title: Role of high mobility group box 1 (HMGB1) in wound healing.
abstract: BACKGROUND
  HMGB1, a non-histone chromosomal protein, can bind to the receptor for advanced glycation end products (RAGE) and act as an inflammatory mediator. We examined the role of HMGB1 in incisional wound healing and its possible mechanism of action through receptor for advanced glycation end products (RAGE).
  
  
  METHODS
  Male Sprague-Dawley rats undergoing full-thickness incisional wounding with subcutaneous implantation of PVA sponges were given daily injections of ethyl pyruvate (EP) (40 mg/kg, i.p.), a potent inhibitor of HMGB1 release. At 7 d post-wounding, wound breaking strength, sponge collagen content, and wound fluid HMGB1 levels were assessed. In vitro rat dermal or wound-derived fibroblasts were cultured with recombinant HMGB1 or advanced glycation end product (AGE). Some cultures were co-treated with a RAGE-blocking antibody. Fibroblast proliferation and collagen synthesis were assayed.
  
  
  RESULTS
  In vivo treatment with EP significantly decreased wound HMGB1 levels (P < 0.05), which was paralleled by increased wound breaking strength (P < 0.05) and wound collagen content (P < 0.05). In vitro treatment with HMGB1 (100 ng/mL) had no effect on fibroblast proliferation but significantly reduced collagen synthesis (P < 0.05). This effect was abrogated by co-treatment with anti-RAGE antibody. Fibroblasts treated with AGE had lower collagen synthesis (P < 0.01), which was restored by anti-RAGE antibody treatment.
  
  
  CONCLUSIONS
  HMGB1 impairs fibroblast collagen synthesis. Reducing wound HMGB1 levels lead to increased tensile strength and collagen synthesis. The data suggest that HMGB1 affects collagen synthesis through activation of RAGE.
authors.affiliation: Department of Surgery, Sinai Hospital of Baltimore, Baltimore, Maryland, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Sean
authors.initials: S
authors.lastname: O'Hearn
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Kavalukas
authors.forename: Adrian
authors.initials: A
authors.lastname: Barbul
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D007249:Inflammation / Q000503:physiopathology*; D008297:Male; D023421:Models, Animal; D011773:Pyruvates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D011773:Pyruvates; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C046522:ethyl pyruvate; D003094:Collagen