Urokinase Attenuates Pulmonary Thromboembolism in an Animal Model by Inhibition of Inflammatory Response

Abstract

Inflammatory response is an important determining factor for the mortality of patients with pulmonary thromboembolism. Inflammatory mediators can promote thrombus formation and increase hemodynamic instability. Urokinase is a commonly used drug for the treatment of PTE. The effect of urokinase on inflammatory reaction in PTE is still unclear. Our study was aimed at evaluating the effects of the intervention of urokinase and urokinase combined with aspirin in PTE rats. Results revealed that a large amount of infiltrated inflammatory cells surrounding the bronchus, vessels, and pulmonary mesenchyme, and even pulmonary abscess were observed in the PTE rats. CX3CL1/CX3CR1 coexpression, CX3CL1/NF-κB coexpression, and TXA2 were significantly higher. After treatment with urokinase, pulmonary embolism was partially dissolved and inflammatory cell infiltration was significantly reduced. The expression of TNNI3, BNP, D2D, PASP, PADP, PAMP, and TXA2, as well as CX3CL1/CX3CR1 coexpression and CX3CL1/NF-κB coexpression were significantly lowered. Aspirin showed no synergistic action. Therefore, these findings suggested the occurrence of inflammation during the process of PTE in rats. Urokinase treatment reduced the inflammatory response.

Exogenous Urokinase Inhibits Proteasomal Degradation of Its Cognate Urokinase Plasminogen Activator Receptor

“…Treatment with UK significantly decreased apoptosis induced by H/R to levels observed in control cells (Figures 1A,B). Since APE is associated with increased secretion of inflammatory cytokines (Zagorski et al, 2003;Wang et al, 2013;Wang et al, 2014;Zhang et al, 2017;Shi et al, 2018), we next determined the expression of BNP, TNFα, and fractalkine (CX3CL1) in cell supernatants. Compared to control cells, H/R resulted in a significant increase in the expression of BNP, TNFα, and CX3CL1 (Figure 1C).…”

“…It has been well documented that APE is associated with inflammatory response and cell death, in parts mediated by mitogen-activated protein kinase, phosphoinositide 3-kinases/ protein kinase B, and nuclear factor-kappa beta signaling pathways (Apostolakis and Spandidos, 2013;Wang et al, 2013;Wang et al, 2014). APE-associated ischemia and pulmonary hypertension induce an increase in serum levels of cytokines and chemokines, including tumor necrosis factor-alpha (TNFα), interleukin (IL)-1β, IL-8, CX3CR1, CXCRL1, brain natriuretic peptide (BNP), troponin T, and D-dimer (Zagorski et al, 2003;Wang et al, 2013;Wang et al, 2014;Zhang et al, 2017;Shi et al, 2018). Pro-inflammatory chemokines and cytokines induce infiltration of immune cells in the lungs, including natural killer cells and T cells (Lang et al, 2013;Saghazadeh et al, 2015;Saghazadeh and Rezaei, 2016).…”

Rodent models of pulmonary embolism and chronic thromboembolic pulmonary hypertension

“… TE administration – jugular vein 32 days CTEPH + [ 90 ] 11 Rats Autologous thrombi – 1 × 2 mm 30 TE – Urokinase effect on PE formation Blood sampling – tail vein. TE administration – jugular vein 6 h – [ 121 ] 12 Rats Autologous thrombi + tranexamic acid – 1 × 3 mm Administration was repeated after 4 and 7 days from the 1st administration – Study of transcription factor O-1 and apoptosis role in remodeling of pulmonary artery branches in CTEPH Blood sampling – orbital vein. TE administration – jugular vein 1,2 and 4 weeks CTEPH + [ 86 ] 13 Rats Autologous thrombi – 1,1 × 2 mm 25 TE Incubation on water bath 70 °C, 10 min Evaluation of low molecular weight heparin effect on intimal hyperplasia in acute PE.…”

MicroRNA 449a can Attenuate Protective Effect of Urokinase Against Pulmonary Embolism

“…It has been well documented that APE is associated with inflammatory response and cell death, which might be mediated by mitogen activated protein kinase (MAPK), Phosphoinositide 3-kinases/protein kinase B (PI3K/Akt), and nuclear factor—kappa beta (NF-κβ) signaling pathways ( Apostolakis and Spandidos, 2013 ; Wang et al, 2013 ; Wang et al, 2014 ). The ischemia and pulmonary hypertension involved in APE can induce an increase in serum levels of cytokines and chemokines, including tumor necrosis factor-alpha (TNFα), interleukin (IL)-1β, IL-8, CX3CR1, CXCRL1, brain natriuretic peptide (BNP), troponin T (TnT) and D-dimer (D2D) ( Zagorski et al, 2003 ; Wang et al, 2013 ; Wang et al, 2014 ; Zhang et al, 2017 ; Shi et al, 2018 ). These pro-inflammatory chemokines and cytokines subsequently induce infiltration of immune cells in the lungs including natural killer cells and T cells ( Lang et al, 2013 ; Saghazadeh et al, 2015 ; Saghazadeh and Rezaei, 2016 ).…”