title: Dose-dependent impairment of collagen deposition by topical granulocyte-macrophage colony-stimulating factor in human experimental wounds.
abstract: OBJECTIVE
  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.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  Expanded polytetrafluoroethylene tubes were implanted subcutaneously and GM-CSF was applied locally at concentrations of 0.1 micro g/mL (total dose 0.4 micro g), 1.0 micro g/mL (4.0 micro g), 10 micro g/mL (40 micro g), or 75 micro g/mL (300 micro g) 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.
  
  
  RESULTS
  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 micro g 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.
  
  
  CONCLUSIONS
  Inhibition of fibrogenesis with GM-CSF intervention may impair tissue repair processes during surgery.
authors.affiliation: Copenhagen Wound Healing Center and the Department of Surgical Gastroenterology, Sundby Hospital, University of Copenhagen, Copenhagen, Denmark. lnj@dadlnet.dk
authors.forename: Lars N
authors.initials: LN
authors.lastname: Jorgensen
authors.forename: Magnus S
authors.initials: MS
authors.lastname: Agren
authors.forename: Søren M
authors.initials: SM
authors.lastname: Madsen
authors.forename: Finn
authors.initials: F
authors.lastname: Kallehave
authors.forename: Faranak
authors.initials: F
authors.lastname: Vossoughi
authors.forename: Annette
authors.initials: A
authors.lastname: Rasmussen
authors.forename: Finn
authors.initials: F
authors.lastname: Gottrup
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002455:Cell Division; D002851:Chromatography, High Pressure Liquid; D003094:Collagen / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006097:Granulation Tissue / Q000187:drug effects / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003094:Collagen; D011392:Proline; D006909:Hydroxyproline