TUMOR-NECROSIS-FACTOR-ALPHA INHIBITS COLLAGEN ALPHA-1(I) GENE-EXPRESSION AND WOUND-HEALING IN A MURINE MODEL OF CACHEXIA

The mechanisms responsible for impaired wound healing in patients with cachexia-associated infection, inflammation, and cancer are unknown. As tumor necrosis factor (TNF)-alpha is elevated in these diseases, an d TNF-alpha inhibits collagen alpha 1(I) gene expression in cultured f ibroblasts, we analyzed whether chronically elevated serum TNF-alpha a ffects collagen metabolism in vivo by inoculating nude mice with Chine se hamster ovary cells secreting TNF-alpha (TNF-alpha mice) or control Chinese hamster ovary cells (control mice). Before the onset of weigh t loss, TNF-alpha mice had a selective decrease in collagen synthesis and collagen alpha 1(I) mRNA in the skirt. In addition, TNF-alpha mice displayed impaired healing of incisional and excisional skin wounds, compared with control animals, before the onset of cachexia, The expre ssion of transforming growth factor-beta 1, a potent fibrogenic factor , was inhibited by TNF-alpha in the skin. In studies with transgenic m ice expressing the human growth hormone under the direction of 5' regu latory regions of the human collagen alpha 1(I) gene, TNF-alpha treatm ent inhibited the expression of the collagen alpha 1(I) human growth h ormone transgene containing -2.3 kb of the 5' region, whereas transgen e expression directed by -0.44 kb of the 5' region was not affected, T hese experiments suggest that TNF-alpha may play an important role in the impaired wound healing of chronic diseases that are characterized by a high production of this cytokine and provide insights for potenti al therapeutic approaches.