Gadolinium chloride inhibits pulmonary macrophage influx and prevents O-2-induced pulmonary hypertension in the neonatal rat

Newborn rats exposed to 60% O-2 for 14 d demonstrated a bronchopulmonary dy splasia-like lung morphology and pulmonary hypertension. A 21-aminosteroid antioxidant, U74389G, attenuated both pulmonary hypertension and macrophage accumulation in the O-2-exposed lungs. To determine Whether macrophage acc umulation played an essential role in the development of pulmonary hyperten sion in this model, pups were treated with gadolinium chloride (GdCl3) to r educe lung macrophage content. Treatment of 60% O-2-exposed animals with Gd Cl3 prevented right ventricular hypertrophy (p < 0.05) and smooth muscle hy perplasia around pulmonary vessels, but had no effect on morphologic change s in the lung parenchyma. In addition, GdCl3 inhibited 60% O-2-mediated inc reases in endothelin-1, 8-isoprostane, and nitrotyrosine residues. Organoty pic cultures of fetal rat distal lung cells were subjected to cyclical mech anical strain to assess the potential role of GdCl3-induced blockade of str etch-mediated cation channels in these effects. Mechanical strain caused a moderate increase of endothelin-1 (p < 0.05), which was unaffected by GdCl3 but had no effect on 8-isoprostane or nitric oxide synthesis. A critical r ole for endothelin-1 in O-2-mediated pulmonary hypertension was confirmed u sing the combined endothelin receptor antagonist SB217242. We concluded tha t pulmonary macrophage accumulation, in response to 60% O-2 mediated pulmon ary hypertension through upregulation of endothelin-1.