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Severe burn injuries are defined by a prolonged hypermetabolic response characterized by increases in resting energy expenditure, systemic catabolism, and multi-organ dysfunction. The sustained elevation of catecholamines following a burn injury is thought to significantly contribute to this hypermetabolic response, leading to changes in adipose tissue such as increased lipolysis and the browning of subcutaneous white adipose tissue (WAT). Failure to mitigate these adverse changes within the adipose tissue has been shown to exacerbate the post-burn hypermetabolic response and lead to negative outcomes. Propranolol, a non-selective ß-blocker, has been clinically administered to improve outcomes of pediatric and adult burn patients, but there is inadequate knowledge of its effects on the distinct adipose tissue depots. In this study, we investigated the adipose depot-specific alterations that occur in response to burn injury. Moreover, we explored the therapeutic effects of ß-adrenoceptor blockade via the drug propranolol in attenuating these burn-induced pathophysiological changes within the different fat depots. Using a murine model of thermal injury, we show that burn injury induces endoplasmic reticulum (ER) stress in the epididymal (eWAT) but not in the inguinal (iWAT) WAT depot. Conversely, burn injury induces the activation of key lipolytic pathways in both eWAT and iWAT depots. Treatment of burn mice with propranolol effectively mitigated adverse burn-induced alterations in the adipose by alleviating ER stress in the eWAT and reducing lipolysis in both depots. Furthermore, propranolol treatment in post-burn mice attenuated UCP1-mediated subcutaneous WAT browning following injury. Overall, our findings suggest that propranolol serves as an effective therapeutic intervention to mitigate the adverse changes induced by burn injury, including ER stress, lipotoxicity, and WAT browning, in both adipose tissue depots. KEY MESSAGES: Burn injury adversely affects adipose tissue metabolism via distinct changes in both visceral and subcutaneous adipose depots. Propranolol, a non-selective ß-adrenergic blocker, attenuates many of the adverse adipose tissue changes mediated by burn injury.
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ABSTRACT: Hypermetabolic reprogramming triggered by thermal injury causes substantial morbidity and mortality. Despite the therapeutic potential of targeting this response, the underlying mechanisms remain poorly understood. Interestingly, protein S-acylation is a reversible posttranslational modification induced by metabolic alterations via DHHC acyltransferases. While this modification aids in the regulation of cellular functions, deregulated S-acylation contributes to various diseases by altering protein structure, stability, and localization. However, whether and how S-acylation may impact morbidity and mortality during postburn hypermetabolism is unknown. In this study, we discovered that alterations in the acyl proteome play a key role in mediating adverse outcomes that occur after burn injury. Using a murine model, we show that burn injury induces profound changes in the expression of various DHHC isoforms in metabolic organs central to regulating postburn hypermetabolism, the adipose tissue, and liver. This was accompanied by increased levels of S-acylated proteins in several pathways involved in mediating the adverse hypermetabolic response, including ER stress, lipolysis, and browning. In fact, similar results were also observed in adipose tissue from severely burned patients, as reflected by increased S-acylation of ERK1/2, eIF2a, ATGL, FGF21, and UCP1 relative to nonburn controls. Importantly, pharmacologically targeting this posttranslational modification using a nonselective DHHC inhibitor effectively attenuated burn-induced ER stress, lipolysis, and browning induction in an ex vivo explant model. Together, these findings suggest that S-acylation may facilitate the protein activation profile that drives burn-induced hypermetabolism and that targeting it could potentially be an effective strategy to restore metabolic function and improve outcomes after injury.
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Quemaduras , Proteoma , Animales , Quemaduras/metabolismo , Ratones , Humanos , Proteoma/metabolismo , Masculino , Acilación , Ratones Endogámicos C57BL , Femenino , Hígado/metabolismo , Estrés del Retículo EndoplásmicoRESUMEN
Background: Dermal scaffolds have created a paradigm shift for burn and wound management by providing improved healing and less scarring, while improving cosmesis and functionality. Dermal regeneration template (DRT) is a bilayer membrane for dermal regeneration developed by Yannas and Burke in the 1980s. The aim of this review is to summarize clinical evidence for dermal scaffolds focusing on DRT for the management and reconstruction of burn injuries and complex wounds. Methods: A comprehensive search of PubMed was performed from the start of indexing through November 2022. Articles reporting on DRT use in patients with burns, limb salvage, and wound reconstruction were included with focus on high-level clinical evidence. Results: DRT has become an established alternative option for the treatment of full-thickness and deep partial-thickness burns, with improved outcomes in areas where cosmesis and functionality are important. In the management of diabetic foot ulcers, use of DRT is associated with high rates of complete wound healing with a low risk of adverse outcomes. DRT has been successfully used in traumatic and surgical wounds, showing particular benefit in deep wounds and in the reconstruction of numerous anatomical sites. Conclusions: Considerable clinical experience has accrued with the use of DRT beyond its original application for thermal injury. A growing body of evidence from clinical studies reports the successful use of DRT to improve clinical outcomes and quality of life across clinical indications at a number of anatomical sites.
