title: Resolvin D1 and lipoxin A4 improve alveolarization and normalize septal wall thickness in a neonatal murine model of hyperoxia-induced lung injury.
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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neonatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America; Division of Translational Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Camilia R
authors.initials: CR
authors.lastname: Martin
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Munir M
authors.initials: MM
authors.lastname: Zaman
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Calvin
authors.initials: C
authors.lastname: Gilkey
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Salguero
authors.affiliation: Department of Applied Oral Sciences, Center for Periodontology, Forsyth Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Hatice
authors.initials: H
authors.lastname: Hasturk
authors.affiliation: Department of Applied Oral Sciences, Center for Periodontology, Forsyth Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Alpdogan
authors.initials: A
authors.lastname: Kantarci
authors.affiliation: Department of Applied Oral Sciences, Center for Periodontology, Forsyth Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Van Dyke
authors.affiliation: Division of Translational Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Freedman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000627:therapeutic use*; D005260:Female; D018496:Hyperoxia / Q000150:complications*; D044045:Lipoxins / Q000627:therapeutic use*; D055370:Lung Injury / Q000188:drug therapy* / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology
chemical_list: D044045:Lipoxins; C040527:lipoxin A4; C518399:resolvin D1; D004281:Docosahexaenoic Acids