Abstract
BackgroundProteolytic 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.Methodology/Principal FindingsTo 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-deficent mice. Immunohistochemistry revealed that fibrin accumulated in the wounds of such mU1-treated tPA-deficent mice and that keratinocyte tongues were aberrant. Together these abnormalities lead to compromised epidermal closure.Conclusions/SignificanceOur 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.
Highlights
Tissue remodeling and confined degradation of the extracellular matrix (ECM) is pivotal in several physiological and pathological processes involving cell migration [1,2,3,4,5]
In order to obtain acute disruption of urokinase-type plasminogen activator (uPA) activity, we used a neutralizing monoclonal antibody directed against murine uPA, mU1, in a thoroughly characterized wound-healing model [19,29], where a 20 mm full thickness incisional skin wound is inflicted along the back midline of an anaesthetized mouse
We have previously shown that mU1 is capable of inhibiting uPA-mediated plasminogen activation without interfering with uPA receptor binding in vitro as well as in vivo
Summary
Tissue remodeling and confined degradation of the extracellular matrix (ECM) is pivotal in several physiological and pathological processes involving cell migration [1,2,3,4,5]. This tightly controlled proteolytic degradation of the ECM is mainly performed by the serine protease plasmin and members of the matrix metalloproteinase (MMP) family [3,6]. 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). Individual genetic deficiencies in either uPA or tPA lead to wound healing kinetics with no or only slightly delayed closure of skin wounds
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