Pressure ulcers are one of the most debilitating and costly problems faced by elderly and spinal cord injury patients. Treatment of this growing problem remains empirical. Progress in the development of strategies for improving treatment of pressure ulcers has been hampered greatly by the lack of a fundamental definition of the pressure ulcer microenvironment and the underlying cellular, biochemical, and molecular mechanisms responsible for the poor rate of healing of these lesions. Therefore we have pursued the hypothesis and generated extensive evidence that the chronicity of these lesions is related to the enhanced proteolytic environment associated with an over exuberant presence of polymorphonuclear leukocytes (neutrophils). Neutrophils are the predominant inflammatory cell in pressure ulcers and are a source for a number of proteinases including collagenase (MMP-8) and elastase. Recent findings based on in situ hybridization analyses, indicate that mesenchymal cells in the beds of pressure ulcers contain abundant levels of procollagen transcripts suggesting that these cells are synthetically active. Therefore, the major objective of this project will be to test the hypothesis that the excessive proteolytic environment can be diminished by good wound care and this will be associated with increased collagen matrix accumulation, and restitution of the integrity of key growth factor receptors. In addition, the hypothesis that the synthetic/degradative equilibrium of pressure ulcers can be altered using a therapeutic agent already approved for use in humans will also be tested. A longitudinal characterization of pressure ulcers will include histochemical identification of neutrophils and other cell populations, an assessment of levels and activities of proteinases that are primarily neutrophil-derived, and measurement of levels of specific proteinase inhibitors. Expression of extracellular matrix will be monitored by analyzing collagen synthesis and deposition and the location and levels of procollagen transcripts. Similarly, expression of growth factor receptors will be examined by qualitative and quantitative protein assessment and by in situ hybridization and quantitative ribonuclease protection assay. These data should provide key inforrnation for the development of new strategies for the treatment of pressure ulcers as well as other chronic non-healing wounds.
