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Propranolol, a nonselective [[beta].sub.2]-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 [+ or -] 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 [+ or -] 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 [+ or -] 12.9 nmol*[min.sup.-1]* 100 ml leg [volume.sup.-1] for placebo and +69.3 [+ or -] 34.9 nmol*[min.sup.-1]*100 ml leg [volume.sup.-1] in the propranolol-treated 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. propranolol; microarray analysis; hypermetabolism; muscle catabolism

Recovery from a massive burn is characterized by catabolic and hypermetabolic responses that persist up to 2 years and impair rehabilitation and reintegration. The objective of this study was to determine the effects of long-term treatment with recombinant human growth hormone (rhGH) on growth, hypermetabolism, body composition, bone metabolism, cardiac work, and scarring in a large prospective randomized single-center controlled clinical trial in pediatric patients with massive burns.A total of 205 pediatric patients with massive burns over 40% total body surface area were prospectively enrolled between 1998 and 2007 (clinicaltrials.gov ID NCT00675714). Patients were randomized to receive either placebo (n = 94) or long-term rhGH at 0.05, 0.1, or 0.2 mg/kg/d (n = 101). Changes in weight, body composition, bone metabolism, cardiac output, resting energy expenditure, hormones, and scar development were measured at patient discharge and at 6, 9, 12, 18, and 24 months postburn. Statistical analysis used Tukey t test or ANOVA followed by Bonferroni correction. Significance was accepted at P < 0.05.RhGH administration markedly improved growth and lean body mass, whereas hypermetabolism was significantly attenuated. Serum growth hormone, insulin-like growth factor-I, and IGFBP-3 was significantly increased, whereas percent body fat content significantly decreased when compared with placebo, P < 0.05. A subset analysis revealed most lean body mass gain in the 0.2 mg/kg group, P < 0.05. Bone mineral content showed an unexpected decrease in the 0.2 mg/kg group, along with a decrease in PTH and increase in osteocalcin levels, P < 0.05. Resting energy expenditure improved with rhGH administration, most markedly in the 0.1 mg/kg/d rhGH group, P < 0.05. Cardiac output was decreased at 12 and 18 months postburn in the rhGH group. Long-term administration of 0.1 and 0.2 mg/kg/d rhGH significantly improved scarring at 12 months postburn, P < 0.05.This large prospective clinical trial showed that long-term treatment with rhGH effectively enhances recovery of severely burned pediatric patients. [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]

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]

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]

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.

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.

Background: Recombinant human growth hormone (rhGH) has been shown to favorably modulate the acute-phase response and may improve the clinical outcome. Objective: To examine whether rhGH attenuates the elevated tumor necrosis factor α (TNF-α) levels that correlate with increased multiorgan failure and mortality in burned adults and children. Design: Twenty children with burns of greater than 40% of the total body surface area were randomly divided into 2 groups to receive placebo (n=10) or rhGH, 0.2 mg/kg per day intramuscularly (n=10). Setting: Pediatric burn hospital. Main Outcome Measure: Serum TNF-α levels by enzyme-linked immunoassay at baseline (day 0) and at 21 and 42 days after injury. For statistical analysis, we used the Kruskal-Wallis and Friedman tests. Results: No significant differences in age (mean ± SD, 6.2 ± 1.6 vs 5.0 ± 1.2 years) or percentage of total body surface area burn (mean ± SD, 65.1% ± 8.2% vs 57.1% ± 5.2%) could be shown between the groups given rhGH and placebo. Baseline TNF-α levels were elevated from reference values in both groups. Twenty-one and 42 days after rhGH administration, serum TNF-α levels were significantly decreased from those at baseline (P<.05). No significant decrease in TNF-α levels was observed in the placebo group (P=.5). Conclusions: Recombinant human growth hormone significantly lowers serum TNF-α levels after burn injury. This is consistent with the beneficial effect that rhGH has on the acute-phase response. [ABSTRACT FROM AUTHOR]