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BACKGROUND: Despite the growing prevalence of burn survivors, a gap persists in our understanding of the correlation between acute burn trauma and the long-term impact on psychosocial health. This study set out to investigate the prevalence of long-term pain and symptoms of anxiety and depression in survivors of extensive burns, comparing this to the general population, and identify injury and demographic-related factors predisposing individuals to psychosocial compromise. METHODS: RE-ENERGIZE was an international, double-blinded, randomized-controlled trial that enrolled 1200 patients with partial- or full-thickness burns that required surgical treatment. For the post hoc analysis, we excluded participants who did not complete the Short Form Health Survey (SF-36) questionnaire. Normative data were taken from the 2021 National Health Interview Survey dataset. Propensity score matching was performed using the nearest-neighbor 1-to-1 method, and the two cohorts were compared in terms of chronic pain, and symptoms of anxiety and depression. A multivariable analysis was performed on the burns cohort to identify factors predicting post-discharge pain and symptoms of anxiety and depression. RESULTS: A total of 600 burn patients and 26,666 general population adults were included in this study. Following propensity score matching, both groups comprised 478 participants each, who were predominately male, white, overweight and between 20 and 60 years old. Compared to the general population, burn patients were significantly more likely to report the presence of moderate and a lot of pain (p = 0.002). Symptoms of anxiety were significantly higher in the burn population in two of four levels (most of the time; some of the time; p < 0.0001 for both). Responders in the burn population were significantly less likely to report the absence of depressive symptoms (p < 0.0001). Burn patients were also significantly more likely to report that their mental health affects their social life. TBSA, history of depression, and female sex were identified as independently associated factors for pain, anxiety, and depressive symptoms. The presence of chronic pain and anxiety symptoms independently predicted for symptoms of depression. CONCLUSIONS: Analyzing the largest multicenter cohort of patients with extensive burns, we find that burn injury is associated with chronic pain, and symptoms of anxiety and depression. In addition, TBSA-burned and history of depression directly correlate with the prevalence of chronic pain, and symptoms of anxiety and depression. Finally, pain, and symptoms of anxiety and depression are interrelated and may have interactive effects on the process of recovery following burn injury. Burn patients would, therefore, benefit from a multidisciplinary team approach with early mobilization of pain and mental health experts, in order to promptly prevent the development of psychosocial challenges and their consequences.
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Dolor Crónico , Depresión , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Cuidados Posteriores , Ansiedad/epidemiología , Ansiedad/etiología , Ansiedad/psicología , Dolor Crónico/epidemiología , Dolor Crónico/etiología , Depresión/epidemiología , Depresión/etiología , Depresión/psicología , Alta del Paciente , Calidad de Vida , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
ABSTRACT: The analysis of the single-cell transcriptome has emerged as a powerful tool to gain insights on the basic mechanisms of health and disease. It is widely used to reveal the cellular diversity and complexity of tissues at cellular resolution by RNA sequencing of the whole transcriptome from a single cell. Equally, it is applied to discover an unknown, rare population of cells in the tissue. The prime advantage of single-cell transcriptome analysis is the detection of stochastic nature of gene expression of the cell in tissue. Moreover, the availability of multiple platforms for the single-cell transcriptome has broadened its approaches to using cells of different sizes and shapes, including the capture of short or full-length transcripts, which is helpful in the analysis of challenging biological samples. And with the development of numerous packages in R and Python, new directions in the computational analysis of single-cell transcriptomes can be taken to characterize healthy versus diseased tissues to obtain novel pathological insights. Downstream analysis such as differential gene expression analysis, gene ontology term analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, cell-cell interaction analysis, and trajectory analysis has become standard practice in the workflow of single-cell transcriptome analysis to further examine the biology of different cell types. Here, we provide a broad overview of single-cell transcriptome analysis in health and disease conditions currently applied in various studies.
