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Introduction: Cutaneous wounds that involve loss of tissue heal through a complex process of generating granulation tissue to initially cover the wound, followed by epithelialization, and contraction. Normal healing requires a delicate balance between cellular, matrix, and vascularity build up and breakdown. Defects in the regulation of this balance can alter normal scar formation through fibroblastic hyperproliferation, which is characteristic of hypertrophic scar formation. Methods: Primary fibroblasts cultures from hypertrophic scar or adjacent normal skin were seeded in growth medium. Half of each was stimulated with interleukin (IL)-1β for 6 h and half served as control nonstimulated fibroblasts. Supernatants were tested for expressed proteins and the fibroblasts for changes in gene expression. Results: Comparison between normal skin and hypertrophic scar fibroblasts stimulated with IL-1β indicate that 15 genes increased and 8 genes decreased expression. When normal skin was stimulated with IL-1β, there were increases in the expression of heat shock transcription factor-1, hsp70, and IL-6 When hypertrophic scar was stimulated with IL-1β, there was a decrease in nuclear factor-κB, GADD45-α, p53, p53 binding protein, and Cox-2 genes. These genes may play specific but different roles in controlling the cellular response to cell stress and apoptosis. Conclusion: Data presented suggest that oxidative and heat stress proteins, stimulated through IL-1β, may be important mediators of abnormal scarring. [Copyright &y& Elsevier]

Background: Pulmonary failure has emerged as one of the leading causes of mortality in burned children due, in part, to the success in reducing the incidence of sepsis, early surgery and fluid resuscitation, and new advances in nutritional support. To evaluate the effect of pulmonary injury, age, gender, race, and burn size on mortality, the records of 3179 burned children admitted to our burn center from 1985 to 2001 were reviewed. In this population, 1246 were admitted within 14 days of injury with burns greater than 20% of their total body surface area (TBSA). Methods: Lethal burn areas (LAs) for a thermal injury only or burn plus inhalation injury were estimated from best fit probit curve within 95% confidence limits. Data analysis was by χ2-test, t-test, or Fisher’s exact test where appropriate. Results: The lethal burn area for a 10% mortality rate with and without concomitant inhalation injury was a 50 and 73% TBSA burn, respectively. Children up to the age of 3 with ≥20% TBSA burns had a higher rate of mortality (9.9%) compared to those 3–12 years of age (4.9%) and 13–18 years of age (4.2%). Children with 21–80% TBSA burns showed a significant difference in mortality (P<0.05) between those with burn plus inhalation injury (13.9%) and burn only (2.9%), while those with 81–100% TBSA burns showed no significant difference between burn only and burn plus inhalation injury. Conclusion: Inhalation injury remains one of the primary contributors to burn mortality. Children under the age of 3 years, however, are at a higher risk both with and without inhalation injury. [Copyright &y& Elsevier]

In this study, we investigated the effect of inflammatory cytokines on matrix metalloproteinase (MMP-1) and TIMP-1 production in human dermal fibroblasts, which play a pivotal role in wound healing, ranging from the synthesis and remodeling of extracellular matrix (ECM) to the synthesis of growth factors. The balance of MMPs and TIMPs is crucial in directing successful wound repair. Human adult dermal fibroblasts were seeded in six well plates (7.5×104 cells/ml) in complete media. Eighty to ninety percent confluent cells were treated with interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) (10 ng/ml) for 6 h in serum free media with suitable controls run in triplicate. Supernatants were assayed for pro-MMP-1 & TIMP-1. Extracted total RNA was used for reverse transcription polymerase chain reaction (RT-PCR) with sequence specific primers for MMP-1, TIMP-1 and β-actin. Signal intensity was normalized to the internal control (β-actin). Statistical analysis used ANOVA. MMP-1 and TIMP-1 mRNA expression were markedly increased with IL-6 and TNF-α treatment and remains unchanged with IL-1β. Pro-MMP-1 protein levels are unchanged with TNF-α and significantly increased with IL-1β and IL-6 treatment. However, TNF-α significantly increases TIMP-1 protein levels. Data suggests differential regulation of MMP-1 and TIMP-1 protein levels by the cytokines found in stimulated dermal fibroblasts. Further characterization of this response will provide an understanding of the mechanisms of pathogenesis of extracellular matrix (ECM) and the potential role of metalloproteinases in tissue remodeling after injury. [Copyright &y& Elsevier]

