title: Inhibition of PAI-1 Via PAI-039 Improves Dermal Wound Closure in Diabetes.
abstract: Diabetes impairs the ability to heal cutaneous wounds, leading to hospitalization, amputations, and death. Patients with diabetes experience elevated levels of plasminogen activator inhibitor 1 (PAI-1), regardless of their glycemic control. It has been demonstrated that PAI-1-deficient mice exhibit improved cutaneous wound healing, and that PAI-1 inhibition improves skeletal muscle repair in mice with type 1 diabetes mellitus, leading us to hypothesize that pharmacologically mediated reductions in PAI-1 using PAI-039 would normalize cutaneous wound healing in streptozotocin (STZ)-induced diabetic (STZ-diabetic) mice. To simulate the human condition of variations in wound care, wounds were aggravated or minimally handled postinjury. Following cutaneous injury, PAI-039 was orally administered twice daily for 10 days. Compared with nondiabetic mice, wounds in STZ-diabetic mice healed more slowly. Wound site aggravation exacerbated this deficit. PAI-1 inhibition had no effect on dermal collagen levels or wound bed size. PAI-039 treatment failed to improve angiogenesis in the wounds of STZ-diabetic mice and blunted angiogenesis in the wounds of nondiabetic mice. Importantly, PAI-039 treatment significantly improved epidermal cellular migration and wound re-epithelialization compared with vehicle-treated STZ-diabetic mice. These findings support the use of PAI-039 as a novel therapeutic agent to improve diabetic wound closure and demonstrate the primary mechanism of its action to be related to epidermal closure.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Irena A
authors.initials: IA
authors.lastname: Rebalka
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Raleigh
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Donna M
authors.initials: DM
authors.lastname: D'Souza
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Samantha K
authors.initials: SK
authors.lastname: Coleman
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Rebalka
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada hawke@mcmaster.ca.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hawke
mesh_terms: D000818:Animals; D002465:Cell Movement; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D007210:Indoleacetic Acids / Q000494:pharmacology*; D037181:Lectins, C-Type / Q000032:analysis; D008264:Macrophages / Q000502:physiology; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis; D012867:Skin / Q000293:injuries*; D013311:Streptozocin; D014945:Wound Healing
chemical_list: D007210:Indoleacetic Acids; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D017395:Plasminogen Activator Inhibitor 1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface; C488103:tiplaxtinin; D013311:Streptozocin