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Effects of phosphodiesterase 4 inhibition on alveolarization and hyperoxia toxicity in newborn rats.

Méhats C, Franco-Montoya ML, Boucherat O, Lopez E, Schmitz T, Zana E, Evain-Brion D, Bourbon J, Delacourt C, Jarreau PH - PLoS ONE (2008)

Bottom Line: The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury.Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count.The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche médicale U767, Paris, France.

ABSTRACT

Background: Prolonged neonatal exposure to hyperoxia is associated with high mortality, leukocyte influx in airspaces, and impaired alveolarization. Inhibitors of type 4 phosphodiesterases are potent anti-inflammatory drugs now proposed for lung disorders. The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury.

Methodology/findings: Rat pups were placed under hyperoxia (FiO2>95%) or room air from birth, and received rolipram or its diluent daily until sacrifice. Mortality rate, weight gain and parameters of lung morphometry were recorded on day 10. Differential cell count and cytokine levels in bronchoalveolar lavage and cytokine mRNA levels in whole lung were recorded on day 6. Rolipram diminished weight gain either under air or hyperoxia. Hyperoxia induced huge mortality rate reaching 70% at day 10, which was prevented by rolipram. Leukocyte influx in bronchoalveolar lavage under hyperoxia was significantly diminished by rolipram. Hyperoxia increased transcript and protein levels of IL-6, MCP1, and osteopontin; rolipram inhibited the increase of these proteins. Alveolarization was impaired by hyperoxia and was not restored by rolipram. Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count.

Conclusions: Although inhibition of phosphodiesterases 4 prevented mortality and lung inflammation induced by hyperoxia, it had no effect on alveolarization impairment, which might be accounted for by the aggressiveness of the model. The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.

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Total cell, polymorphonuclear neutrophil, and macrophage counts in BAL from rat pups exposed to hyperoxia and treated or not with rolipram.BAL fluid was collected on day 6 of life from rat pups exposed to normoxia or hyperoxia from birth and either treated with rolipram (n = 6/group) or receiving the diluent alone (littermate controls, n = 6/group). Total and differential cell counts were performed as described in Materials and Methods. Data are expressed as mean±sem. * Significantly different from the air-diluent group; † significantly different from the air-rolipram group; ‡ significant difference between oxygen-diluent and oxygen-rolipram groups.
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pone-0003445-g001: Total cell, polymorphonuclear neutrophil, and macrophage counts in BAL from rat pups exposed to hyperoxia and treated or not with rolipram.BAL fluid was collected on day 6 of life from rat pups exposed to normoxia or hyperoxia from birth and either treated with rolipram (n = 6/group) or receiving the diluent alone (littermate controls, n = 6/group). Total and differential cell counts were performed as described in Materials and Methods. Data are expressed as mean±sem. * Significantly different from the air-diluent group; † significantly different from the air-rolipram group; ‡ significant difference between oxygen-diluent and oxygen-rolipram groups.

Mentions: On day 6 of life, hyperoxia increased 2.5 times the total number of inflammatory cells in BAL (ANOVA p<0.05), and induced a preferential recruitment of neutrophils that were increased 10 times as compared with control group (ANOVA p<0.001). The trend of macrophages to increase slightly was not significant (Figure 1). Rolipram had no effect on inflammatory-cell count under air condition but prevented totally the hyperoxia-induced increase in total cell number (p<0.01), and prevented partly the neutrophil increase (p<0.01).


Effects of phosphodiesterase 4 inhibition on alveolarization and hyperoxia toxicity in newborn rats.

Méhats C, Franco-Montoya ML, Boucherat O, Lopez E, Schmitz T, Zana E, Evain-Brion D, Bourbon J, Delacourt C, Jarreau PH - PLoS ONE (2008)

Total cell, polymorphonuclear neutrophil, and macrophage counts in BAL from rat pups exposed to hyperoxia and treated or not with rolipram.BAL fluid was collected on day 6 of life from rat pups exposed to normoxia or hyperoxia from birth and either treated with rolipram (n = 6/group) or receiving the diluent alone (littermate controls, n = 6/group). Total and differential cell counts were performed as described in Materials and Methods. Data are expressed as mean±sem. * Significantly different from the air-diluent group; † significantly different from the air-rolipram group; ‡ significant difference between oxygen-diluent and oxygen-rolipram groups.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2563688&req=5

pone-0003445-g001: Total cell, polymorphonuclear neutrophil, and macrophage counts in BAL from rat pups exposed to hyperoxia and treated or not with rolipram.BAL fluid was collected on day 6 of life from rat pups exposed to normoxia or hyperoxia from birth and either treated with rolipram (n = 6/group) or receiving the diluent alone (littermate controls, n = 6/group). Total and differential cell counts were performed as described in Materials and Methods. Data are expressed as mean±sem. * Significantly different from the air-diluent group; † significantly different from the air-rolipram group; ‡ significant difference between oxygen-diluent and oxygen-rolipram groups.
Mentions: On day 6 of life, hyperoxia increased 2.5 times the total number of inflammatory cells in BAL (ANOVA p<0.05), and induced a preferential recruitment of neutrophils that were increased 10 times as compared with control group (ANOVA p<0.001). The trend of macrophages to increase slightly was not significant (Figure 1). Rolipram had no effect on inflammatory-cell count under air condition but prevented totally the hyperoxia-induced increase in total cell number (p<0.01), and prevented partly the neutrophil increase (p<0.01).

Bottom Line: The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury.Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count.The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche médicale U767, Paris, France.

ABSTRACT

Background: Prolonged neonatal exposure to hyperoxia is associated with high mortality, leukocyte influx in airspaces, and impaired alveolarization. Inhibitors of type 4 phosphodiesterases are potent anti-inflammatory drugs now proposed for lung disorders. The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury.

Methodology/findings: Rat pups were placed under hyperoxia (FiO2>95%) or room air from birth, and received rolipram or its diluent daily until sacrifice. Mortality rate, weight gain and parameters of lung morphometry were recorded on day 10. Differential cell count and cytokine levels in bronchoalveolar lavage and cytokine mRNA levels in whole lung were recorded on day 6. Rolipram diminished weight gain either under air or hyperoxia. Hyperoxia induced huge mortality rate reaching 70% at day 10, which was prevented by rolipram. Leukocyte influx in bronchoalveolar lavage under hyperoxia was significantly diminished by rolipram. Hyperoxia increased transcript and protein levels of IL-6, MCP1, and osteopontin; rolipram inhibited the increase of these proteins. Alveolarization was impaired by hyperoxia and was not restored by rolipram. Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count.

Conclusions: Although inhibition of phosphodiesterases 4 prevented mortality and lung inflammation induced by hyperoxia, it had no effect on alveolarization impairment, which might be accounted for by the aggressiveness of the model. The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.

Show MeSH
Related in: MedlinePlus