1. Resolvin D1 and Lipoxin A4 Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury
- Author
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Munir M. Zaman, Camilia R. Martin, Thomas E. Van Dyke, Maria V. Salguero, Hatice Hasturk, Calvin Gilkey, Steven D. Freedman, and Alpdogan Kantarci
- Subjects
Male ,medicine.medical_specialty ,Docosahexaenoic Acids ,Pediatric Pulmonology ,lcsh:Medicine ,Inflammation ,Hyperoxia ,Lung injury ,Pediatrics ,Mice ,chemistry.chemical_compound ,Internal medicine ,Medicine and Health Sciences ,medicine ,Animals ,lcsh:Science ,Nutrition ,chemistry.chemical_classification ,Multidisciplinary ,Lung ,Chemistry ,lcsh:R ,Biology and Life Sciences ,Fatty acid ,Lung Injury ,respiratory system ,medicine.disease ,3. Good health ,Lipoxins ,Mice, Inbred C57BL ,Pulmonary Alveoli ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Animals, Newborn ,Bronchopulmonary dysplasia ,Docosahexaenoic acid ,Immunology ,Female ,lcsh:Q ,lipids (amino acids, peptides, and proteins) ,Arachidonic acid ,Neonatology ,medicine.symptom ,Research Article - Abstract
Background 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). 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. Objective To determine the effect of Resolvin D1 and/or Lipoxin A4 on hyperoxia-induced lung injury. Methods C57/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. Result The 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). Conclusion The 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.
- Published
- 2014