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Chih-Ching Chang,¹ Hui-Fen Chiu,² Yih-Shyuan Wu,¹ Yi-Chih Li,³ Mei-Ling Tsai,⁴ Chen-Kuo Shen,¹ and Chun-Yuh Yang¹

¹Graduate Institute of Public Health, ²Department of Pharmacology, and ³Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; ⁴Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Abstract
Ultrafine carbon black (ufCB) can cause proinflammatory response and increase alveolar-capillary permeability. However, the mechanism underlying the increased permeability is not well characterized. Vascular endothelial growth factor (VEGF) is originally recognized as a vascular permeability factor. Oxidative stress generated by hydrogen peroxide (H₂O₂) stimulates VEGF gene expression. The purpose of this study was to explore the role of VEGF in ufCB-induced alveolar-capillary permeability. Intratracheal instillation of 200 µg ufCB in mice caused a significant and sustained increase of total proteins in bronchoalveolar lavage (BAL) fluid, with the maximal increase at 21 hr postinstillation. The influx of neutrophils did not significantly increase until 16 hr. It reached the highest level at 21 hr and returned to the basal level by 42 hr. Tumor necrosis factor- was significantly elevated only at 4 hr. ufCB induced significant increases of VEGF in BAL fluid throughout the study period, with the peak increase at 16 hr. The nonsecreted isoform VEGF188 was not altered after 16 hr of exposure to ufCB. Moreover, there was a strong correlation between VEGF and total proteins in BAL fluid (R² = 0.7352, p < 0.01) . In vivo study supported the role of reactive oxygen species (ROSs) in ufCB-induced VEGF release and protein leakage. The involvement of ROSs was strengthened by the fact that interventions with N-acetylcysteine prevented ufCB-induced generation of ROSs and VEGF in vitro. Our study for the first time demonstrates that ufCB induces the production of VEGF, which is associated with the increase of alveolar-capillary permeability. The induction of VEGF by ufCB acts through an ROS-dependent pathway. Key words: intratracheal instillation, permeability, reactive oxygen species, ultrafine carbon black, vascular endothelial growth factor, VEGF. Environ Health Perspect 113:454-460 (2005) . doi:10.1289/ehp.7457 available via http://dx.doi.org/ [Online 4 January 2005]

Address correspondence to C.-Y. Yang, Graduate Institute of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan. Telephone: 886-7-3121101, ext. 2141. Fax: 886-7-3110811. E-mail: chunyuh@kmu.edu.tw

This study was supported by a grant from National Health Research Institute, Taiwan, Republic of China (NHRI-CN-EO-9201S) .

The authors declare they have no competing financial interests.

Received 28 July 2005 ; accepted 4 January 2005.