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Perfilación de la Expresión Génica , Análisis de Expresión Génica de una Sola Célula , Transcriptoma/genética , Análisis de Secuencia de ARN , Comunicación CelularRESUMEN
Severe burns induce a chronic hypermetabolic state that persists well past wound closure, indicating that additional internal mechanisms must be involved. Adipose tissue is suggested to be a central regulator in perpetuating hypermetabolism, although this has not been directly tested. Here, we show that thermogenic adipose tissues are activated in parallel to increases in hypermetabolism independent of cold stress. Using an adipose tissue transplantation model, we discover that burn-derived subcutaneous white adipose tissue alone is sufficient to invoke a hypermetabolic response in a healthy recipient mouse. Concomitantly, transplantation of healthy adipose tissue alleviates metabolic dysfunction in a burn recipient. We further show that the nicotinic acetylcholine receptor signaling pathway may mediate an immune-adipose crosstalk to regulate adipose tissue remodeling post-injury. Targeting this pathway could lead to innovative therapeutic interventions to counteract hypermetabolic pathologies.
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Quemaduras , Grasa Subcutánea , Animales , Ratones , Grasa Subcutánea/metabolismo , Tejido Adiposo Blanco/metabolismo , Obesidad/metabolismo , Metabolismo Energético/fisiología , Quemaduras/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo/metabolismoRESUMEN
Surgeons in their daily practice are at the forefront in preventing and managing infections. However, among surgeons, appropriate measures of infection prevention and management are often disregarded. The lack of awareness of infection and prevention measures has marginalized surgeons from this battle. Together, the Global Alliance for Infections in Surgery (GAIS), the World Society of Emergency Surgery (WSES), the Surgical Infection Society (SIS), the Surgical Infection Society-Europe (SIS-E), the World Surgical Infection Society (WSIS), the American Association for the Surgery of Trauma (AAST), and the Panamerican Trauma Society (PTS) have jointly completed an international declaration, highlighting the threat posed by antimicrobial resistance globally and the need for preventing and managing infections appropriately across the surgical pathway. The authors representing these surgical societies call all surgeons around the world to participate in this global cause by pledging support for this declaration for maintaining the effectiveness of current and future antibiotics.
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Antibacterianos , Cirujanos , Humanos , Estados Unidos , Antibacterianos/uso terapéuticoRESUMEN
Wound healing occurs as a response to disruption of the epidermis and dermis. It is an intricate and well-orchestrated response with the goal to restore skin integrity and function. However, in hundreds of millions of patients, skin wound healing results in abnormal scarring, including keloid lesions or hypertrophic scarring. Although the underlying mechanisms of hypertrophic scars and keloid lesions are not well defined, evidence suggests that the changes in the extracellular matrix are perpetuated by ongoing inflammation in susceptible individuals, resulting in a fibrotic phenotype. The lesions then become established, with ongoing deposition of excess disordered collagen. Not only can abnormal scarring be debilitating and painful, it can also cause functional impairment and profound changes in appearance, thereby substantially affecting patients' lives. Despite the vast demand on patient health and the medical society, very little progress has been made in the care of patients with abnormal scarring. To improve the outcome of pathological scarring, standardized and innovative approaches are required.
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Cicatriz Hipertrófica , Queloide , Humanos , Queloide/patología , Cicatriz Hipertrófica/patología , Piel/patología , Cicatrización de Heridas , FibrosisRESUMEN
Scar development remains a common occurrence and a major healthcare challenge affecting the lives of millions of patients annually. Severe injuries to the skin, such as burns can lead to pathological wound healing patterns, often characterized by dermal fibrosis or excessive scarring, and chronic inflammation. The two most common forms of fibrotic diseases following burn trauma are hypertrophic scars (HSCs) and keloids, which severely impact the patient's quality of life. Although the cellular and molecular mechanisms are similar, HSC and keloids have several distinct differences. In this review, we discuss the different forms of fibrosis that occur postburn injury, emphasizing how the extent of burn influences scar development. Moreover, we highlight how a systemic response induced by a burn injury drives wound fibrosis, including both the role of the inflammatory response, as well as the fate of fibroblast during skin healing. Finally, we list potential therapeutics aimed at alleviating pathological scar formation. An understanding of the mechanisms of postburn fibrosis will allow us to effectively move studies from bench to bedside.
