Long-term inhalation of high-dose nitric oxide increases intraalveolar activation of coagulation system in mice

Inhalation of nitric oxide (NO) is useful for the treatment of patients wit h pulmonary hypertension. However, the potential toxicity of inhaled NO is still unclear. Coagulation activation plays an important role in lung injur y. We assessed the effect of low- and high-dose inhaled NO on the coagulati on 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+O-2] group, fresh air, 2 ppm NO and O-2; and [RA+40 pp m NO+O-2] group, fresh air, 40 ppm NO and O-2. Each group was treated for 3 wk. Lung specimens of [RA+40 ppm NO] and [RA+40 ppm NO+O-2] groups showed significant nitrotyrosine immunoreactivity. BALF concentrations of total pr otein, thrombin and soluble tissue factor were significantly increased in m ice of [RA+40 ppm NO] and [RA+40 ppm NO+O-2] groups compared with [RA] grou p. However, BALF concentrations of total protein, thrombin, and soluble tis sue factor were not significantly increased in mice of [RA+2 ppm NO] and [R A+2 ppm NO+O-2] groups compared with [RA] group. Lung tissue factor mRNA ex pression was higher in the high-dose NO group than in the low-dose NO group . NO donor increased significantly tissue factor activity on alveolar epith elial cells. This study has shown for the first time that long-term inhalat ion of high, but not low, concentration of NO may activate the clotting sys tem by increasing the lung expression of tissue factor.