Pre-existing skin diseases as predictors of post-burn pruritus.

BACKGROUND: Post-burn pruritus (PBP) has been shown to adversely affect burn patients' quality of life. However, the predictors of PBP are not known. We hypothesize a pre-existing pruritic skin diagnosis is associated with an increased risk of adverse outcomes following a burn injury. METHODS: This retrospective study utilized data from the TriNetX electronic health record. Burn patients with a history of a pruritic skin disorder were compared to patients without a diagnosed skin disorder and the occurrence of pruritus was compared between the two cohorts. RESULTS: Patients with pre-existing skin conditions were more likely to develop PBP. The risk of PBP was highest 1 year after injury. Stratification by percent TBSA burned, gender, race, and age showed an increased risk of PBP for females, Caucasians, older patients, and those with large burns. CONCLUSION: A pre-existing pruritic skin diagnosis is highly associated with developing pruritus following a burn injury.

Therapeutic Strategies to Reduce Burn Wound Conversion.

Burn wound conversion refers to the phenomenon whereby superficial burns that appear to retain the ability to spontaneously heal, convert later into deeper wounds in need of excision. While no current treatment can definitively stop burn wound conversion, attempts to slow tissue damage remain unsatisfactory, justifying the need for new therapeutic interventions. To attenuate burn wound conversion, various studies have targeted at least one of the molecular mechanisms underlying burn wound conversion, including ischemia, inflammation, apoptosis, autophagy, generation of reactive oxygen species, hypothermia, and wound rehydration. However, therapeutic strategies that can target various mechanisms involved in burn wound conversion are still lacking. This review highlights the pathophysiology of burn wound conversion and focuses on recent studies that have turned to the novel use of biologics such as mesenchymal stem cells, biomaterials, and immune regulators to mitigate wound conversion. Future research should investigate mechanistic pathways, side effects, safety, and efficacy of these different treatments before translation into clinical studies.

Galunisertib Exerts Antifibrotic Effects on TGF-ß-Induced Fibroproliferative Dermal Fibroblasts.

Dermal fibroblasts in pathological scars secrete constitutively elevated levels of TGF-ß, signaling the transcription of fibrotic genes via activin-like kinase 5 (ALK5). In the present study, we examine the antifibrotic effects of galunisertib, a small-molecule inhibitor of ALK5, on fibroproliferative dermal fibroblasts in an in vitro model of wound healing. We induced fibrosis in human dermal fibroblasts with exogenous TGF-ß and performed cellular proliferation assays after treatment with varying concentrations of galunisertib. Dermal fibroblast proliferation was diminished to homeostatic levels without cytotoxicity at concentrations as high as 10 µM. An in vitro scratch assay revealed that galunisertib significantly enhanced cellular migration and in vitro wound closure beginning 24 h post-injury. A gene expression analysis demonstrated a significant attenuation of fibrotic gene expression, including collagen-1a, alpha-smooth muscle actin, fibronectin, and connective tissue growth factor, with increased expression of the antifibrotic genes MMP1 and decorin. Protein synthesis assays confirmed drug activity and corroborated the transcription findings. In summary, galunisertib simultaneously exerts antifibrotic effects on dermal fibroblasts while enhancing rates of in vitro wound closure. Galunisertib has already completed phase II clinical trials for cancer therapy with minimal adverse effects and is a promising candidate for the treatment and prevention of pathological cutaneous scars.

Role of Exosomes in Dermal Wound Healing: A Systematic Review.

