:BACKGROUND:We identified recently esophageal cancer related gene-4 (ECRG4) as a candidate cytokine that is expressed on the surface of quiescent polymorphonuclear leukocytes (PMNs) and shed in response to ex vivo treatment with lipopolysaccharide. To investigate the potential biologic relevance of changes in cell surface ECRG4 in human samples, we performed a pilot study to examine a population of burn patients in whom blood could be analyzed prospectively. We hypothesized that cutaneous burn injury would alter cell surface expression of ECRG4 on PMNs. METHODS:Patients admitted with more than 20% total burn surface area (TBSA) (n?=?10) had blood collected at the time of admission and weekly thereafter. For comparison, blood was obtained from a control group of healthy human volunteers (n?=?4). We used flow cytometry to measure changes in ECRG4(+) PMNs from patients during recovery from injury. Esophageal cancer related gene-4 expression at each time point was compared with the patient's clinical status based on a Multiple Organ Dysfunction (MOD) score. RESULTS:Esophageal cancer related gene-4 was detected on the PMN surface of cells collected from healthy volunteers, however, within 48?h of admission after burn injury (n?=?10 patients), the number of PMNs with cell surface ECRG4 was decreased. Esophageal cancer related gene-4 expression in PMNs was re-established over the course of patient recovery, unless complications occurred. In this case, the decrease in cell surface ECRG4(+) PMNs preceded the clinical diagnosis of infectious complications and was reflected by increased organ injury scores. CONCLUSION:From a small sample set, we were able to determine that PMN cell surface ECRG4 expression was decreased after burn injury and returned to baseline during recovery from injury. Although larger studies are needed to define the role of ECRG4 in human PMNs further, this report is the first assessment of cell surface ECRG4 protein in a patient population to support analogous findings in animal studies.

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Severity of thermal burn injury is associated with systemic neutrophil activation

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