MACROPHAGE-COLONY-STIMULATING FACTOR ACCELERATES WOUND-HEALING AND UP-REGULATES TGF-BETA-1 MESSENGER-RNA LEVELS THROUGH TISSUE MACROPHAGES

Macrophage colony-stimulating factor (M-CSF) is produced by many cell types involved in wound repair, yet it acts specifically on monocytes and macrophages, The monocyte-derived cell is thought to be important in wound healing, but the importance of the role of tissue macrophages in wound healing has not been well defined, Dermal ulcers were create d in normal and ischemic ears of young rabbits. Either rhM-CSF (17 mu g/wound) or buffer was applied to each wound, Wounds were bisected and analyzed histologically at Days 7 and 10 postwounding. The amounts of epithelial growth and granulation tissue deposition were measured in all wounds. The level of increase of TGF-beta 1 mRNA level in M-CSF-tr eated wounds was examined using competitive RT-PCR, M-CSF increased ne w granulation tissue formation by 37% (N = 21, P < 0.01) and 50% (P < 0.01) after single and multiple treatments, respectively, in nonischem ic wounds, TGF-beta 1 mRNA levels in rhM-CSF-treated wounds increased 5.01-fold (N = 8) over vehicle-treated wounds under nonischemic condit ions. In contrast, no effect could be detected in ischemic wounds trea ted with rhM-CSF, and these wounds only showed a 1.66-fold increase in TGF-beta 1 mRNA levels when compared to ischemic wounds treated with vehicle alone, GAPDH, a housekeeping gene, showed no change. As mesenc hymal cells lack receptors for M-CSF, the improved healing of wounds t reated with topical rhM-CSF must reflect a generalized enhancement of activation and function of tissue macrophages, as demonstrated by upre gulation of TGF-beta. The lack of effect under ischemic conditions sug gests that either macrophage activity and/or response to M-CSF is adve rsely affected under those conditions; this may suggest the pathogenes is of impaired wound healing at the cellular level. (C) 1997 Academic Press.