Cell-based therapy imparts its therapeutic effects through soluble GFs and vesicular bodies such as exosomes. A systematic review with a meta-analysis of preclinical studies was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the modified Stroke Therapy Academic Industry Roundtable guidelines to identify exosomes as an archetype biological therapy for dermal wound healing and to provide guidelines for the concentrations to be used in preclinical studies. A total of 51 rodent studies were included in the systematic review and 9 were included in the meta-analysis section. Three independent reviewers cross-screened eligibility and selected studies for quality assessment from 3,064 published studies on exosomes and wound healing. The mean quality scores for all studies were 5.08 ± 0.752 and 5.11 ± 1.13 for systematic review and meta-analysis, respectively. Exosome effects were reported to have the highest efficacy at 7 days (OR = 1.82, 95% confidence interval = 0.69‒2.95) than at 14 days (OR = 2.29, 95% confidence interval = 0.01‒4.56) after administration. Exosomes were reported to regulate all phases of skin wound healing, mostly by the actions of circulating microRNA. The outcome of this review may be used to guide preclinical and clinical studies on the role of exosomes in wound healing.

Carotid smooth muscle contractility changes after severe burn.

Severe burns result in cardiovascular dysfunction, but responses in the peripheral vasculature are unclear. We hypothesize that severe burns disturb arterial contractility through acute changes in adrenergic and cholinergic receptor function. To address this, we investigated the changes in carotid artery contractility and relaxation following a severe burn. Thirty-four adult Sprague-Dawley male rats received a 40% total body surface area (TBSA) scald burn and fluid resuscitation using the Parkland formula. Control animals received sham burn procedure. Animals were serially euthanized between 6 h and 14 days after burn and endothelium-intact common carotid arteries were used for ex vivo force/relaxation measurements. At 6 h after burn, carotid arteries from burned animals demonstrated a > 50% decrease in cumulative dose-responses to norepinephrine (p < 0.05) and to 10-7 M angiotensin II (p < 0.05). Notably, pre-constricted carotid arteries also demonstrated reduced relaxation responses to acetylcholine (p < 0.05) 6 h after burn, but not to sodium nitroprusside. Histologic examination of cross-sectional planes revealed significant increases in carotid artery wall thickness in burned rats at 6 h versus 3 days, with increased collagen expression in tunica media at 3 days (p < 0.05). Carotid artery dysfunction occurs within 6 h after severe burn, demonstrating decreased sensitivity to adrenergic- and angiotensin II-induced vasoconstriction and acetylcholine-induced relaxation.

Current Approaches Targeting the Wound Healing Phases to Attenuate Fibrosis and Scarring.

Cutaneous fibrosis results from suboptimal wound healing following significant tissue injury such as severe burns, trauma, and major surgeries. Pathologic skin fibrosis results in scars that are disfiguring, limit normal movement, and prevent patient recovery and reintegration into society. While various therapeutic strategies have been used to accelerate wound healing and decrease the incidence of scarring, recent studies have targeted the molecular regulators of each phase of wound healing, including the inflammatory, proliferative, and remodeling phases. Here, we reviewed the most recent literature elucidating molecular pathways that can be targeted to reduce fibrosis with a particular focus on post-burn scarring. Current research targeting inflammatory mediators, the epithelial to mesenchymal transition, and regulators of myofibroblast differentiation shows promising results. However, a multimodal approach addressing all three phases of wound healing may provide the best therapeutic outcome.

Buprenorphine-Sustained Release Alters Hemodynamic Parameters in a Rat Burn Model.

BACKGROUND: It has been previously shown that anesthesia and analgesia can affect outcomes in the rat burn model and that buprenorphine alleviated pain without drastically altering the outcomes of interest. Recently, the use of a sustained release (SR) formulation of buprenorphine has been promoted over conventional buprenorphine. In this study, we assessed whether buprenorphine-SR altered hemodynamic parameters in our rat model of severe burn injury. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were randomized to receive either conventional buprenorphine (0.05 mg/kg) or buprenorphine-SR (1 mg/kg). Buprenorphine-SR was administered 24 h before the experiment. Buprenorphine was administered on the day of experiment. These groups were further randomized to control or scald burn (60% of total body surface area). Systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR) were measured using a noninvasive blood pressure system before receiving analgesia and after 72 h. RESULTS: As expected, HR was significantly higher after burn injury regardless of analgesic (P <0.0001). Both SBP and DBP were significantly decreased in burned animals receiving conventional buprenorphine (P < 0.0001), but neither was altered in the buprenorphine-SR-treated burned animals. However, SBP, DBP, and HR were significantly increased after 72 h in control animals receiving buprenorphine-SR (P < 0.0001). CONCLUSIONS: These data indicate that buprenorphine-SR alters the hemodynamic response to injury and may not be an appropriate choice for a model of severe burn injury. If this analgesic is used, investigators must cautiously form conclusions, especially in experimental conditions that would be expected to alter cardiac hemodynamics.

