BPD is characterized primarily by impaired alveolar and vascular growth (25
). Following ibuprofen-induced ductus closure, premature baboons have improved pulmonary mechanics and increased alveolar surface area compared with premature baboons with a persistent PDA (9
). It has been hypothesized that the decreased need for mechanical ventilation may contribute to the improved alveolarization that occurs following pharmacologic PDA closure (28
). In contrast, baboons that have their PDA closed by surgical ligation show no signs of improved pulmonary mechanics (see Results) or increased alveolar growth (13
). We hypothesized that the trauma of PDA surgery may have obscured the potential benefits of PDA closure on postnatal lung mechanics and development.
Alterations in the production of proinflammatory cytokines/chemokines and mediators of parenchymal and vascular remodeling have been associated with the development of BPD. Premature delivery and mechanical ventilation are known to alter the expression of inflammatory mediators in both human and baboon lungs (9
). Compared with non-ventilated fetuses, we found that premature newborn baboons have both decreased expression of genes involved with new vessel growth and lung remodeling and increased expression of genes involved with pulmonary inflammation (). Similar changes have been observed previously, in other studies using premature newborn baboons (9
). These findings are consistent with other studies that suggest that disruption of angiogenesis may play a significant role in impaired alveolarization (45
The novel findings in the current study relate to the effects of surgical PDA ligation on pulmonary gene expression. We found that, in contrast to no intervention (leaving the ductus patent), surgical PDA closure increased the expression of several inflammatory mediators (COX-2, TNF-alpha, and cells expressing CD14), and decreased the expression of several genes involved in angiogenesis (angiopoietin-2 and TGF beta 3) (46
). Surgical PDA closure also decreased the expression of pulmonary alpha-ENaC containing channels (which are involved in transepithelial sodium transport). It should be noted that the changes we observed were in lung tissue taken from the side opposite to the ligation, more than a week after the surgery.
Clearance of fluid from alveolar airspaces requires the presence of amiloride-sensitive alpha-ENaC channels (47
). In contrast with full term newborn baboons, preterm baboons have diminished expression of alpha-ENaC channels and slow rates of fluid clearance from their lungs (9
). The improvement in pulmonary mechanics that follows pharmacologic closure of the PDA (with ibuprofen or indomethacin) is associated with increased pulmonary expression of the alpha-ENaC channels and increased lung water clearance (9
). The effects of ibuprofen and indomethacin on alpha-ENaC expression appear to be due to their inhibition of cyclooxygenase activity, rather than their effect on ductus closure (9
). We speculate that the increased expression of cyclooxygenase 2, that follows PDA ligation (), may account for the decreased expression of alpha-ENaC in the lungs of ligated animals (). We also speculate that reduced expression of pulmonary alpha-ENaC channels may decrease the rate of fluid movement out of the alveolar compartment and contribute to the lack of improvement in pulmonary mechanics after surgical PDA closure. Unfortunately, the lungs of the ligated animals were not harvested at the time of necropsy in a manner that would allow us to examine them for changes in lung water content or distribution.
Our study has several other limitations. We were limited in the number of control groups we could study, due to the expense and need to restrict the use of this precious animal model. Having a control group that received a thoracotomy, without a PDA ligation, could have helped to identify which aspect of the surgery leads to altered pulmonary gene expression. Similarly, because surgical closure in the NICU often follows failure of medical treatment, having a control group that received a thoracotomy after treatment with indomethacin, could have identified whether the use of indomethacin prior to ligation would ameliorate the ‘detrimental’ effects of the surgical ligation in this animal model.
In conclusion, our findings are consistent with the limited amount of data available from clinical studies. There is little evidence to suggest that surgical ductus closure prevents the evolution of BPD (15
). We speculate that the persistent alterations in inflammatory mediators and alpha-ENaC channels (that we observed with ligation) may account for the lack of improvement in pulmonary mechanics and BPD (13
) following surgical closure.
In addition to the changes we observed, ductus ligation has also been associated with several other significant morbidities: thoracotomy, post-operative myocardial dysfunction (48
), hypotension (18
), pneumothorax, chylothorax, infection, and vocal cord paralysis (10
). In sum, ductus ligation, while eliminating one potential cause for neonatal morbidity, may introduce another set of problems. We suggest that both the desired and achievable goals of ductus ligation be carefully evaluated prior to committing infants to early or routine surgical closure.