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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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Morphometric assessment of lung histology.Shown in Figure 3A, B, and C are the morphometric assessment of the mean linear intercept (MLI), radial alveolar count (RAC) and septal thickness (ST) respectively. Bars represent means +/- SEM. 37 mice were analyzed for the MLI and ST morphometric measures. A mean of 6 images were analyzed per section/mouse. 34 mice were analyzed for RAC. A mean of 3 images were analyzed per section per mouse. RA, room air; H, hyperoxia; RvD1, Resolvin D1; LXA4, Lipoxin A4 a = p<0.05 compared to RA group; b = p<0.05 compared to Hyperoxia alone group; c = p<0.05 compared to the Hyperoxia + RvD1 group.
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pone-0098773-g003: Morphometric assessment of lung histology.Shown in Figure 3A, B, and C are the morphometric assessment of the mean linear intercept (MLI), radial alveolar count (RAC) and septal thickness (ST) respectively. Bars represent means +/- SEM. 37 mice were analyzed for the MLI and ST morphometric measures. A mean of 6 images were analyzed per section/mouse. 34 mice were analyzed for RAC. A mean of 3 images were analyzed per section per mouse. RA, room air; H, hyperoxia; RvD1, Resolvin D1; LXA4, Lipoxin A4 a = p<0.05 compared to RA group; b = p<0.05 compared to Hyperoxia alone group; c = p<0.05 compared to the Hyperoxia + RvD1 group.

Mentions: To quantitate the differences between the different experimental groups, well-established morphometric analyses were performed using MLI, RAC and ST (Figure 3). Hyperoxia-induced lung injury increased the MLI from a mean of 49.0 ± 2.5 µm in the RA group to 99.4 ± 9.2 µm (p<0.0001, Figure 3A). Compared to hyperoxia, there was no change in the MLI with RvD1 treatment (89.8 ± 4.5 µm). In contrast, treatment with LXA4 and the combination of RvD1/LXA4 significantly decreased the MLI to 67.3 ± 4.5 µm (p = 0.006) and 67.7 ± 4.4 µm (p = 0.002), respectively.


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)

Morphometric assessment of lung histology.Shown in Figure 3A, B, and C are the morphometric assessment of the mean linear intercept (MLI), radial alveolar count (RAC) and septal thickness (ST) respectively. Bars represent means +/- SEM. 37 mice were analyzed for the MLI and ST morphometric measures. A mean of 6 images were analyzed per section/mouse. 34 mice were analyzed for RAC. A mean of 3 images were analyzed per section per mouse. RA, room air; H, hyperoxia; RvD1, Resolvin D1; LXA4, Lipoxin A4 a = p<0.05 compared to RA group; b = p<0.05 compared to Hyperoxia alone group; c = p<0.05 compared to the Hyperoxia + RvD1 group.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098773-g003: Morphometric assessment of lung histology.Shown in Figure 3A, B, and C are the morphometric assessment of the mean linear intercept (MLI), radial alveolar count (RAC) and septal thickness (ST) respectively. Bars represent means +/- SEM. 37 mice were analyzed for the MLI and ST morphometric measures. A mean of 6 images were analyzed per section/mouse. 34 mice were analyzed for RAC. A mean of 3 images were analyzed per section per mouse. RA, room air; H, hyperoxia; RvD1, Resolvin D1; LXA4, Lipoxin A4 a = p<0.05 compared to RA group; b = p<0.05 compared to Hyperoxia alone group; c = p<0.05 compared to the Hyperoxia + RvD1 group.
Mentions: To quantitate the differences between the different experimental groups, well-established morphometric analyses were performed using MLI, RAC and ST (Figure 3). Hyperoxia-induced lung injury increased the MLI from a mean of 49.0 ± 2.5 µm in the RA group to 99.4 ± 9.2 µm (p<0.0001, Figure 3A). Compared to hyperoxia, there was no change in the MLI with RvD1 treatment (89.8 ± 4.5 µm). In contrast, treatment with LXA4 and the combination of RvD1/LXA4 significantly decreased the MLI to 67.3 ± 4.5 µm (p = 0.006) and 67.7 ± 4.4 µm (p = 0.002), respectively.

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