| Description |
Preterm infants are at increased risk for developing bronchopulmonary dysplasia (BPD). BPD is characterized by impaired lung development, with decreased lung compliance and increased lung tissue resistance. Decreased airway resistance is a related complication. Male infants typically experience worse outcomes of BPD than female infants and have a higher risk for acquiring the disease. BPD is induced by poor lung development, mechanical ventilation, and postnatal growth restriction (PGR) related to feeding complications. Poor feeding can result in limited consumption of specific nutrients essential to lung development, including docosahexaenoic acid (DHA). Decreased circulating DHA levels have been found in preterm infants who develop BPD. However, outcomes from clinical studies examining the effects of postnatal DHA supplementation on BPD outcomes are conflicting. DHA is a ligand for the transcriptional regulator peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor transcription factor that contributes to lung development. The SET-domain containing histone methyltransferase (Setd8) is a transcriptional target of PPARγ in the lung, and serves as a useful downstream parameter for assessing PPARγ activity. We hypothesize that postnatal DHA supplementation will have a dose- and sex-dependent impact on lung function and structure, lung PPARγ and Setd8 protein, and Setd8 expression, and circulating fatty acids in the juvenile rat. To test our hypothesis, we induced PGR in Sprague Dawley rat pups and observed the effect of high (0.1%), low (0.01%), and no DHA (0.0%) supplementation compared to age- and sex-matched controls. Lung function was measured through tissue compliance, tissue damping, and airway resistance. PPARγ and Setd8 mRNA transcript and protein levels were measured in lung homogenate. Sex-divergent outcomes were found in PPARγ protein, Setd8 protein, and tissue damping. DHA was found to ameliorate the impact of PGR in all functional tests, with females showing greater sensitivity to DHA in restoration of compliance. In conclusion, DHA causes sex- and dose-dependent changes in lung function and lung PPARγ levels in PGR rat pups. We speculate that sex-divergent responses to DHA reflect sex-divergent metabolism of DHA. We further speculate that sex-divergent effects of PGR on lung mechanics may reflect differences in the structural organization and composition of the lung. |
