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Elevated Oxidative Stress and Reciprocal Reduction of Vascular Endothelial Growth Factor Levels With Severity of COPD^*

^* 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

Study objectives: The prevalent theory concerning the pathogenesis of COPD is that it is an imbalance between oxidants and antioxidants. However, it has been reported that a decrease in vascular endothelial growth factor (VEGF) might affect the pathogenesis of COPD. Therefore, this study was designed to examine the differences between oxidative stress and VEGF levels, and the severity of COPD.

Design: Controlled cross-sectional analysis.

Setting: University hospital.

Participants: Twelve healthy control subjects and 57 COPD patients were included in this study. These COPD patients were divided into four groups based on the Global Initiative for Chronic Obstructive Lung Disease classification (mild COPD, 14 patients; moderate COPD, 15 patients; severe COPD, 16 patients; very severe COPD, 12 patients).

Measurements and results: Inflammatory markers, degree of oxidative stress, and VEGF levels were examined in sputum samples from all subjects. Nitrogen oxide levels in induced sputum were significantly higher in COPD patients than in healthy control subjects, and they increased with increases in the severity of COPD. In contrast, peroxynitrite inhibitory activity decreased with increases in the severity of COPD. Therefore, the mean (SD) peroxynitrite stress (ie, the nitrogen oxide level/peroxynitrite inhibitory activity ratio) steeply increased with increases in the severity of COPD (mild COPD: 8.4; SD, 1.5; p = 0.02; moderate COPD: 10.8; SD, 1.4; p < 0.0001; severe COPD: 14.5; SD, 2.5; p < 0.0001; very severe COPD: 18.3; SD, 4.1; p < 0.0001) compared with that of healthy control subjects. VEGF levels in induced sputum reciprocally decreased with severity of COPD (mild COPD: 1,360 pg/mL; SD, 800 pg/mL; p = 0.97; moderate COPD: 1,180 pg/mL; SD, 760 pg/mL; p = 0.50; severe COPD: 650 pg/mL; SD, 450 pg/mL; p = 0.007; very severe COPD: 480 pg/mL, SD, 240 pg/mL; p = 0.002). In addition, peroxynitrite inhibitory activity in COPD patients exhibited an accelerated decline from the mean VEGF level in healthy control subjects.

Conclusions: Elevated oxidative stress levels and a reciprocal reduction of VEGF levels in induced sputum were prominent with increases in the severity of COPD. Thus, epithelial cell injury mediated by oxidative stress may induce the decrease in lung VEGF levels, resulting in the promotion of the development of COPD.

Key Words: COPD • interleukin-8 • nitrogen oxides • peroxynitrite • vascular endothelial growth factor