Patients with chronic infections or cancer frequently develop cachexia out of proportion to the metabolic demands of the parasite of tumor. The monocyte-derived factor tumor necrosis factor alpha (TNF alpha) (also called cachexin) is excessively produced in several chronic disease states. Also, chronic administration of TNF alpha as well as TNF alpha secreting tumors induced cachexia in animal models. Cachetic patients, who frequently require surgery for their underlying diseases, display poor wound healing. Collagen is an important extracellular matrix protein for tensile strength in would healing. Impaired wound healing could be the result of malnutrition or a humoral factor, such as TNF alpha. Therefore, in order to gain insight int the mechanisms underlying this clinical problem, we will evaluate the effects of TNF alpha on collagen metabolism in cultured cells and apply our observations to the study of wound healing in an animal model of cachexia.
The specific aims are assess: 1. The effect of TNF alpha on collagen metabolism in cultured cells; 2. The effect of TNF alpha on collagenase gene expression in cultured cells, and 3. The effects of TNF alpha on skin collagen and wound healing in a murine model of cachexia. The pathophysiological significance of the in vitro effects of TNF alpha on collagen metabolism must be validated in an in vivo model. This proposal requires a wide range of experimental approaches,including measurements of transcriptional activity, mRNA levels, collagen synthetic rates in vitro and in vivo, and wound healing. Preliminary studies in vitro reveal that TNF alpha decreases type I collagen gene transcription and increases collagenase gene transcription. Thus, in cachexia, TNF alpha may directly affect collagen deposition in tissues, independent of the associated malnutrition and weight loss.
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