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Quemaduras , Queloide , Humanos , Queloide/etiología , Queloide/terapia , Queloide/patología , Calidad de Vida , Piel/patología , Fibrosis , Quemaduras/complicaciones , Quemaduras/terapia , Quemaduras/patologíaRESUMEN
High levels of plasma lactate are associated with increased mortality in critically injured patients, including those with severe burns. Although lactate has long been considered a waste product of glycolysis, it was recently revealed that it acts as a potent inducer of white adipose tissue (WAT) browning, a response implicated in mediating postburn cachexia, hepatic steatosis, and sustained hypermetabolism. Despite the clinical presentation of hyperlactatemia and browning in burns, whether these two pathological responses are linked is currently unknown. Here, we report that elevated lactate plays a causal signaling role in mediating adverse outcomes after burn trauma by directly promoting WAT browning. Using WAT obtained from human burn patients and mouse models of thermal injury, we show that the induction of postburn browning is positively correlated with a shift toward lactate import and metabolism. Furthermore, daily administration of l-lactate is sufficient to augment burn-induced mortality and weight loss in vivo. At the organ level, increased lactate transport amplified the thermogenic activation of WAT and its associated wasting, thereby driving postburn hepatic lipotoxicity and dysfunction. Mechanistically, the thermogenic effects of lactate appeared to result from increased import through MCT transporters, which in turn increased intracellular redox pressure, [NADH/NAD+], and expression of the batokine, FGF21. In fact, pharmacological inhibition of MCT-mediated lactate uptake attenuated browning and improved hepatic function in mice after injury. Collectively, our findings identify a signaling role for lactate that impacts multiple aspects of postburn hypermetabolism, necessitating further investigation of this multifaceted metabolite in trauma and critical illness.NEW & NOTEWORTHY To our knowledge, this study was the first to investigate the role of lactate signaling in mediating white adipose tissue browning after burn trauma. We show that the induction of browning in both human burn patients and mice is positively correlated with a shift toward lactate import and metabolism. Daily l-lactate administration augments burn-induced mortality, browning, and hepatic lipotoxicity in vivo, whereas pharmacologically targeting lactate transport alleviates burn-induced browning and improves liver dysfunction after injury.
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Quemaduras , Ácido Láctico , Humanos , Animales , Ratones , Ácido Láctico/metabolismo , Tejido Adiposo Blanco/metabolismo , Quemaduras/metabolismo , Caquexia/metabolismo , Transporte Biológico , Tejido Adiposo Pardo/metabolismoRESUMEN
BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, severe mucocutaneous adverse reactions. Severity prediction at early onset is urgently required for treatment. However, previous prediction scores have been based on data of blood tests. OBJECTIVE: This study aimed to present a novel score that predicts mortality in patients with SJS/TEN in the early stages based on only clinical information. METHODS: We retrospectively evaluated 382 patients with SJS/TEN in a development study. A clinical risk score for TEN (CRISTEN) was created according to the association of potential risk factors with death. We calculated the sum of these risk factors using CRISTEN, and this was validated in a multinational survey of 416 patients and was compared with previous scoring systems. RESULTS: The significant risk factors for death in SJS/TEN comprised 10 items, including patients' age of ≥65 years, ≥10% body surface area involvement, the use of antibiotics as culprit drugs, the use of systemic corticosteroid therapy before the onset, and mucosal damage affecting the ocular, buccal, and genital mucosa. Renal impairment, diabetes, cardiovascular disease, malignant neoplasm, and bacterial infection were included as underlying diseases. The CRISTEN model showed good discrimination (area under the curve [AUC] = 0.884) and calibration. In the validation study, the AUC was 0.827, which was statistically comparable to those of previous systems. CONCLUSION: A scoring system based on only clinical information was developed to predict mortality in SJS/TEN and was validated in an independent multinational study. CRISTEN may predict individual survival probabilities and direct the management and therapy of patients with SJS/TEN.
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OBJECTIVE AND BACKGROUND: Propranolol, a nonselective beta-receptor blocker, improves outcomes of severely burned patients. While the clinical and physiological benefits of beta-blockade are well characterized, the underlying metabolic mechanisms are less well defined. We hypothesized that propranolol improves outcomes after burn injury by profoundly modulating metabolic pathways. METHODS: In this phase II randomized controlled trial, patients with burns ≥20% of total body surface area were randomly assigned to control or propranolol (dose given to decrease heart rate <100 bpm). Outcomes included clinical markers, inflammatory and lipidomic profiles, untargeted metabolomics, and molecular pathways. RESULTS: Fifty-two severely burned patients were enrolled in this trial (propranolol, n=23 and controls, n=29). There were no significant differences in demographics or injury severity between groups. Metabolomic pathway analyses of the adipose tissue showed that propranolol substantially alters several essential metabolic pathways involved in energy and nucleotide metabolism, as well as catecholamine degradation ( P <0.05). Lipidomic analysis revealed that propranolol-treated patients had lower levels of proinflammatory palmitic acid ( P <0.05) and saturated fatty acids ( P <0.05) with an increased ratio of polyunsaturated fatty acids ( P <0.05), thus shifting the lipidomic profile towards an anti-inflammatory phenotype after burn ( P <0.05). These metabolic effects were mediated by decreased activation of hormone-sensitive lipase at serine 660 ( P <0.05) and significantly reduced endoplasmic reticulum stress by decreasing phospho-JNK ( P <0.05). CONCLUSION: Propranolol's ability to mitigate pathophysiological changes to essential metabolic pathways results in significantly improved stress responses.
