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Background Topical inhibition of activated p38 MAPK within burn wounds attenuates the local and systemic inflammatory response. In this study, we investigated the effects of local activated p38 MAPK inhibition on burn-induced cardiac dysfunction. Methods Using a standardized rat model of scald burn injury, rats were given a 30% total body surface area partial thickness burn or sham injury, and the wounds were treated with an activated p38 MAPK inhibitor (SB) or vehicle. Systemic blood pressure measurements were recorded in vivo followed by in vitro assessment of sarcomere contraction in single-cell suspensions of isolated cardiomyocytes. Results Systolic blood pressure or maximum left ventricular pressures in vivo and peak cardiomyocyte sarcomere contractility in vitro were significantly reduced after burn injury. These functional deficits were abolished 24 h after burn injury following local p38 MAPK inhibition. In vitro incubation of normal cardiomyocytes with homogenate from burned skin or burn serum resulted in a similar pattern of impaired cardiomyocyte contractility. These effects were reversed in normal cardiomyocytes exposed to burn skin homogenates treated topically with a p38 MAPK inhibitor. A Western blot analysis showed that cardiac p38 MAPK activation was not affected by dermal blockade of activated p38 MAPK, arguing against systemic absorption of the inhibitor and indicating the involvement of systemic cytokine signaling. Conclusion Topical activated p38 MAPK inhibition within burned skin attenuates the release of proinflammatory mediators and prevents burn-induced cardiac dysfunction after thermal injury. These results support the inhibition of burn-wound inflammatory signaling as a new therapeutic approach to prevent potential postthermal injury multiorgan dysfunction syndrome.

There are various approaches to the treatment of superficial burns. No modality exists to date for determining treatment efficiency on morphological features. We review the first application of high-resolution in vivo confocal-laser-scanning microscopy (CLSM) to the evaluation of superficial burns on a histomorphological level. Sixteen patients (6 women, 10 men; 34.5 +/- 16.2 years) with first-degree thermal contact injuries to a maximum extent of 1% of the body surface were enrolled into the study. CLSM was performed with the Vivascope 1500 (Lucid Inc., Rochester, NY) 24 hours after injury. The following parameters were assessed: cell size of the granular layer, thickness of the basal layer, minimal thickness of the epidermis, and diameter of capillary loops. Compared with the control sites 24 hours postburn, the minimal thickness of the epidermis increased on average by approximately 11% (P = .01; t-test); the thickness of the basal layer increased about 7% (P = .008; t-test); the diameter of capillary loops increased approximately by 17% (P = 0.003; t-test); and the cell size of the granular layer increased about 8% (P = .009; Wilcoxon's test). In vivo CLSM allows characterizing and quantifying histomorphological alterations in superficial burns. CLSM could be helpful in assessing the effects of various treatment approaches for superficial burns on a histomorphological level.

We previously reported that generation of the anaphylatoxin C5a is linked to the development of cardiac dysfunction in sepsis due to C5a interaction with its receptor (C5aR) on cardiomyocytes. Burn injury involves inflammatory mechanisms that can lead to C5a generation as well. In this study, we investigated the effects of C5a blockade on burn-induced cardiac dysfunction. Using a standardized rat model of full thickness scald injury, left ventricular pressures were recorded in vivo followed by in vitro assessment of sarcomere contraction of single cardiomyocytes. Left ventricular pressures in vivo and cardiomyocyte sarcomere contractility in vitro were significantly reduced following burn injury. In the presence of anti-C5a Ab, these defects were greatly attenuated 1, 6, and 12 h after burn injury and completely abolished 24 h after burn. In vitro incubation of cardiomyocytes with bacterial LPS accentuated the impaired contractility, which was partially prevented in cardiomyocytes from burned rats that had received an anti-C5a Ab. Based on Western blot analyses, real-time PCR, and immunostaining of left ventricular heart tissue, there was a significant increase in cardiomyocyte expression of C5aR after burn injury. In conclusion, an in vivo blockade of C5a attenuates burn-induced cardiac dysfunction. Further deterioration of contractility due to the exposure of cardiomyocytes to LPS was partially prevented by C5a-blockade. These results suggest a linkage between C5a and burn-induced cardiac dysfunction and a possible contribution of LPS to these events.

