Systemic administration of anti-urokinase plasminogen activator receptor monoclonal antibodies induces hepatic fibrin deposition in tissue-type plasminogen activator deficient mice

Research output: Contribution to journalArticle

Standard

Systemic administration of anti-urokinase plasminogen activator receptor monoclonal antibodies induces hepatic fibrin deposition in tissue-type plasminogen activator deficient mice. / Jögi, Annika; Pass, J; Hoyer-Hansen, G; Lund, L R; Nielsen, B S; Dano, K; Romer, J.

In: Journal of Thrombosis and Haemostasis, Vol. 5, No. 9, 2007, p. 1936-1944.

Research output: Contribution to journalArticle

Harvard

APA

CBE

MLA

Vancouver

Author

RIS

TY - JOUR

T1 - Systemic administration of anti-urokinase plasminogen activator receptor monoclonal antibodies induces hepatic fibrin deposition in tissue-type plasminogen activator deficient mice

AU - Jögi, Annika

AU - Pass, J

AU - Hoyer-Hansen, G

AU - Lund, L R

AU - Nielsen, B S

AU - Dano, K

AU - Romer, J

N1 - The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200)

PY - 2007

Y1 - 2007

N2 - BACKGROUND: Degradation of extracellular matrix proteins, such as fibrin, is pivotal to tumor invasion. Inhibition of the interaction between urokinase plasminogen activator (u-PA) and its receptor (u-PAR), and hence pro-u-PA activation, is an attractive approach to anti-invasive cancer therapy. A number of inhibitors exist for the human system, but because of species specificity none of these are efficient in mice. We have recently generated an inhibitory monoclonal antibody (mAb) against mouse u-PAR (mR1) by immunization of u-PAR-deficient mice. OBJECTIVES: To evaluate the effect of mR1 in vivo in a physiological setting sensitive to deregulated fibrinolysis, we have administered mR1 systemically and quantitated the effect on liver fibrin accumulation. METHODS: Wild-type and tissue-type plasminogen activator (t-PA) deficient mice were administered with mR1, or control antibody, during 6 weeks. Thereafter, the livers were retrieved and the amount of liver fibrin measured by unbiased morphometrical analysis of immunofluorescence signal. RESULTS: Systemic administration of mR1 caused significantly increased fibrin signal in anti-u-PAR treated t-PA-deficient mice compared to mock-treated, which mimics the phenotype of u-PAR;t-PA double-deficient mice. Fibrin and fibronectin accumulated within the sinusoidal space and was infiltrated by inflammatory cells. Analysis of small and rare hepatic fibrin plaques observed in t-PA-deficient mice showed infiltrating macrophages that, contrary to surrounding Kuppfer cells, expressed u-PAR. CONCLUSION: We show that u-PAR-expressing macrophages are involved in cell-mediated fibrinolysis of liver fibrin deposits, and that the antimouse-u-PAR mAb is effective in vivo and thus suited for studies of the effect of targeting the u-PA/u-PAR interaction in mouse cancer models.

AB - BACKGROUND: Degradation of extracellular matrix proteins, such as fibrin, is pivotal to tumor invasion. Inhibition of the interaction between urokinase plasminogen activator (u-PA) and its receptor (u-PAR), and hence pro-u-PA activation, is an attractive approach to anti-invasive cancer therapy. A number of inhibitors exist for the human system, but because of species specificity none of these are efficient in mice. We have recently generated an inhibitory monoclonal antibody (mAb) against mouse u-PAR (mR1) by immunization of u-PAR-deficient mice. OBJECTIVES: To evaluate the effect of mR1 in vivo in a physiological setting sensitive to deregulated fibrinolysis, we have administered mR1 systemically and quantitated the effect on liver fibrin accumulation. METHODS: Wild-type and tissue-type plasminogen activator (t-PA) deficient mice were administered with mR1, or control antibody, during 6 weeks. Thereafter, the livers were retrieved and the amount of liver fibrin measured by unbiased morphometrical analysis of immunofluorescence signal. RESULTS: Systemic administration of mR1 caused significantly increased fibrin signal in anti-u-PAR treated t-PA-deficient mice compared to mock-treated, which mimics the phenotype of u-PAR;t-PA double-deficient mice. Fibrin and fibronectin accumulated within the sinusoidal space and was infiltrated by inflammatory cells. Analysis of small and rare hepatic fibrin plaques observed in t-PA-deficient mice showed infiltrating macrophages that, contrary to surrounding Kuppfer cells, expressed u-PAR. CONCLUSION: We show that u-PAR-expressing macrophages are involved in cell-mediated fibrinolysis of liver fibrin deposits, and that the antimouse-u-PAR mAb is effective in vivo and thus suited for studies of the effect of targeting the u-PA/u-PAR interaction in mouse cancer models.

U2 - 10.1111/j.1538-7836.2007.02653.x

DO - 10.1111/j.1538-7836.2007.02653.x

M3 - Article

VL - 5

SP - 1936

EP - 1944

JO - Journal of Thrombosis and Haemostasis

T2 - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

IS - 9

ER -