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The events occurring early in the burn wound trigger a sequence of local and systemic responses that influence cell and tissue survival and, consequently, wound healing and recovery. Using high-density oligonucleotide arrays we identified gene expression patterns in skin samples taken from a region of injury in the burn rat model. The associated genomic events include the differential expression of genes involved in cell survival and death, cell growth regulation, cell metabolism, inflammation, and immune response. The functional gene cluster detected and their time appearance matched the time sequence known to occur in burn wound healing. gene expression profile; microarray; wound healing; skin; rat burn model

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]

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]

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]