The relationship between local inflammation and the subsequent systemic inflammatory response is poorly described. In a burn injury model, the dermal inflammatory response may act as an ongoing trigger for the systemic inflammatory response syndrome (SIRS) and subsequent systemic complications. We hypothesized that topical attenuation of burn wound inflammatory signaling will control the dermal inflammatory source, attenuate SIRS, and reduce acute lung injury. Mice received a 30% total body surface area burn. Subgroups were treated with specific p38 MAPK inhibitor or vehicle, which was topically applied to wounds. Topical p38 MAPK inhibition significantly reduced burn wound inflammatory signaling and subsequent systemic expression of proinflammatory cytokines and chemokines. In vitro macrophage functional assays demonstrated a significant attenuation in serum inflammatory mediators from animals receiving the topical inhibitor. Topical p38 MAPK inhibition resulted in significantly less pulmonary inflammatory response via reduction of pulmonary neutrophil sequestration, pulmonary cytokine expression, and a significant reduction in pulmonary microvascular injury and edema formation. Although dermal activating transcription factor-2, a downstream p38 MAPK target, was significantly reduced, there was no reduction in pulmonary activating transcription factor-2 expression, arguing against significant systemic absorption of the topical inhibitor. These experiments demonstrate a strong interaction between dermal inflammation and systemic inflammatory response. Attenuating local inflammatory signaling appears effective in reducing SIRS and subsequent systemic complications after burn injury.

A component of multiorgan dysfunction in burned patients is heart failure. Burn trauma induces cytokine synthesis of interleukin (IL) 1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) which can negatively impact cardiac function. Infectious complications are common following severe burn injury. We hypothesized that burn injury and lipopolysaccharide (LPS) exposure independently influence peak cardiomyocyte contraction and cytokine secretion. Rats underwent a full-thickness 30% total body surface area scald or sham burn. At 1, 6, 12, and 24 h after burn, cardiomyocytes were isolated and incubated with increasing LPS doses. Peak sarcomere shortening and contractile velocity parameters were recorded using a variable-rate video camera with sarcomere length detection software. Supernatants were assayed for IL-1beta, IL-6, and TNF-alpha by ELISA. Peak sarcomere shortening was decreased in the burn group at 1, 6, 12, and 24 h after burn. IL-1beta, IL-6, and TNF-alpha levels were increased in cardiomyocytes isolated 1 h after burn compared with sham controls, but returned to sham levels at 6, 12, and 24 h after burn. LPS exposure caused dose-dependent decreases in sarcomere shortening in sham and burn animals. LPS exposure did not produce increased cardiomyocyte cytokine expression. Burn injury diminished peak sarcomere shortening. Whereas exposure to LPS did not have an effect on cardiomyocyte cytokine expression, LPS significantly inhibited sarcomere shortening in a dose-dependent fashion. Combined burn and LPS exposure inhibited sarcomere shortening more than each alone. These results demonstrate that LPS exposure and burn injury independently decrease peak cardiac shortening. These decreases did not directly correlate with the levels of cytokines released in response to each stressor.

Background. Severe burn trauma leads to an immediate and strong inflammatory response inciting cardiac dysfunction that is associated with high morbidity and mortality. The aim of this study was to determine whether transdermal application of nicotine could influence the burn-induced cardiac dysfunction via its known immunomodulatory effects.Material and Methods. A standardized rat burn model was used in 35 male Sprague Dawley rats. The experimental animals were divided into a control group, a burn trauma group, a burn trauma group with additional nicotine treatment, and a sham group with five experimental animals per group. The latter two groups received nicotine administration. Using microtip catheterization, functional parameters of the heart were assessed 12 or 24 hours after infliction of burn trauma.Results. Burn trauma led to significantly decreased blood pressure (BP) values whereas nicotine administration normalized BP. As expected, burn trauma also induced a significant deterioration of myocardial contractility and relaxation parameters. After application of nicotine these adverse effects were attenuated.Conclusion. The present study showed that transdermal nicotine administration has normalizing effects on burn-induced myocardial dysfunction parameters. Further research is warranted to gain insight in molecular mechanisms and pathways and to evaluate potential treatment options in humans.

