Abstract
BackgroundThe critical fatty acids Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) decline in preterm infants within the first postnatal week and are associated with neonatal morbidities, including bronchopulmonary dysplasia (BPD). DHA and AA are precursors to downstream metabolites that terminate the inflammatory response. We hypothesized that treatment with Resolvin D1 and/or Lipoxin A4 would prevent lung injury in a murine model of BPD.ObjectiveTo determine the effect of Resolvin D1 and/or Lipoxin A4 on hyperoxia-induced lung injury.MethodsC57/BL6 pups were randomized at birth to Room Air, Hyperoxia (>90% oxygen), Hyperoxia + Resolvin D1, Hyperoxia + Lipoxin A4, or Hyperoxia + Resolvin D1/Lipoxin A4. Resolvin D1 and/or Lipoxin A4 (2 ng/g) were given IP on days 0, 3, 6, and 9. On day 10, mice were sacrificed and lungs collected for morphometric analyses including Mean Linear Intercept (MLI), Radial Alveolar Count (RAC), and Septal Thickness (ST); RT-PCR analyses of biomarkers of lung development and inflammation; and ELISA for TGFβ1 and TGFβ2.ResultThe increased ST observed with hyperoxia exposure was normalized by both Resolvin D1 and Lipoxin A4; while, hyperoxia-induced alveolar simplification was attenuated by Lipoxin A4. Relative to hyperoxia, Resolvin D1 reduced the gene expression of CXCL2 (2.9 fold), TIMP1 (6.7 fold), and PPARγ (4.8 fold). Treatment with Lipoxin A4 also led to a reduction of CXCL2 (2.4 fold) while selectively increasing TGFβ2 (2.1 fold) and Smad3 (1.58 fold).ConclusionThe histologic and biochemical changes seen in hyperoxia-induced lung injury in this murine model can be reversed by the addition of DHA and AA fatty acid downstream metabolites that terminate the inflammatory pathways and modulate growth factors. These fatty acids or their metabolites may be novel therapies to prevent or treat lung injury in preterm infants.
Highlights
Bronchopulmonary dysplasia (BPD) is an acquired form of chronic lung disease that is unique to the preterm infant
On day 10, mice were sacrificed and lungs collected for morphometric analyses including Mean Linear Intercept (MLI), Radial Alveolar Count (RAC), and Septal Thickness (ST); reverse transcriptase-PCR (RT-PCR) analyses of biomarkers of lung development and inflammation; and ELISA for TGFb1 and TGFb2
The final weights were statistical different between the experimental groups (p = 0.04), with the significant difference being between the room air (RA) and Hyperoxia alone groups (p = 0.04) and between the Hyperoxia alone and Hyperoxia + Resolvin D1 (RvD1)/Lipoxin A4 (LXA4) group (p = 0.003)
Summary
Bronchopulmonary dysplasia (BPD) is an acquired form of chronic lung disease that is unique to the preterm infant. BPD is clinically diagnosed at 36 weeks postmenstrual age or later if there is a persistent need for oxygen reflecting underlying abnormal lung development. BPD is multifactorial in its pathogenesis and, in general, is a consequence of chronic lung injury with a failure to repair and resume normal lung development. Infants with BPD experience significant clinical sequelae even after discharge from the neonatal intensive care unit including persistently altered lung function [1,2] and poor neurocognitive outcomes in early childhood [3,4]. The critical fatty acids Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) decline in preterm infants within the first postnatal week and are associated with neonatal morbidities, including bronchopulmonary dysplasia (BPD). We hypothesized that treatment with Resolvin D1 and/or Lipoxin A4 would prevent lung injury in a murine model of BPD
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