Severe burns cause not only skin injury but several marked systemic derangements. During wound healing, matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases play an important role in tissue regeneration and remodeling processes. Therefore, in the present study, we determined the serum levels of MMPs and tissue inhibitor of metalloproteinase-1 in burn patients over time. Serum samples from 12 severely burned children (mean age 7.9 ± 2.5 years) with >40% total body surface area burns were obtained within 0.5 hours, 3, 7, and 21 days after injury. Pro-MMP-1, MMP-3, MMP-9, and tissue inhibitor of metalloproteinase-1 serum levels were assayed by enzyme-linked immunoassay and compared to normal healthy volunteers. Two-way analysis of variance and Bonferroni's test were used for statistical analysis. Pro-MMP-1 levels in the serum were significantly elevated by the seventh day after burn. MMP-3 and MMP-9 levels showed significant increases by day 3 and 21 compared to normals, respectively. Tissue inhibitor of metalloproteinase-1 levels did not change with time after burn but were significantly higher by 3 days after burn compared to normal serum. In conclusion, changes in MMPs and tissue inhibitor of metalloproteinase-1 occur in burn patients and those changes may be a mechanism beneficial to wound healing. (WOUND REP REG 2003;11:177–180). [ABSTRACT FROM AUTHOR]

The hypercatabolism after massive pediatric burns has been effectively treated with recombinant human growth hormone, an anabolic agent that stimulates protein synthesis and abrogates growth arrest. While experimental studies have shown increased potential for fibrosis induced by growth hormone therapy, adverse effects on human scars have not been investigated. Our aim was to evaluate hypertrophic scar formation in 62 patients randomized to receive injections of 0.05 mg/kg/day of recombinant human growth hormone or placebo, from discharge until 1 year after burn. Scar scales were used to evaluate scar-severity at discharge, 6, 9, 12, and 18–24 months after burn, by three observers blinded to treatment. Computer-assisted planimetry allowed quantification of percentage of hypertrophic scar formation. Types I and III collagens were localized and quantified in scars and normal skin of patients from both groups, using immunohistochemistry with confocal laser microscopy analysis. Insulin-like growth factor-1 blood levels helped assess compliance. Statistical analysis showed that scar hypertrophy significantly increased from 6 to 12 months after injury in both groups, while decreasing at 18–24 months postburn. Types I and III collagens were statistically increased in the reticular layer of scars from both groups when compared to paired normal skin. Insulin-like growth factor-1 was significantly increased in the recombinant human growth factor-treated group. No differences were seen when recombinant human growth factor and control groups were compared using the scar scales, planimetry, or immunohistochemistry. We concluded that recombinant human growth hormone therapy did not adversely affect scar formation and should not contraindicate the administration of recombinant human growth hormone as a therapeutic approach to severely burned children. [ABSTRACT FROM AUTHOR]

The liver plays an important role in a severe thermal injury by modulating immune function, inflammatory processes and the acute phase response, which are an orchestrated attempt to restore homeostasis. Using high-density oligonucleotide arrays, we examined the gene expression profile in the livers of rats between 2 and 240 h after a 40% total body surface area (TBSA) burn. Alterations in gene expression unique to a thermal injury were identified. Approximately 39 genes out of 8700 genes on each array across all the time points showed a significant change in expression patterns. Real time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses verified significant changes in early growth response-1 (Egr-1) messenger RNA (mRNA) and protein levels corresponding to the array data. Significant increases in serum levels of α-2-macroglobulin that correspond to changes in its mRNA levels were observed at 6 and 24 h after burn, p<0.05. The genomic pattern for liver in the hypermetabolic phase after the burn injury involves transcription factors, stress and inflammatory responses, cytoskeletal and extracellular matrix modifications, and regulation of cell proliferation and differentiation. During the initial phase of thermal injury gene expression profiles in the liver may provide some insight into how cellular protection mechanisms and systemic hypermetabolism are initiated and controlled. The genome wide changes observed may provide a rational therapeutic strategy to improve burn care. [Copyright &y& Elsevier]

