Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice.
Simultaneous ablation of the two known activators of plasminogen (Plg), urokinase-type (uPA) and the tissue-type (tPA), results in a substantial delay in skin wound healing. However, wound closure and epidermal re-epithelialization are significantly less impaired in uPA;tPA double-deficient mice than in Plg-deficient mice. Skin wounds in uPA;tPA-deficient mice treated with the broad-spectrum matrix metalloproteinase (MMP) inhibitor galardin (N-[(2R)-2-(hydroxamido-carbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide) eventually heal, whereas skin wounds in galardin-treated Plg-deficient mice do not heal. Furthermore, plasmin is biochemically detectable in wound extracts from uPA;tPA double-deficient mice. In vivo administration of a plasma kallikrein (pKal)-selective form of the serine protease inhibitor ecotin exacerbates the healing impairment of uPA;tPA double-deficient wounds to a degree indistinguishable from that observed in Plg-deficient mice, and completely blocks the activity of pKal, but not uPA and tPA in wound extracts. These findings demonstrate that an additional plasminogen activator provides sufficient plasmin activity to sustain the healing process albeit at decreased speed in the absence of uPA, tPA and galardin-sensitive MMPs and suggest that pKal plays a role in plasmin generation.
Lund
Leif R
LR
Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, Copenhagen, Denmark. lund@inet.uni2.dk
Green
Kirsty A
KA
Stoop
Allart A
AA
Ploug
Michael
M
Almholt
Kasper
K
Lilla
Jennifer
J
Nielsen
Boye S
BS
Christensen
Ib J
IJ
Craik
Charles S
CS
Werb
Zena
Z
Danø
Keld
K
Rømer
John
J
D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020842:Plasma Kallikrein / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D012867:Skin / Q000166:cytology / Q000473:pathology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D015842:Serine Proteinase Inhibitors; D010958:Plasminogen; D020842:Plasma Kallikrein; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator