Pulmonary feedback and gestational age-dependent regulation of fetal breathing movements

Prenatal lung development requires fetal breathing movements (FBM). To investigate the dependence of FBM on feedback originating from the lung, we hypothesized that pneumonectomy stimulates FBM. Time-dated fetal sheep underwent bilateral pneumonectomy, unilateral pneumonectomy, or sham surgery at 125-130 days gestation. The incidence of FBM decreased in sham-operated fetuses at 142 days versus 130 days (p = 0.013), but was unchanged across all gestational ages in bilaterally pneumonectomized fetuses (p > or = 0.52). In unilaterally pneumonectomized fetuses, the incidence of FBM remained unchanged until 139 days and was higher than that of the bilaterally pneumonectomized fetuses at 130-136 days gestation (p < or = 0.03). The amplitude of integrated diaphragmatic electromyographic activity (integralEMG(di)) and total respiratory output (frequency of breathing x integralEMG(di)) were lower in pneumonectomized fetuses versus sham-operated fetuses at later gestational ages (p < 0.05). These decreases in integralEMG(di) and total respiratory output were most pronounced at 142 days in bilaterally pneumonectomized fetuses versus sham-operated fetuses (p = 0.006 and 0.016, respectively). Low-voltage electrocortical activity (ECoG) increased, and high-voltage ECoG decreased, in unilaterally pneumonectomized fetuses compared with sham-operated fetuses (p = 0.04). In conclusion, we provide new evidence that feedback from the fetal lung modulates the incidence and various components of phrenic nerve output, suggesting a positive feedback mechanism between FBM and lung development.