Dose-Dependent Impairment of Collagen Deposition by Topical Granulocyte-Macrophage Colony-Stimulating Factor in Human Experimental Wounds

Abstract

The authors studied the dose-dependent effect of topically administered granulocyte-macrophage colony-stimulating factor (GM-CSF) on the connective tissue response using an experimental repair model in surgical patients. GM-CSF is primarily indicated in the treatment of immunosuppressed states. The effect of GM-CSF on the tissue repair response in humans is unclear. Expanded polytetrafluoroethylene tubes were implanted subcutaneously and GM-CSF was applied locally at concentrations of 0.1 μg/mL (total dose 0.4 μg), 1.0 μg/mL (4.0 μg), 10 μg/mL (40 μg), or 75 μg/mL (300 μg) in one arm and saline alone (control) in the contralateral arm of 56 surgical patients. The content of collagen and total protein in the tubes was quantified as hydroxyproline and proline by high-performance liquid chromatography 10 days after implantation. Cellularity and the number of procollagen I-positive fibroblasts were determined by histology and immunohistochemistry. The direct effects of GM-CSF on collagen production by and proliferation of wound fibroblasts cultured from granulation tissue were also measured. Local application of GM-CSF stimulated the inflammatory cell infiltration but reduced the number of fibroblasts in the granulation tissue. GM-CSF treatment suppressed specifically and dose-dependently collagen deposition by up to 81%. A reduced collagen accumulation was also found in the control-treated arm at GM-CSF doses of 4 μg or more, indicating a systemic depressive effect of GM-CSF on tissue repair. The selective downregulation of collagen production by GM-CSF was also found in wound fibroblasts in vitro. Inhibition of fibrogenesis with GM-CSF intervention may impair tissue repair processes during surgery.