Purpose Microcirculatory disturbances are well known during shock; however, the accompanied histomorphological alterations are widely unknown. We used high resolution confocal-laser-scanning microscopy for the evaluation of microcirculation and histomorphology during Burn Shock treatment. Methods Confocal-laser-scanning microscopy was performed in 10 burn shock patients (4 women, 6 men; aged 40.6 ± 11.4 years, burn extent >20% body surface area) initially and 24 hours after shock resuscitation. Ten matched hemodynamic stable burn intensive care unit patients served as controls. The following parameters were evaluated: quantitative blood cell flow, cell size of the granular layer, basal layer thickness, and epidermal thickness. Results Quantitative blood cell flow in controls was 62.45 ± 3.39 cells per minute. Burn shock significantly reduced blood cell flow to 37.27 ± 3.64 cells per minute; fluid resuscitation effectively restored baseline blood flow (65.18 ± 3.76 cells per minute) after 24 hours. Granular cell size was 793.61 ± 41.58 μ m 2 in controls vs 644.27 ± 42.96 μ m 2 during burn shock. Post resuscitation granular cell size measured 932.74 ± 38.83 μ m 2 . Basal layer thickness was 14.84 ± 0.59 μ m in controls, 13.26 ± 0.54 μ m in burn patients at admission and before resuscitation, and 17.50 ± 0.46 μ m after resuscitation. Epidermal thickness in control patients was 49.60 ± 2.36 μ m, 37.83 ± 2.47 μ m in burn patients at admission and 69.50 ± 3.18 μ m after resuscitation. Conclusions Confocal-laser-scanning microscopy provides a noninvasive tool for simultaneous evaluation of microcirculation and tissue histomorphology. It may help to assess the adequacy of and response to resuscitation of burn patients early after trauma.

The stage-adjusted therapy of thermal injuries is based on pathophysiologic mechanisms as well as functional and aesthetic requirements. Plastic reconstructive surgical approaches are highly important in the prevention of the frequent grave sequelae of thermal trauma and to achieve optimal functional rehabilitation and favourable outcome. In reconstructive surgery of burns operative goals are subdivided into acute, secondary reconstructive, functional and aesthetic indications. The achievement of early wound closure to preserve functional skin and soft tissue components is an essential part of acute reconstructive procedures. Functional reconstructive and aesthetic procedures supplement the conservative treatment modalities of the secondary phase of burn care with physical therapy, ergotherapy and psychological support.

Regardless of the underlying cause, both sunburn and superficial thermal injuries are classified as first-degree burns, since data on morphological differences are scarce. Reflectance-Mode-Confocal Microscopy (RMCM) enables high-resolution non-invasive investigation of the human skin.We studied in vivo histomorphological alterations in both sunburn and superficial thermal injuries using RMCM.Ten patients (6 female, 4 male; aged 28.4 +/- 10.6 years) with first-degree thermal-contact Injuries (TI group), and 9 sunburned patients (SB group; 7 female, 2 male; aged 30.2 +/- 16.4 years), to a maximum extent of 10% of the body surface were evaluated 24 h after burn injury using RMCM. The following parameters were obtained using RMCM: stratum corneum thickness, epidermal thickness, basal layer thickness, granular cell size.Compared to the controls (12.8 +/- 2.5 microm), stratum corneum thickness decreased significantly to 10.6 +/- 2.1 microm in the TI group, whereas it increased significantly to 16.4 +/- 3.1 microm in the SB group. The epidermal thickness did not differ significantly in the TI group (47.9 +/- 2.3 microm) and SB group (49.1 +/- 3.5 microm); however, both increased significantly compared to their respective controls (41.8 +/- 1.4 microm). The basal layer thickness increased more in the SB group compared to the TI group (17.9 +/- 1.4 microm vs. 15.6 +/- 1.1 microm). Both differed also significantly compared to their controls (13.8 +/- 0.9 microm). The granular cell size increased significantly in both groups compared to the controls (731 +/- 42 microm); however, a significantly higher increase was observed in the TI group (852 +/- 58 microm) compared to the SB group (784 +/- 61 microm).Ultraviolet radiation seems to influence predominantly deeper epidermal layers, whereas heat-induced burns affect more superficial epidermal layers. The term 'First-degree burn' should not be used synonymously for sunburn and superficial thermal burn injuries. Conflicts of interest None declared.

