Insulin-like Growth Factor I and Pulmonary Hypertension Induced by Continuous Air Embolization in Sheep

Chronic pulmonary hypertension is associated with arterial structural remodeling. Insulin-like growth factor I (IGF-I) has been proposed as one of the mediators of vascular change because of its ability to stimulate proliferation in, and elastin production by, cultured vascular smooth muscle cells. We have shown previously that 12 days of continuous air embolization into the pulmonary arterial circulation of sheep results in the functional and structural changes of chronic pulmonary hypertension. In the present study, measurements of IGF-I (by radioimmunoassay) and IGF-I binding protein activity in sheep lung lymph and plasma were made before and during the 12 days of air embolization in six sheep. Two untreated animals served as controls. Baseline lung lymph contained 23.5 ± 3.6 ng/ml (mean ± SEM) of IGF-I, and there was a slight increase to 36.7 ± 9.8 on day 3, but by day 6 levels were back to baseline. The flux of IGF-I from the lung (concentration times lymph flow) increased significantly by day 2 embolization and remained elevated through day 12 (baseline = 37.2 ± 11.1 ng/15 min; day 2 = 237.7 ± 55.8; day 5 = 190.2 ± 53.4; day 6 = 82.6 ± 21.9; day 12 = 78.7 ± 12.5). IGF-I binding protein activity was also present in lung lymph at baseline (29.6 ± 3.0%) and was unchanged during air embolization. Plasma levels of IGF-I and plasma binding protein activity remained at baseline throughout the 12 days of embolization (71.51 ± 34.48 ng/ml and 36.4 ± 3.5%, respectively). Immunohistochemical staining of lung biopsy tissue after 12 days of embolization demonstrated IGF immunoreactivity in the hyperplastic intima of muscular preacinar arteries. The increased levels of IGF-I in lung lymph and its appearance in the hyperplastic intima suggest a role for IGF-I in the pulmonary vascular remodeling of chronic pulmonary hypertension.