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Am. J. Respir. Crit. Care Med., Volume 163, Number 7, June 2001, 1676-1682

Long-term Inhalation of High-dose Nitric Oxide Increases Intraalveolar Activation of Coagulation System in Mice

TETSU KOBAYASHI, ESTEBAN C. GABAZZA, SHINO SHIMIZU, HIROKI YASUI, HISAMICHI YUDA, OSAMU HATAJI, KAZUO MARUYAMA, TORU YAMAUCHI, KOJI SUZUKI, YUKIHIKO ADACHI, and OSAMU TAGUCHI

Third Department of Internal Medicine, Department of Molecular Pathobiology, Department of Anesthesiology, and Department of Public Hygiene, Mie University School of Medicine, Tsu, Mie, Japan

Inhalation of nitric oxide (NO) is useful for the treatment of patients with pulmonary hypertension. However, the potential toxicity of inhaled NO is still unclear. Coagulation activation plays an important role in lung injury. We assessed the effect of low- and high-dose inhaled NO on the coagulation system in the intraalveolar space of mice. The animals were assigned to five groups (n = 6): [RA] group, mice exposed to fresh air alone; [RA+2 ppm NO] group, fresh air and 2 ppm NO; [RA+40 ppm NO] group, fresh air and 40 ppm NO; [RA+2 ppm NO+O2] group, fresh air, 2 ppm NO and O2; and [RA+40 ppm NO+O2] group, fresh air, 40 ppm NO and O2. Each group was treated for 3 wk. Lung specimens of [RA+40 ppm NO] and [RA+40 ppm NO+O2] groups showed significant nitrotyrosine immunoreactivity. BALF concentrations of total protein, thrombin and soluble tissue factor were significantly increased in mice of [RA+40 ppm NO] and [RA+40 ppm NO+O2] groups compared with [RA] group. However, BALF concentrations of total protein, thrombin, and soluble tissue factor were not significantly increased in mice of [RA+2 ppm NO] and [RA+2 ppm NO+O2] groups compared with [RA] group. Lung tissue factor mRNA expression was higher in the high-dose NO group than in the low-dose NO group. NO donor increased significantly tissue factor activity on alveolar epithelial cells. This study has shown for the first time that long-term inhalation of high, but not low, concentration of NO may activate the clotting system by increasing the lung expression of tissue factor.




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