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Quemaduras , Propranolol , Humanos , Propranolol/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Metabolómica , Tejido AdiposoAsunto(s)
Sepsis , Procedimientos Quirúrgicos Operativos , Humanos , Sepsis/diagnóstico , Sepsis/etiologíaRESUMEN
Hypermetabolism is a hallmark of larger burn injuries. The hypermetabolic response is characterized by marked and sustained increases in catecholamines, glucocorticoids, and glucagon. There is an increasing body of literature for nutrition and metabolic treatment and supplementation to counter the hypermetabolic and catabolic response secondary to burn injury. Early and adequate nutrition is key in addition to adjunctive therapies, such as oxandrolone, insulin, metformin, and propranolol. The duration of administration of anabolic agents should be at minimum for the duration of hospitalization, and possibly up to 2 to 3 years postburn.
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Anabolizantes , Quemaduras , Humanos , Oxandrolona , Insulina , Apoyo Nutricional , Quemaduras/terapiaRESUMEN
OBJECTIVE: We conducted a large-scale investigation of the systemic and adipose tissue-specific alterations in a clinical population of burn patients to identify factors that may influence hypermetabolism. BACKGROUND: Previous research has identified chronic disturbances in adipose tissue inflammation, lipolysis, and browning, which may drive the perpetuation of hypermetabolism following the severe adrenergic stress of a burn injury. Given that adipose tissue is thought to be a central node in the regulation of systemic metabolism, we believe that systematically delineating the pathologic role of adipose tissue postburn, will lead to the identification of novel interventions to mitigate morbidity and mortality from severe burns. METHODS: This was a single-institution cohort study, which obtained plasma and subcutaneous adipose tissue samples from severely burn adult patients over various time points during acute hospitalization. Whole-body clinical, metabolic, and inflammatory mediators were assessed in plasma, while genetic analyses through RT-qPCR and single-nuclei RNA sequencing were conducted in adipose tissue. RESULTS: Systemic inflammation and adrenergic stress increase IL-6 signaling, lipolysis, browning, and adipokine dysfunction in the adipose tissue of adult burn patients, which may further propagate the long-term hypermetabolic response. Moreover, using single-nuclei RNA sequencing, we provide the first comprehensive characterization of alterations in the adipose tissue microenvironment occurring at acute and chronic stages postburn. CONCLUSION: We provide novel insight toward the effect of burns on adipokine release, inflammatory signaling pathways, and adipose heterogeneity over the trajectory of acute and chronic stages.
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Quemaduras , ARN , Adulto , Humanos , Adipoquinas , Estudios de Cohortes , Tejido Adiposo , Quemaduras/metabolismo , Inflamación/metabolismo , AdrenérgicosRESUMEN
OBJECTIVES: Evidence supporting glutamine supplementation in severe adult burn patients has created a state of uncertainty due to the variability in the treatment effect reported across small and large randomized controlled trials (RCTs). We aimed to systematically review the effect of glutamine supplementation on mortality in severe adult burn patients. DATA SOURCES: MEDLINE, Embase, CINAHL, and Cochrane Central were searched from inception to February 10, 2023. STUDY SELECTION: RCTs evaluating the effect of enteral or IV glutamine supplementation alone in severe adult burn patients were included. DATA EXTRACTION: Two reviewers independently extracted data on study characteristics, burn injury characteristics, description of the intervention between groups, adverse events, and clinical outcomes. DATA SYNTHESIS: Random effects meta-analyses were performed to estimate the pooled risk ratio (RR). Trial sequential analyses (TSA) for mortality and infectious complications were performed. Ten RCTs (1,577 patients) were included. We observed no significant effect of glutamine supplementation on overall mortality (RR, 0.65, 95% CI, 0.33-1.28; p = 0.21), infectious complications (RR, 0.83; 95% CI, 0.63-1.09; p = 0.18), or other secondary outcomes. In subgroup analyses, we observed no significant effects based on administration route or burn severity. We did observe a significant subgroup effect between single and multicenter RCTs in which glutamine significantly reduced mortality and infectious complications in singe-center RCTs but not in multicenter RCTs. However, TSA showed that the pooled results of single-center RCTs were type 1 errors and further trials would be futile. CONCLUSIONS: Glutamine supplementation, regardless of administration, does not appear to improve clinical outcomes in severely adult burned patients.