Published ahead of print on February 16, 2006, doi:10.1165/rcmb.2005-0254OC
© 2006 American Thoracic Society DOI: 10.1165/rcmb.2005-0254OC Nitric Oxide Donor Restores Lung Growth Factor and Receptor Expression in Hyperoxia-Exposed Rat PupsInstitut National de la Santé et de la Recherche Médicale U651, Université Paris XII, Faculté de Médecine, Créteil; Université Paris Descartes, Faculté de Médecine; Assistance Publique-Hôpitaux de Paris; Hôpital Cochin; Service de Médecine Néonatale de Port-Royal, Paris, France Correspondence and requests for reprints should be addressed to Pierre-Henri Jarreau, Service de Médecine Néonatale de Port-Royal, Centre Hospitalier Cochin-Saint-Vincent-de-Paul-La Roche-Guyon 123, Bd de Port-Royal, 75014 Paris, France. E-mail: pierre-henri.jarreau{at}cch.ap-hop-paris.fr Exposure of newborn rats to hyperoxia impairs alveolarization. Nitric oxide (NO) may prevent this evolution. Angiogenesis and factors involved in this process, but also other growth factors (GFs) involved in alveolar development, are likely potential therapeutic targets for NO. We studied the effects of the NO donor, [Z]-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)aminio]diazen-1-ium-1, 2-diolate, also termed DETANONOate (D-NO), on hyperoxia-induced changes in key regulatory factors of alveolar development in neonatal rats, and its possible preventive effect on the physiologic consequences of hyperoxia. Newborn rat pups were randomized at birth to hyperoxia (> 95% O2) or room air exposure for 6 or 10 d, while receiving D-NO or its diluent. On Day 6, several GFs and their receptors were studied at pre- and/or post-translational levels. Elastin transcript determination on Day 6, and elastin deposition in tissue and morphometric analysis of the lungs on Day 10, were also performed. Hyperoxia decreased the expression of vascular endothelial growth factor (VEGF) receptor (VEGFR) 2, fibroblast growth factor (FGF)-18, and FGF receptors (FGFRs) FGFR3 and FGFR4, increased mortality, and impaired alveolarization and capillary growth. D-NO treatment of hyperoxia-exposed pups restored the expression level of FGF18 and FGFR4, induced an increase of both VEGF mRNA and protein, enhanced elastin expression, and partially restored elastin deposition in alveolar walls. Although, under the present conditions, D-NO failed to prevent the physiologic consequences of hyperoxia in terms of survival and lung alveolarization, our findings demonstrate molecular effects of NO on GFs involved in alveolar development that may have contributed to the protective effects previously reported for NO.
Key Words: alveolarization • angiogenesis • bronchopulmonary dysplasia • lung development, vascular endothelial growth factor This article has been cited by other articles:
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