Abstract
Rationale: Intrauterine growth restriction (IUGR) increases the risk of bronchopulmonary dysplasia (BPD), one of the major complications of prematurity. Antenatal low-protein diet (LPD) exposure in rats induces IUGR and mimics BPD-related alveolarization disorders. Proliferator-activated receptor (PPARg) plays a key role in normal lung development and was found deregulated following LPD exposure.
Objectives: Investigate the effects of nebulized curcumin, a natural PPARg agonist, to prevent IUGR-related abnormal lung development.
Methods: We studied rat pups antenatally exposed to an LPD or control diet (CTL) and treated with nebulized curcumin (50 mg/kg) or vehicle from postnatal (P) days 1 to 5. The primary readouts were lung morphometric analyses at P21. Immunohistochemistry (P21) and microarrays (P6 and P11) were compared within animals exposed to LPD versus controls, with and without curcumin treatment.
Results: Quantitative morphometric analyses revealed that LPD induced abnormal alveolarization as evidenced by a significant increase in Mean Linear Intercept (MLI) observed in P21 LPD-exposed animals. Early curcumin treatment prevented this effect and two-way ANOVA analysis demonstrated significant interaction between diet and curcumin both for MLI (F(1,39)=12.67,p=0.001) and Radial Alveolar Count at P21 (F(1,40)= 6.065, p=0.0182). Immunohistochemistry for FABP4, a major regulator of PPARg pathway showed a decreased FABP4+ alveolar cell density in LPD-exposed animals treated by curcumin. Transcriptomic analysis showed that early curcumin significantly prevented the activation of pro-fibrotic pathways observed at P11 in LPD-exposed animals.
Conclusion: Nebulized curcumin appears to be a promising strategy to prevent alveolarization disorders in IUGR rat pups, targeting pathways involved in lung development.