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Nebulized PPARγ agonists: a novel approach to augment neonatal lung maturation and injury repair in rats.

Morales E, Sakurai R, Husain S, Paek D, Gong M, Ibe B, Li Y, Husain M, Torday JS, Rehan VK - Pediatr. Res. (2014)

Bottom Line: Nebulized RGZ and PGZ enhanced lung maturation in both males and females, as evidenced by the increased expression of markers of alveolar epithelial and mesenchymal maturation.This approach also protected against hyperoxia-induced lung injury, since hyperoxia-induced changes in bronchoalveolar lavage cell and protein contents and lung injury markers were all blocked by nebulized PGZ.Nebulized PPARγ agonist administration promotes lung maturation and prevents neonatal hyperoxia-induced lung injury in both males and females.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pediatrics, Harbor-University of California Los Angeles (UCLA) Medical Center, Los Angeles Biomedical Research Institute, David Geffen School of Medicine at UCLA, Torrance, California [2] Department of Pediatrics, Children's Hospital Orange County, Orange, California.

ABSTRACT

Background: By stimulating lipofibroblast maturation, parenterally administered peroxisome proliferator-activated receptor γ (PPARγ) agonists promote lung homeostasis and injury repair in the neonatal lung. In this study, we determined whether PPARγ agonists could be delivered effectively via nebulization to neonates, and whether this approach would also protect against hyperoxia-induced lung injury.

Methods: One-day old Sprague-Dawley rat pups were administered PPARγ agonists rosiglitazone (RGZ, 3 mg/kg), pioglitazone (PGZ, 3 mg/kg), or the diluent, via nebulization every 24 h; animals were exposed to 21% or 95% O2 for up to 72 h. Twenty-four and 72 h following initial nebulization, the pups were sacrificed for lung tissue and blood collection to determine markers of lung maturation, injury repair, and RGZ and PGZ plasma levels.

Results: Nebulized RGZ and PGZ enhanced lung maturation in both males and females, as evidenced by the increased expression of markers of alveolar epithelial and mesenchymal maturation. This approach also protected against hyperoxia-induced lung injury, since hyperoxia-induced changes in bronchoalveolar lavage cell and protein contents and lung injury markers were all blocked by nebulized PGZ.

Conclusion: Nebulized PPARγ agonist administration promotes lung maturation and prevents neonatal hyperoxia-induced lung injury in both males and females.

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Related in: MedlinePlus

Comparison of the efficacy for protection against hyperoxia-induced lung injury using nebulized PGZ (1 mg/kg body weight) with that afforded by intraperitoneal PGZ (3 mg/kg body weight)Nebulized PGZ at a lower dose (1 mg/kg/ body weight) was equally effective in blocking hyperoxia induced decreases in PPARγ, ADRP, and BcL2, and increase in fibronectin protein levels compared to that achieved by the higher intraperitoneally administered dose (3 mg/kg body weight). White bars, 21% O2; black bars, 95% O2; gray bars, 95% O2 + nebulized PGZ; hatched bars, 95% O2 + intraperitoneal PGZ. N=3 for all; *, p<0.05 vs. control; **, p<0.05 vs. 95% O2.
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Figure 8: Comparison of the efficacy for protection against hyperoxia-induced lung injury using nebulized PGZ (1 mg/kg body weight) with that afforded by intraperitoneal PGZ (3 mg/kg body weight)Nebulized PGZ at a lower dose (1 mg/kg/ body weight) was equally effective in blocking hyperoxia induced decreases in PPARγ, ADRP, and BcL2, and increase in fibronectin protein levels compared to that achieved by the higher intraperitoneally administered dose (3 mg/kg body weight). White bars, 21% O2; black bars, 95% O2; gray bars, 95% O2 + nebulized PGZ; hatched bars, 95% O2 + intraperitoneal PGZ. N=3 for all; *, p<0.05 vs. control; **, p<0.05 vs. 95% O2.

Mentions: Compared to the controls, the BAL total cell count (Figure 3A), macrophage count (Figure 3B), and protein content (Figure 3C) after exposure to hyperoxia increased significantly, effects that were counteracted in the PGZ nebulized group. Examining markers of alveolar differentiation indicated significant decreases in triolein uptake (Figure 4A), PPARγ (Figure 4B) and ADRP (Figure 4C) protein levels, and significant increases in fibronectin (Figure 4D) protein levels in the hyperoxia-exposed group (p<0.05 vs. control); all of these changes were blocked in the PGZ nebulized group. Hyperoxia-induced decreases in vascular markers such as VEGF (Figure 5A) and PECAM-1 (Figure 5B) were blocked with PGZ nebulization. Similarly, hyperoxia-induced alterations in the lung cytokine (IL-6, IL-1β, CCL-2, MIF) profile were blocked in the PGZ nebulized group (Figures 6A–6D). Hyperoxia-induced lung injury, as reflected by the decreased BcL2/Bax protein ratio, was also blocked by PGZ nebulization (Figure 6E). In line with these data, and perhaps even more importantly, hyperoxia-induced lung morphometric changes, as determined by radial alveolar count and mean linear intercept, were also blocked in the PGZ nebulized group (Figure 7). To compare the efficacy of protection against hyperoxia-induced neonatal lung injury, using nebulized PGZ (1 mg/kg body weight) versus that afforded by the intraperitoneally administered PGZ (3 mg/kg body weight), alterations in select injury repair markers (PPARγ, ADRP, BcL2, and fibronectin) were determined. There was equally effective protection in hyperoxia-induced alterations in these markers using the lower nebulized dose versus the higher intraperitoneally administered dose (Figure 8).


