Persistent Pulmonary Hypertension Syndrome of the Neonate (PPHN) is commonly seen in association with lung hypoplasia, but its pathogenesis is unknown. We studied fetal rats subjected to closure of the ductus arteriosus to evaluate the associated lung changes. Indomethacin (1.6 mg/kg gastric, BID) was administered to pregnant rats on day 19 of gestation for two, three, or four days. Animals receiving water, served as controls. Following completion of the treatment, the fetuses were delivered by Cesarean section, killed and the lungs and heart were studied. Results: Whereas closure of the ductus for two days resulted in a significant increase in right ventricular weight, only following three or four days treatment, histological changes compatible with PPHN were observed. The right to left ventricular wall ratio increased from 1.2±0.4 in the control to 1.6±0.1 in the four days treatment group (P<0.01). The medial thickness of 0-25 μ external diameter vessels was significantly greater (39.2±1.3 vs 31.8±1.5%; P<0.01) and for arterial vessels of all diameters the adventicia was significantly thicker (P<0.01) in the four days experimental group. Following ductus closure for four days, lung hypoplasia characterized by a reduction in the lung/body weight from 0.03±0.001 to 0.02±0.001 (P<0.01) (Figure), total wet lung weight from 146±4 to 97±4 mg (P<0.01), and total lung extractable protein from 5.7±0.7 to 4.0±0.3 mg (P<0.01) were observed. In conclusion, indomethacin-induced closure of the ductus arteriosus in the fetal rat results in pulmonary hypertension and lung hypoplasia. We speculate that in the PPHN syndrome, a decreased lung blood flow and/or vascular remodelling changes may result in pulmonary hypoplasia. (Supported by grants from the Heart and Stroke Found, and MRC)

figure 1

Figure 1