Reduced Postburn Hypertrophic Scarring and Improved Physical Recovery With Yearlong Administration of Oxandrolone and Propranolol.

BACKGROUND: Massive burns induce a hypermetabolic response that leads to total body wasting and impaired physical and psychosocial recovery. The administration of propranolol or oxandrolone positively affects postburn metabolism and growth. The combined administration of oxandrolone and propranolol (OxProp) for 1 year restores growth in children with large burns. Here, we investigated whether the combined administration of OxProp for 1 year would reduce scarring and improve quality of life compared with control. STUDY DESIGN: Children with large burns (n = 480) were enrolled into this institutional review board-approved study; patients were randomized to control (n = 226) or administration of OxProp (n = 126) for 1 year postburn. Assessments were conducted at discharge and 6, 12, and 24 months postburn. Scar biopsies were obtained for histology. Physical scar assessments and patient reported outcome measures of physical and psychosocial function were obtained. RESULTS: Reductions in cellularity, vascular structures, inflammation, and abnormal collagen (P < 0.05) occurred in OxProp-treated scars. With OxProp, scar severity was attenuated and pliability increased (both P < 0.05). Analyses of patient-reported outcomes showed improved general and emotional health within the OxProp-treated group (P < 0.05). CONCLUSIONS: Here, we have shown improvements in objective and subjective measures of scarring and an increase in overall patient-reported physical function. The combined administration of OxProp for up to a year after burn injury should be considered for the reduction of postburn scarring and improvement of long-term psychosocial outcomes in children with massive burns.

Burn Trauma Acutely Increases the Respiratory Capacity and Function of Liver Mitochondria.

BACKGROUND: A complete understanding of the role of the liver in burn-induced hypermetabolism is lacking. We investigated the acute effect of severe burn trauma on liver mitochondrial respiratory capacity and coupling control as well as the signaling events underlying these alterations. METHODS: Male BALB/c mice (8-12 weeks) received full-thickness scald burns on ∼30% of the body surface. Liver tissue was harvested 24 h postinjury. Mitochondrial respiration was determined by high-resolution respirometry. Citrate synthase activity was determined as a proxy of mitochondrial density. Male Sprague-Dawley rats received full-thickness scald burns to ∼60% of the body surface. Serum was collected 24 h postinjury. HepG2 cells were cultured with serum-enriched media from either sham- or burn-treated rats. Protein levels were analyzed via western blot. RESULTS: Mass-specific (P = 0.01) and mitochondrial-specific (P = 0.01) respiration coupled to ATP production significantly increased in the liver after burn. The respiratory control ratio for ADP (P = 0.04) and the mitochondrial flux control ratio (P = 0.03) were elevated in the liver of burned animals. Complex III and Complex IV protein abundance in the liver increased after burn by 17% and 14%, respectively. Exposure of HepG2 cells to serum from burned rats increased the pAMPKα:AMPKα ratio (P < 0.001) and levels of SIRT1 (P = 0.01), Nrf2 (P < 0.001), and PGC1α (P = 0.02). CONCLUSIONS: Severe burn trauma augments respiratory capacity and function of liver mitochondria, adaptations that augment ATP production. This response may be mediated by systemic factors that activate signaling proteins responsible for regulating cellular energy metabolism and mitochondrial biogenesis.