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Resolvin D1 and lipoxin A4 improve alveolarization and normalize septal wall thickness in a neonatal murine model of hyperoxia-induced lung injury.

Martin CR, Zaman MM, Gilkey C, Salguero MV, Hasturk H, Kantarci A, Van Dyke TE, Freedman SD - PLoS ONE (2014)

Bottom Line: To determine the effect of Resolvin D1 and/or Lipoxin A4 on hyperoxia-induced lung injury.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).These fatty acids or their metabolites may be novel therapies to prevent or treat lung injury in preterm infants.

View Article: PubMed Central - PubMed

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.

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.

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Lung histology by treatment group.Representative images of H and E stained sections were taken at an original magnification of 200x. Bars represent 100 µm. RvD1, Resolvin D1; LXA4, Lipoxin A4.
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pone-0098773-g002: Lung histology by treatment group.Representative images of H and E stained sections were taken at an original magnification of 200x. Bars represent 100 µm. RvD1, Resolvin D1; LXA4, Lipoxin A4.

Mentions: Representative lung histology images taken at 200× magnification are shown in Figure 2. In the RA group, well-formed terminal alveoli were seen with no inflammatory infiltrates or septal wall thickening. In contrast, hyperoxia-exposed mice demonstrated marked alveolar dilation referred to as alveolar simplification in conjunction with lumenal inflammatory infiltrates. The septal walls were noticeably thicker. Treatment with RvD1 resulted in attenuation of septal wall thickening but no improvement in alveolar simplification. LXA4 exposure resulted in similar results to RvD1 but additionally was associated with partial improvement in alveolar simplification. The combination of RvD1/LXA4 reduced alveolar simplification and septal wall thickening approximating morphological characteristics seen in RA mice.


Resolvin D1 and lipoxin A4 improve alveolarization and normalize septal wall thickness in a neonatal murine model of hyperoxia-induced lung injury.

Martin CR, Zaman MM, Gilkey C, Salguero MV, Hasturk H, Kantarci A, Van Dyke TE, Freedman SD - PLoS ONE (2014)

Lung histology by treatment group.Representative images of H and E stained sections were taken at an original magnification of 200x. Bars represent 100 µm. RvD1, Resolvin D1; LXA4, Lipoxin A4.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043836&req=5

pone-0098773-g002: Lung histology by treatment group.Representative images of H and E stained sections were taken at an original magnification of 200x. Bars represent 100 µm. RvD1, Resolvin D1; LXA4, Lipoxin A4.
Mentions: Representative lung histology images taken at 200× magnification are shown in Figure 2. In the RA group, well-formed terminal alveoli were seen with no inflammatory infiltrates or septal wall thickening. In contrast, hyperoxia-exposed mice demonstrated marked alveolar dilation referred to as alveolar simplification in conjunction with lumenal inflammatory infiltrates. The septal walls were noticeably thicker. Treatment with RvD1 resulted in attenuation of septal wall thickening but no improvement in alveolar simplification. LXA4 exposure resulted in similar results to RvD1 but additionally was associated with partial improvement in alveolar simplification. The combination of RvD1/LXA4 reduced alveolar simplification and septal wall thickening approximating morphological characteristics seen in RA mice.

Bottom Line: To determine the effect of Resolvin D1 and/or Lipoxin A4 on hyperoxia-induced lung injury.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).These fatty acids or their metabolites may be novel therapies to prevent or treat lung injury in preterm infants.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus