Detection of platelet-derived growth factor (PDGF)-AA in actively healing human wounds treated with recombinant PDGF-BB and absence of PDGF in chronic nonhealing wounds.
Some human chronic dermal wounds treated with recombinant platelet-derived growth factor-BB (rPDGF-BB) show increased healing coupled with fibroblast activation and granulation tissue formation. To determine whether endogenous PDGF is associated with healing and nonhealing dermal ulcer phenotypes, we developed monoclonal antibodies capable of recognizing the three isoforms of PDGF, AA, AB, and BB dimers, and capable of discriminating between two alternatively spliced A chain transcripts. We detected little PDGF isoform expression in normal skin and in nonhealing dermal ulcers. In contrast, in surgically created acute wounds and chronic ulcers treated with rPDGF-BB, markedly upregulated levels of PDGF-AA (long form) were found. In both types of wounds, increased PDGF-AA was detected primarily in capillaries and fibroblasts, although in rPDGF-BB-treated chronic wounds, widespread expression of PDGF-AA was somewhat delayed. With continued treatment, the long form of PDGF-AA, which can preferentially bind extracellular matrix, was expressed only in capillaries, while fibroblasts began synthesizing the short form of PDGF-AA. Within capillaries, all endothelial cells and varying numbers of pericytes and smooth muscle cells contained PDGF-AA. In all wounds, macrophages and keratinocytes were not a major contributor. While PDGF-BB and PDGF-AB were present in a minority of healing wounds, they were usually present at lower levels than PDGF-AA. PDGF-beta receptors, which bind only PDGF-BB and not other isoforms, were found in normal skin and granulation tissue, providing a molecular basis for treating human chronic wounds with exogenous rPDGF-BB.
Pierce
G F
GF
Department of Experimental Pathology, Amgen Inc., Thousand Oaks, California 91320, USA.
Tarpley
J E
JE
Tseng
J
J
Bready
J
J
Chang
D
D
Kenney
W C
WC
Rudolph
R
R
Robson
M C
MC
Vande Berg
J
J
Reid
P
P
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal; D001160:Arterioles / Q000473:pathology / Q000648:ultrastructure; D000077214:Becaplermin; D016466:CHO Cells; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000473:pathology / Q000648:ultrastructure; D005347:Fibroblasts / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D016253:Microscopy, Immunoelectron; D010982:Platelet-Derived Growth Factor / Q000032:analysis / Q000096:biosynthesis* / Q000627:therapeutic use*; D003668:Pressure Ulcer / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins / Q000032:analysis / Q000627:therapeutic use; D013119:Spinal Cord Injuries / Q000503:physiopathology; D014162:Transfection; D014945:Wound Healing / Q000187:drug effects
D000911:Antibodies, Monoclonal; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; C075278:platelet-derived growth factor A; D000077214:Becaplermin