Hyaluronan is a high molecular weight glycosaminoglycan that is found in abundance in the extracellular matrix of soft connective tissues. Hyaluronan levels often increase in areas in which cellular migration or proliferation is occurring. Hence, elevated levels of hyaluronan are associated with morphogenesis, differentiation, and tumorigenesis. In vitro studies have demonstrated that hyaluronan synthase (HAS) transcript levels are differentially responsive to the proinflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha. Both of these cytokines are present at elevated levels early after wounding and are believed to play important roles in the process of repair. Therefore, the overall objective of this proposed study is: 1) to determine whether differential expression of the HAS transcripts occurs during wound repair and 2) to determine whether the proinflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, participate in the regulation of the gene expression of these genes. Hyaluronan levels will be measured in rat dermal wounds using a cartilage binding protein-based assay. RNase protection assays will be used to quantify HAS1, HAS2, and HAS3 transcript levels and transcript location will be determined by in situ hybridization. In addition, the hypothesis that interleukin-1 beta and tumor necrosis factor-alpha differentially regulate HAS transcript levels in vivo will be tested by measuring the effects of sustained release of interleukin-1 receptor antagonist and soluble tumor necrosis factor receptor. Understanding the mechanisms regulating the expression of hyaluronan will provide opportunities to devise novel strategies for the treatment of problem wounds and possibly metastatic tumors associated with elevated hyaluronan.
| Kennedy, C I; Diegelmann, R F; Haynes, J H et al. (2000) Proinflammatory cytokines differentially regulate hyaluronan synthase isoforms in fetal and adult fibroblasts. J Pediatr Surg 35:874-9 |
