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Up-Regulation of Thrombin Activity Induced by Vascular Endothelial Growth Factor in Asthmatic Airways^*

^* From the Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Correspondence to: Hiroshi Kanazawa, MD, PhD, Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abenoku, Osaka, 545-8585, Japan; e-mail: kanazawa-h{at}med.osaka-cu.ac.jp

Abstract

Background: High expression of vascular endothelial growth factor (VEGF) induces subepithelial fibrosis associated with angiogenesis in patients with asthma. Thrombin is recognized as a new candidate mediating airway remodeling. Therefore, this study was designed to determine the role of up-regulated thrombin activity induced by VEGF on airway remodeling in patients with asthma.

Methods: Levels of biochemical parameters in induced sputum were examined in 21 asthmatic patients and 11 normal control subjects.

Results: Thrombin activity in induced sputum was significantly higher in asthmatic patients than in normal control subjects: median, 3.67 U/mL; range, 1.15 to 10.2 U/mL; vs median, 1.26 U/mL; range, 0.93 to 2.42 U/mL (p < 0.0001). In contrast, protein C activity in induced sputum was lower in asthmatic patients than in normal control subjects: median, 20%; range, 5 to 30%; vs 41%; range, 30 to 59% (p < 0.0001). VEGF level in induced sputum was positively correlated with thrombin activity in asthmatic patients (r = 0.55, p = 0.02), while inversely correlated with protein C activity (r = – 0.57, p = 0.01). Levels of basic fibroblast growth factor (bFGF), a major profibrotic factor, were also significantly higher in asthmatic patients than in normal control subjects. Moreover, thrombin activity was significantly correlated with bFGF level in asthmatic patients (r = 0.67, p = 0.003).

Conclusions: Increase in VEGF level leads to up-regulation of thrombin activity in asthmatic airways, and this elevated thrombin activity induces elevation of bFGF level. It will become to be a new strategy of asthma therapy to attenuate thrombin activity for the regulation of airway remodeling.

Key Words: airway remodeling • basic fibroblast growth factor • induced sputum