Background Burn injury is frequently complicated by bacterial infection. Following burn injury, exposure to endotoxin produces a measurable decrease in cardiomyocyte sarcomere contractile function. Lipopolysaccharide-binding protein (LBP) is an acute phase protein that potentiates the recognition of lipopolysaccharide (LPS) by binding to the lipid A moiety of LPS. In this study, we sought to determine the effect of recombinant rat LBP (rLBP) on cardiomyocyte sarcomere function after burn or sham injury in the presence or absence of bacterial endotoxin. Methods Rats underwent a full-thickness 30% total body surface area scald or sham burn. At 24 h post-injury, cardiomyocytes were isolated, plated at 50,000 cells/well, and incubated with 50 μg/mL LPS and rLBP or chloramphenicol acetyltransferase (BVCat, an irrelevant control protein produced using the same expression system as rLBP) at concentrations by volume of 1%, 5%, 10%, and 30%. Subsets of cardiomyocytes were incubated with 5% rat serum or 30% rLBP and blocking experiments were conducted using an LBP-like synthetic peptide (LBPK95A). In vitro sarcomere function was measured using a variable rate video camera system with length detection software. Results Co-culture of burn and sham injury derived cardiomyocytes with high-dose rLBP in the presence of LPS resulted in a significant reduction to the functional impairment observed in peak sarcomere shortening following exposure to LPS alone. LBP-like peptide LBPK95A at a concentration of 20 μg/mL, in the presence of LPS, abolished the ability of 30% rLBP and 5% rat serum to restore peak sarcomere shortening of cardiomyocytes isolated following burn injury to levels of function exhibited in the absence of endotoxin exposure. Conclusions In the setting of LPS challenge following burn injury, rLBP at high concentrations restores cardiomyocyte sarcomere contractile function in vitro . Rather than potentiating the recognition of LPS by the cellular LPS receptor complex, rLBP at high concentrations likely results in an inhibitory binding effect that minimizes the impact of endotoxin exposure on cardiomyocyte function following thermal injury.

Introduction The interaction of the CNS and the immune system is well known. A parasympathetic anti-inflammatory pathway has recently been described. Both electrical and pharmacological parasympathetic stimulation attenuate proinflammatory mediator generation. Burn induces abacterial cytokine generation and we sought to evaluate whether parasympathetic stimulation after experimental burn decreases cardiodepressive mediator generation. Material and methods A 30% TBSA full-thickness rat burn model was used. After microsurgical preparation of the cervical portion of the vagus nerve, we performed electric vagus nerve stimulation. Serum was harvested and organ samples of heart and liver were homogenized. Samples were subjected to sandwich-ELISA specific for TNF-α, IL-1β and IL-6. Heart rate measurements were done using left ventricular microcatheterization. Statistical analysis was done using Student's t-tests and analysis of variance (ANOVA). Results Burn induced a significant rise of TNF-α, IL-1β and IL-6 in organ homogenates and serum. After cervical vagal electrostimulation, serum and organ homogenate levels of proinflammatory cytokines were markedly reduced compared to burn controls. Left ventricular microcatheter assessment demonstrated no cardiodepressive effect of the vagal stimulation itself. Conclusion Our results encourage further research regarding the neuroimmunologic background of burn, possibly leading to the development of a novel therapeutic approach to burn-induced organ dysfunction and immunodysregulation.

The success of modern burn therapy is based mainly on special burn intensive care, topical treatment, early eschar excision, and wound closure by immediate skin grafting or skin substitutes. This paper describes the current state of wound care and skin substitutes in burn therapy.

Thermal injury induces dermal inflammatory and proapoptotic signaling. These phenomena extend burn wound size and trigger a systemic inflammatory response, factors known to adversely affect outcomes. p38MAPK is known to trigger inflammatory responses and induce epithelial proapoptotic genes. We hypothesize that topical p38MAPK inhibition will attenuate excessive inflammatory and apoptotic signaling and reduce dermal tissue loss. Rats were given a 30% total body surface area partial thickness burn or sham injury. Some of the animals were treated with a p38MAPK inhibitor or vehicle, which was applied directly to the wound. Dermal inflammation was investigated with enzyme-linked immunosorbent assay, reverse transcriptase polymerase chain reaction, myeloperoxidase assay, and Evans blue extravasation. Apoptotic changes were detected using terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Caspase-3 in situ staining. Burn injury activated dermal p38MAPK and induced a significant rise in dermal IL-6, TNF-alpha, and IL-1beta expression. Neutrophil sequestration, microvascular damage, and hair follicle apoptosis were significantly elevated after injury. Topical p38MAPK inhibition significantly attenuated downstream dermal p38MAPK targets, proinflammatory cytokine expression, neutrophil sequestration, and microvascular injury. A significant reduction in hair follicle apoptosis was seen. This study demonstrates the attenuation of burn-induced cellular stress by topical application of p38MAPK inhibitors. Blunting early excessive inflammatory signaling may be an efficient strategy to improve patient outcomes after burn injury.

The success of modern burn therapy is based on an understanding of the pathophysiology and application of burn intensive care implying fluid resuscitation and management of pulmonary or other organ failure. With the development of early eschar excision and wound closure by immediate grafting, survival and cosmetic outcome were further improved. Especially in post-acute therapy, early physical rehabilitation, early reintegration, and early plastic surgical correction of the sequelae are indispensable for the outcome.