Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice

TY - JOUR

T1 - Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice

AU - Lund, Leif R

AU - Green, Kirsty A

AU - Stoop, Allart A

AU - Ploug, Michael

AU - Almholt, Kasper

AU - Lilla, Jennifer

AU - Nielsen, Boye S

AU - Christensen, Ib J.

AU - Craik, Charles S

AU - Werb, Zena

AU - Danø, Keld

AU - Rømer, John

N1 - Keywords: Animals; Dipeptides; Enzyme Activation; Fibrinolysin; Fibrinolysis; Keratinocytes; Male; Mice; Mice, Inbred C57BL; Plasma Kallikrein; Plasminogen; Serine Proteinase Inhibitors; Skin; Time Factors; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Wound Healing

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

U2 - 10.1038/sj.emboj.7601173

DO - 10.1038/sj.emboj.7601173

M3 - Journal article

C2 - 16763560

SN - 0261-4189

VL - 25

SP - 2686

EP - 2697

JO - E M B O Journal

JF - E M B O Journal

IS - 12

ER -