Neutralisation of uPA with a monoclonal antibody reduces plasmin formation and delays skin wound healing in tPA-deficient mice.
BACKGROUND
Proteolytic degradation by plasmin and metalloproteinases is essential for epidermal regeneration in skin wound healing. Plasminogen deficient mice have severely delayed wound closure as have mice simultaneously lacking the two plasminogen activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). In contrast, individual genetic deficiencies in either uPA or tPA lead to wound healing kinetics with no or only slightly delayed closure of skin wounds.


RESULTS
To evaluate the therapeutic potential in vivo of a murine neutralizing antibody directed against mouse uPA we investigated the efficacy in skin wound healing of tPA-deficient mice. Systemic administration of the anti-mouse uPA monoclonal antibody, mU1, to tPA-deficient mice caused a dose-dependent delay of skin wound closure almost similar to the delayed kinetics observed in uPA;tPA double-deficient mice. Analysis of wound extracts showed diminished levels of plasmin in the mU1-treated tPA-deficient mice. Immunohistochemistry revealed that fibrin accumulated in the wounds of such mU1-treated tPA-deficient mice and that keratinocyte tongues were aberrant. Together these abnormalities lead to compromised epidermal closure.


CONCLUSIONS
Our findings demonstrate that inhibition of uPA activity with a monoclonal antibody in adult tPA-deficient mice mimics the effect of simultaneous genetic ablation of uPA and tPA. Thus, application of the murine inhibitory mU1 antibody provides a new and highly versatile tool to interfere with uPA-activity in vivo in mouse models of disease.
Jögi
Annika
A
Finsen Laboratory, Copenhagen University Hospital, Copenhagen Biocenter, Copenhagen, Denmark.
Rønø
Birgitte
B
Lund
Ida K
IK
Nielsen
Boye S
BS
Ploug
Michael
M
Høyer-Hansen
Gunilla
G
Rømer
John
J
Lund
Leif R
LR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009500:Neutralization Tests; D012867:Skin / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology*; D010959:Tissue Plasminogen Activator / Q000172:deficiency* / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000276:immunology*; D014945:Wound Healing / Q000187:drug effects*; D014947:Wounds and Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
D000911:Antibodies, Monoclonal; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator