title: Targeted Inhibition of PAI-1 Activity Impairs Epithelial Migration and Wound Closure Following Cutaneous Injury.
abstract: Objective:Aberrant plasminogen activator inhibitor-1 (PAI-1) expression and activity have been implicated in bleeding disorders, multiorgan fibrosis, and wound healing anomalies. This study details the physiological consequences of targeted PAI-1 functional inhibition on cutaneous injury repair.Approach:Dorsal skin wounds from FVB/NJ mice, created with a 4 mm biopsy punch, were treated topically with the small-molecule PAI-1 antagonist tiplaxtinin (or vehicle control) for 5 days and then analyzed for markers of wound repair.Results:Compared to controls, tiplaxtinin-treated wounds displayed dramatic decreases in wound closure and re-epithelialization. PAI-1 immunoreactivity was evident at the migratory front in all injury sites indicating these effects were due to PAI-1 functional blockade and not PAI-1 expression changes. Stimulated HaCaT keratinocyte migration in response to recombinant PAI-1in vitrowas similarly attenuated by tiplaxtinin. While tiplaxtinin had no effect on keratinocyte proliferation, cell cycle progression, or apoptosis, it effectively reduced collagen deposition, the number of Ki-67+fibroblasts, and incidence of differentiated myofibroblasts (i.e., smooth muscle α-actin immunoreactive cells), but not fibroblast apoptosis.Innovation:The role for PAI-1 in hemostasis and fibrinolysis is established; involvement of PAI-1 in cutaneous wound healing, however, remains unclear. This study tests the effect of a small-molecule PAI-1 inhibitor in a murine model of skin wound repair.Conclusion:Loss of PAI-1 activity significantly impaired wound closure. Re-epithelialization and fibroblast recruitment/differentiation were both reduced in tiplaxtinin-treated mice. Therapies directed at manipulation of PAI-1 expression and/or activity may have applicability as a treatment option for chronic wounds and scarring disorders.
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical College , Albany, New York.
authors.forename: Tessa M
authors.initials: TM
authors.lastname: Simone
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical College , Albany, New York.
authors.forename: Whitney M
authors.initials: WM
authors.lastname: Longmate
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida , Gainesville, Florida.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Law
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical College , Albany, New York.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Higgins