title: Platelet-derived growth factor (BB homodimer), transforming growth factor-beta 1, and basic fibroblast growth factor in dermal wound healing. Neovessel and matrix formation and cessation of repair.
abstract: Recombinant platelet-derived growth factor (BB homodimer, rPDGF-BB), transforming growth factor beta 1 (rTGF-beta 1), and basic fibroblast growth factor (rbFGF) can accelerate healing of soft tissues. However, little information is available characterizing the components of wound matrix induced by these growth factors and the molecular mechanisms underlying accelerated repair and wound maturation. In this study, the composition, quantity, and rate of extracellular matrix deposition within growth factor-treated lapine ear excisional wounds were analyzed at different stages of healing using specific histochemical and immunohistochemical stains, coupled with image analysis techniques. Single application of optimal concentrations of each growth factor accelerated normal healing by 30% (P less than 0.0003); rPDGF-BB markedly augmented early glycosaminoglycan (GAG) and fibronectin deposition, but induced significantly greater levels of collagen later in the repair process, compared with untreated wounds rTGF-beta 1 treatment led to rapidly enhanced collagen synthesis and maturation, without increased GAG deposition. In contrast, rbFGF treatment induced a predominantly angiogenic response in wounds, with a marked increase in endothelia and neovessels (P less than 0.0001), and increased wound collagenolytic activity (P less than 0.03). rbFGF-treated wounds did not evolve into collagen-containing scars and continued to accumulate only provisional matrix well past wound closure. These results provide new evidence that growth factors influence wound repair via different mechanisms: 1) rPDGF-BB accelerates deposition of provisional wound matrix; 2) rTGF-beta 1 accelerates deposition and maturation of collagen; and 3) rbFGF induces a profound monocellular angiogenic response which may lead to a marked delay in wound maturation, and the possible loss of the normal signal(s) required to stop repair. These results suggest that specific growth factors may selectively regulate components of the repair response by differing mechanisms, offering the potential for targeted therapeutic intervention.
authors.affiliation: Department of Experimental Pathology, Amgen Inc., Thousand Oaks, California 91320.
authors.forename: G F
authors.initials: GF
authors.lastname: Pierce
authors.forename: J E
authors.initials: JE
authors.lastname: Tarpley
authors.forename: D
authors.initials: D
authors.lastname: Yanagihara
authors.forename: T A
authors.initials: TA
authors.lastname: Mustoe
authors.forename: G M
authors.initials: GM
authors.lastname: Fox
authors.forename: A
authors.initials: A
authors.lastname: Thomason
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006097:Granulation Tissue / Q000503:physiopathology; D006133:Growth Substances / Q000494:pharmacology; D007700:Kinetics; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011817:Rabbits; D012867:Skin / Q000098:blood supply; D012883:Skin Ulcer / Q000378:metabolism / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D005353:Fibronectins; D006025:Glycosaminoglycans; D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D003094:Collagen