Pneumologie 2005; 59 - A30
DOI: 10.1055/s-2005-925514

Role of urokinase type plasminogen (uPA) in pulmonary vascular remodeling in a murine model of hypoxia induced pulmonary hypertension

BK Dahal 1, RT Schermuly 1, P Markat 1, C Ruppert 1, R Schmidt 1, M Korfei 1, W Seeger 1, N Weissman 1, A Guenther 1
  • 1Department of Internal Medicine, University of Gießen Lung Centre, Gießen

Background:

uPA is a serine proteinase involved in intravascular as well as extravascular proteolytic processes. Among the plasminogen activator inhibitors (PAIs), PAI-1 is the principle physiological inhibitor. A balance between fibrinolytic and antifibrinolytic pathways is essential for vascular physiology and alterations of the fibrinolytic system have been reported in patients with primary pulmonary hypertension (PPH). Similarly, intravascular thrombosis and induction of PAI-1 have been described in hypoxia induced pulmonary hypertension in mice. However, the precise role of uPA in vascular remodeling is still uncertain.

Objective:

This study aims to investigate the role of uPA in vascular remodeling in a mouse model of hypoxia induced pulmonary hypertension.

Methods:

Wild type, uPA knock out (KO), specific uPA inhibitor (CJ463) treated- and continuously uPA infused-mice, all with C57BL/6N genetic background, were exposed to normoxia (21% O2) and hypoxia (10% O2) for 4 weeks. At the end of experiment, mice were sacrificed for hemodynamic measurement. The lungs were formalin-fixed for morphometric analysis and hearts were dissected to separate right ventricle (RV) from left ventricle and septum (LV+S).

Results:

Both, uPA inhibitor treated and KO mice showed right ventricular hypertrophy (increased RV/ LV+S ratio) under chronic hypoxia and this ratio was not significantly different from the hypoxic control mice. Continuous infusion of uPA, however, showed a dose dependent response, with reduced right ventricular hypertrophy compared to the hypoxic control mice especially in the high dose group (p<0.05).

Conclusion:

In our model, inhibition of uPA activity or absence of uPA does not seem to impair pulmonary vascular remodeling at the level of right ventricular hypertrophy.

Continuous infusion of uPA through osmotic mini pump reduced right ventricular hypertrophy suggesting a possible beneficial effect of hyperfibrinolysis. Further study on the histomorphometry of the formalin fixed lungs, and expression profiling of uPA and PAI-1 in lungs from both the animal model and human patients are required to the further elucidate the role of uPA in the pulmonary vascular remodeling.