Nebulized PPARγ agonists: a novel approach to augment neonatal lung maturation and injury repair in rats.

Morales E, Sakurai R, Husain S, Paek D, Gong M, Ibe B, Li Y, Husain M, Torday JS, Rehan VK - Pediatr. Res. (2014)

Comparison of the efficacy for protection against hyperoxia-induced lung injury using nebulized PGZ (1 mg/kg body weight) with that afforded by intraperitoneal PGZ (3 mg/kg body weight)Nebulized PGZ at a lower dose (1 mg/kg/ body weight) was equally effective in blocking hyperoxia induced decreases in PPARγ, ADRP, and BcL2, and increase in fibronectin protein levels compared to that achieved by the higher intraperitoneally administered dose (3 mg/kg body weight). White bars, 21% O2; black bars, 95% O2; gray bars, 95% O2 + nebulized PGZ; hatched bars, 95% O2 + intraperitoneal PGZ. N=3 for all; *, p<0.05 vs. control; **, p<0.05 vs. 95% O2.
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Figure 8: Comparison of the efficacy for protection against hyperoxia-induced lung injury using nebulized PGZ (1 mg/kg body weight) with that afforded by intraperitoneal PGZ (3 mg/kg body weight)Nebulized PGZ at a lower dose (1 mg/kg/ body weight) was equally effective in blocking hyperoxia induced decreases in PPARγ, ADRP, and BcL2, and increase in fibronectin protein levels compared to that achieved by the higher intraperitoneally administered dose (3 mg/kg body weight). White bars, 21% O2; black bars, 95% O2; gray bars, 95% O2 + nebulized PGZ; hatched bars, 95% O2 + intraperitoneal PGZ. N=3 for all; *, p<0.05 vs. control; **, p<0.05 vs. 95% O2.
Mentions: Compared to the controls, the BAL total cell count (Figure 3A), macrophage count (Figure 3B), and protein content (Figure 3C) after exposure to hyperoxia increased significantly, effects that were counteracted in the PGZ nebulized group. Examining markers of alveolar differentiation indicated significant decreases in triolein uptake (Figure 4A), PPARγ (Figure 4B) and ADRP (Figure 4C) protein levels, and significant increases in fibronectin (Figure 4D) protein levels in the hyperoxia-exposed group (p<0.05 vs. control); all of these changes were blocked in the PGZ nebulized group. Hyperoxia-induced decreases in vascular markers such as VEGF (Figure 5A) and PECAM-1 (Figure 5B) were blocked with PGZ nebulization. Similarly, hyperoxia-induced alterations in the lung cytokine (IL-6, IL-1β, CCL-2, MIF) profile were blocked in the PGZ nebulized group (Figures 6A–6D). Hyperoxia-induced lung injury, as reflected by the decreased BcL2/Bax protein ratio, was also blocked by PGZ nebulization (Figure 6E). In line with these data, and perhaps even more importantly, hyperoxia-induced lung morphometric changes, as determined by radial alveolar count and mean linear intercept, were also blocked in the PGZ nebulized group (Figure 7). To compare the efficacy of protection against hyperoxia-induced neonatal lung injury, using nebulized PGZ (1 mg/kg body weight) versus that afforded by the intraperitoneally administered PGZ (3 mg/kg body weight), alterations in select injury repair markers (PPARγ, ADRP, BcL2, and fibronectin) were determined. There was equally effective protection in hyperoxia-induced alterations in these markers using the lower nebulized dose versus the higher intraperitoneally administered dose (Figure 8).

Bottom Line: Nebulized RGZ and PGZ enhanced lung maturation in both males and females, as evidenced by the increased expression of markers of alveolar epithelial and mesenchymal maturation.This approach also protected against hyperoxia-induced lung injury, since hyperoxia-induced changes in bronchoalveolar lavage cell and protein contents and lung injury markers were all blocked by nebulized PGZ.Nebulized PPARγ agonist administration promotes lung maturation and prevents neonatal hyperoxia-induced lung injury in both males and females.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pediatrics, Harbor-University of California Los Angeles (UCLA) Medical Center, Los Angeles Biomedical Research Institute, David Geffen School of Medicine at UCLA, Torrance, California [2] Department of Pediatrics, Children's Hospital Orange County, Orange, California.

ABSTRACT

Background: By stimulating lipofibroblast maturation, parenterally administered peroxisome proliferator-activated receptor γ (PPARγ) agonists promote lung homeostasis and injury repair in the neonatal lung. In this study, we determined whether PPARγ agonists could be delivered effectively via nebulization to neonates, and whether this approach would also protect against hyperoxia-induced lung injury.

Methods: One-day old Sprague-Dawley rat pups were administered PPARγ agonists rosiglitazone (RGZ, 3 mg/kg), pioglitazone (PGZ, 3 mg/kg), or the diluent, via nebulization every 24 h; animals were exposed to 21% or 95% O2 for up to 72 h. Twenty-four and 72 h following initial nebulization, the pups were sacrificed for lung tissue and blood collection to determine markers of lung maturation, injury repair, and RGZ and PGZ plasma levels.

Results: Nebulized RGZ and PGZ enhanced lung maturation in both males and females, as evidenced by the increased expression of markers of alveolar epithelial and mesenchymal maturation. This approach also protected against hyperoxia-induced lung injury, since hyperoxia-induced changes in bronchoalveolar lavage cell and protein contents and lung injury markers were all blocked by nebulized PGZ.

Conclusion: Nebulized PPARγ agonist administration promotes lung maturation and prevents neonatal hyperoxia-induced lung injury in both males and females.

Show MeSH
Related in: MedlinePlus