Growth factors in porcine full and partial thickness burn repair. Differing targets and effects of keratinocyte growth factor, platelet-derived growth factor-BB, epidermal growth factor, and neu differentiation factor.
The topical application of recombinant growth factors such as epidermal growth factor, platelet-derived growth factor-BB homodimer (rPDGF-BB), keratinocyte growth factor (rKGF), and neu differentiation factor has resulted in significant acceleration of healing in several animal models of wound repair. In this study, we established highly reproducible and quantifiable full and deep partial thickness porcine burn models in which burns were escharectomized 4 or 5 days postburn and covered with an occlusive dressing to replicate the standard treatment in human burn patients. We then applied these growth factors to assess their efficacy on several parameters of wound repair: extracellular matrix and granulation tissue production, percent reepithelialization, and new epithelial area. In full thickness burns, only rPDGF-BB and the combination of rPDGF-BB and rKGF induced significant changes in burn repair. rPDGF-BB induced marked extracellular matrix and granulation tissue production (P = 0.013) such that the burn defect was filled within several days of escharectomy, but had no effect on new epithelial area or reepithelialization. The combination of rPDGF-BB and rKGF in full thickness burns resulted in a highly significant increase in extracellular matrix and granulation tissue area (P = 0.0009) and a significant increase in new epithelial area (P = 0.007), but had no effect on reepithelialization. In deep partial thickness burns, rKGF induced the most consistent changes. Daily application of rKGF induced a highly significant increase in new epithelial area (P < 0.0001) but induced only a modest increase in reepithelialization (83.7% rKGF-treated versus 70.2% control; P = 0.016) 12 days postburn. rKGF also doubled the number of fully reepithelialized burns (P = 0.02) at 13 days postburn, at least partially because of marked stimulation of both epidermal and follicular proliferation as assessed by proliferating cell nuclear antigen expression. In situ hybridization for KGFR in porcine burns revealed strong expression of KGFR on hair follicles and basal epidermis, confirming direct rKGF action on follicular as well as epidermal keratinocytes. Although the epithelial proliferation induced by rKGF resulted in marked neoepidermal psoriasiform hyperplasia with exaggerated rete ridges and neoepidermal and follicular maturation as assessed by expression of cytokeratin 10, a marker of keratinocyte terminal differentiation was not delayed and appeared to be accelerated in some rKGF-treated burns. Recombinant epidermal growth factor induced a trend toward increased new epithelial area in deep partial thickness burns, but had no effect on reepithelialization. The recombinant neu differentiation factor-alpha 2 isoform had no significant biological effects in either full or deep partial thickness burns.(ABSTRACT TRUNCATED AT 250 WORDS)
D000287:Administration, Topical; D000818:Animals; D000077214:Becaplermin; D002056:Burns / Q000473:pathology* / Q000628:therapy; D002455:Cell Division / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000627:therapeutic use; D004848:Epithelium / Q000187:drug effects; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006023:Glycoproteins / Q000627:therapeutic use; D006133:Growth Substances / Q000627:therapeutic use*; D006965:Hyperplasia; D017403:In Situ Hybridization; D016023:Integrins / Q000187:drug effects; D015603:Keratinocytes / Q000187:drug effects; D020880:Neuregulins; D010982:Platelet-Derived Growth Factor / Q000627:therapeutic use; D020574:Proto-Oncogene Proteins c-sis; D011565:Psoriasis / Q000473:pathology; D011994:Recombinant Proteins / Q000627:therapeutic use; D013552:Swine; D014945:Wound Healing / Q000187:drug effects*
D051526:Fibroblast Growth Factor 10; D006023:Glycoproteins; D006133:Growth Substances; D016023:Integrins; D020880:Neuregulins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D051523:Fibroblast Growth Factor 7; D000077214:Becaplermin; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor