Gallium nitrate accelerates partial thickness wound repair and alters keratinocyte integrin expression to favor a motile phenotype.
The nitrate form of the Group III transitional element gallium (GN) increases expression of specific structural components of the provisional wound matrix (i.e., collagen type I, fibronectin) in human dermal fibroblasts. To evaluate the potential of GN as a therapeutic option in management of cutaneous trauma, GN-treated partial thickness porcine wounds and experimentally "injured" human keratinocyte (NHK) monolayer cultures were compared with mirror image control (i.e., saline-treated) sites. GN suppressed cell proliferation in both models, as determined by reduced Ki-67 reactivity and significant lengthening of keratinocyte cell cycle transit times, while effectively promoting reepithelialization. The primary effect of GN was apparently to promote cell migration, as neither epidermal thickness nor epidermal differentiation was altered as a result of GN exposure in vivo or in vitro. Significantly enhanced epidermal reepithelialization was associated with alterations in expression of several keratinocyte integrin subunits. GN induced a significant increase in alpha5 expression. alpha5beta1 switching is a characteristic of the motile phenotype in the setting of cutaneous injury. Concomitantly, GN treatment also induced a dramatic (70%) decrease in the expression of the alpha3 subunit; alpha3beta1 binds laminin 5 and is associated with hemidesmosome formation and reestablishment of a nonmotile phenotype. Taken together, the GN-induced changes in integrin expression favor acellular migration. While the molecular mechanism of GN action on resident cells of the skin remains to be defined, these data suggest that GN administration which represses MMP activity in the wound and increases matrix synthesis also accelerates NHK motility and, thereby, may be a useful therapeutic agent for wound repair.
Goncalves
John
J
Department of Surgery, Endocrine Division, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA.
Wasif
Nabil
N
Esposito
Darren
D
Coico
Jonathan M
JM
Schwartz
Brian
B
Higgins
Paul J
PJ
Bockman
Richard S
RS
Staiano-Coico
Lisa
L
D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D024042:Collagen Type I / Q000032:analysis; D000078404:Epidermal Cells; D005353:Fibronectins / Q000032:analysis; D005434:Flow Cytometry; D005708:Gallium / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D016023:Integrins / Q000032:analysis*; D015603:Keratinocytes / Q000737:chemistry* / Q000187:drug effects; D019394:Ki-67 Antigen / Q000032:analysis; D012867:Skin / Q000293:injuries; D013552:Swine; D014945:Wound Healing / Q000187:drug effects*
D024042:Collagen Type I; D005353:Fibronectins; D016023:Integrins; D019394:Ki-67 Antigen; D005708:Gallium; C027235:gallium nitrate