Abstract 980: Intratracheal Gene Transfer of Extracellular Superoxide Dismutase Suppresses Monocrotaline-Induced Pulmonary Hypertension
Background: The most commonly used model of pulmonary hypertension (PH) is the monocrotaline (MCT) model. There is no evidence that extracellular superoxide dismutase (ECSOD) plays a role in the MCT-induced PH.
Methods and Results: MCT (40 mg/kg)-injected rats were concomitant intratracheal administered with 0.5 mL of saline (MCT group), an adenovirus expressing β-galactosidase (3×109 plaque-forming units [pfu], Adβgal group), or human ECSOD (3×109 pfu, AdECSOD group). By intratracheal gene transfer, β-galactosidase or ECSOD was diffuse expressed in airway and alveolar epithelial cells. The ECSOD concentrations in lung tissue, bronchoalveolar lavage and plasma reached a peak 5 days after the ECSOD gene transfer and, particularly in lung tissue, decreased gradually over 14 –21 days. These ECSOD concentrations in the AdECSOD group were significantly higher than those in the other groups (n=4 each, p<0.0001). Although systolic blood pressure and heart rate measured by tail-cuff mehod were statistically similar 28 days after the MCT injection, right ventricular systolic pressure and the weight ratio of the right ventricle to the left ventricle plus septum were significantly lower in the AdECSOD group (n=8, 42.50±1.46 mm Hg and 0.453±0.029) than in the MCT group (n=8, 59.89±1.61 mm Hg and 0.636±0.022) or the Adβgal group (n=6, 61.50±2.61 mm Hg and 0.653±0.038). Moreover, vascular remodeling and proliferation of vascular smooth muscle cells in pulmonary arteries were markedly suppressed in the AdECSOD group. As the mechanism of these effects, 8-isoprostane in lung tissue was significantly reduced in the AdECSOD group (n=4 each, p<0.01).
Conclusions: Diffuse ECSOD expression in epithelial cells by intratracheal gene transfer can suppress the development of the MCT-induced PH in rats. We suggest that ECSOD may act as the antioxidant and that increased oxidative stress may be important in the pathogenesis of MCT-induced model of PH.