Propranolol, a nonselective β-blocker, has been shown effective in hypermetabolic burn patients by decreasing cardiac work, protein catabolism, and lipolysis. This study investigates the effect of propranolol on gene and protein expression changes in skeletal muscle of burned children by use of high-density oligonucleotide arrays to establish the genetic profiles and stable isotope technique to quantitate protein synthesis. Thirty-seven children (mean age 9.7 ± 1.1 yr) were randomized into groups to receive placebo (n = 23) or propranolol (n = 14) titrated to reduce heart rate by 15%. Children had >40% total body surface area burns (mean 43 ± 5.6%). Protein net balance was determined by stable-isotope infusion technique. Total RNA from muscle biopsies was isolated, labeled, and cRNA hybridized to the HG-U95Av2 Affymetrix array. Mean net balance of protein synthesis and breakdown was -14.3 ± 12.9 nmol·min[sup -1]·100 ml leg volume[sup -1] for placebo and +69.3 ± 34.9 nmol·min[sup -1]·100 ml leg volume[sup -1] in the propranololtreated children (P = 0.012). Comparison of 12,000 genes in burned children receiving placebo showed increased expression of two genes with time, whereas children receiving propranolol showed increased expression of nine genes with a decrease in five genes. We conclude that burned children receiving propranolol showed a significant upregulation in genes involved in muscle metabolism and downregulation of an important enzyme involved in gluconeogenesis and insulin resistance compared with burned children receiving placebo. The upregulation of genes involved in muscle metabolism correlates well with the increase in net protein balance across the leg. [ABSTRACT FROM AUTHOR]

Analyzes the gene expression in burn wounds of rats. Occurrence of a sequence of local and systemic responses influencing cell and tissue survival; Details on the concept of injury zones in burn wounds; Evidence of metabolic failure of the involved tissue enhancing immune activation.

OBJECTIVES:We investigated the effect of various dietary fats on pulmonary surfactant composition and lung function changes that occur before and after endotoxin infusion in pigs.METHODS:Eighteen pigs were assigned to three groups (n = 6 per group) to receive a diet of protein (20% of calories), carbohydrate (20% of calories), and fat (40% of calories). In one group the fat content consisted entirely of palmitic acid. In the second group, fat came from Intralipid, which provided predominantly linoleic acid. The third group was fed fish oil. Pigs were maintained on these diets for 21 d before the experiment. Cardiovascular and pulmonary functions were determined on day 22. Pigs then were infused with endotoxin (80 mg · kg−1 · min−1) until the pulmonary arterial pressure reached a pressure similar to that found in trauma victims (45 to 50 mmHg). Cardiovascular and pulmonary function tests were then repeated, the animals killed, and the lungs removed for study.RESULTS:Compliance was reduced in the linoleate and fish-oil groups compared with the palmitate group before and after endotoxin. Compliance changes in pigs fed the linoleate and fish-oil diets were consistent with significant increases in lung wet:dry weight ratios, increased CO2 retention, histologic evidence of vascular congestion, intra-alveolar edema, and alveolar septa thickening. Changes in surfactant phosphatidylcholine composition between groups were consistent with the notion that increased unsaturated fatty acids could affect surfactant function.CONCLUSIONS:We concluded that the common practice of providing calories in the form of polyunsaturated fatty acids to critically ill patients carries the risk of being detrimental to lung function. [ABSTRACT FROM AUTHOR]

Examines whether thermal injury increases liver cell apoptosis and proliferation and whether these changes were associated with alterations in hepatic nuclear factor-kappa B (NF-kappaB) expression, changes in live enzymes and amount of protein. Induction of hepatic cell apoptosis and proliferation by thermal injury; Decrease in hepatic protein concentration.

Focuses on a study which determined whether a large thermal injury increases liver cell apoptosis and proliferation and its association to alterations in hepatic nuclear factor kappaB expression. Changes in hepatic protein concentrations; Hepatic enzymes, protein and NF-kappaB activation; Physiological proliferation of hepatocytes.

Children with severe burns benefit from acute therapy with recombinant human growth hormone by maintaining their original stature after injury. This effect is particularly apparent in children injured outside growth-spurt years. [ABSTRACT FROM AUTHOR]