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Archives of Disease in Childhood. Fetal and Neonatal Edition logoLink to Archives of Disease in Childhood. Fetal and Neonatal Edition
. 1998 May;78(3):F204–F208. doi: 10.1136/fn.78.3.f204

Effect of dexamethasone on endothelial nitric oxide synthase in experimental congenital diaphragmatic hernia

B Okoye, P Losty, M Fisher, I Wilmott, D Lloyd
PMCID: PMC1720789  PMID: 9713033

Abstract

AIMS—To study the effect of prenatal glucocorticoid treatment on endothelial nitric oxide synthase (eNOS) expression in rats with congenital diaphragmatic hernia (CDH).
METHODS—CDH was induced in fetal rats by the maternal administration of nitrofen on day 9.5 of gestation. Dexamethasone was administered on days 18.5 and 19.5 before delivery of the fetuses on days 20.5and 21.5. Pulmonary eNOS protein expression was studied by western immunoblotting and immunohistochemistry.
RESULTS—On day 20.5, eNOS expression was significantly reduced in CDH pups compared with normal control rats. Dexamethasone treated CDH pups had eNOS concentrations equivalent to those of normal animals. By day 21.5, however, there was no detectable difference in eNOS expression between the experimental groups.
CONCLUSIONS—eNOS is deficient in near term (day 20.5) CDH rats. Dexamethasone restores eNOS expression in these animals to that seen in normal rat lungs. At term, the precise role of eNOS in the pathophysiology of CDH remains uncertain.



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Selected References

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  1. Abman S. H., Chatfield B. A., Hall S. L., McMurtry I. F. Role of endothelium-derived relaxing factor during transition of pulmonary circulation at birth. Am J Physiol. 1990 Dec;259(6 Pt 2):H1921–H1927. doi: 10.1152/ajpheart.1990.259.6.H1921. [DOI] [PubMed] [Google Scholar]
  2. Bührer C., Merker G., Falke K., Versmold H., Obladen M. Dose-response to inhaled nitric oxide in acute hypoxemic respiratory failure of newborn infants: a preliminary report. Pediatr Pulmonol. 1995 May;19(5):291–298. doi: 10.1002/ppul.1950190508. [DOI] [PubMed] [Google Scholar]
  3. Collins D. L., Pomerance J. J., Travis K. W., Turner S. W., Pappelbaum S. J. A new approach to congenital posterolateral diaphragmatic hernia. J Pediatr Surg. 1977 Apr;12(2):149–156. doi: 10.1016/s0022-3468(77)80001-8. [DOI] [PubMed] [Google Scholar]
  4. Coughlin J. P., Drucker D. E., Cullen M. L., Klein M. D. Delayed repair of congenital diaphragmatic hernia. Am Surg. 1993 Feb;59(2):90–93. [PubMed] [Google Scholar]
  5. Crowley P. A. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol. 1995 Jul;173(1):322–335. doi: 10.1016/0002-9378(95)90222-8. [DOI] [PubMed] [Google Scholar]
  6. Dillon P. W., Cilley R. E., Hudome S. M., Ozkan E. N., Krummel T. M. Nitric oxide reversal of recurrent pulmonary hypertension and respiratory failure in an infant with CDH after successful ECMO therapy. J Pediatr Surg. 1995 May;30(5):743–744. doi: 10.1016/0022-3468(95)90706-8. [DOI] [PubMed] [Google Scholar]
  7. Fineman J. R., Soifer S. J., Heymann M. A. Regulation of pulmonary vascular tone in the perinatal period. Annu Rev Physiol. 1995;57:115–134. doi: 10.1146/annurev.ph.57.030195.000555. [DOI] [PubMed] [Google Scholar]
  8. Fineman J. R., Wong J., Morin F. C., 3rd, Wild L. M., Soifer S. J. Chronic nitric oxide inhibition in utero produces persistent pulmonary hypertension in newborn lambs. J Clin Invest. 1994 Jun;93(6):2675–2683. doi: 10.1172/JCI117281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Finer N. N., Etches P. C., Kamstra B., Tierney A. J., Peliowski A., Ryan C. A. Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: dose response. J Pediatr. 1994 Feb;124(2):302–308. doi: 10.1016/s0022-3476(94)70324-8. [DOI] [PubMed] [Google Scholar]
  10. Geggel R. L., Murphy J. D., Langleben D., Crone R. K., Vacanti J. P., Reid L. M. Congenital diaphragmatic hernia: arterial structural changes and persistent pulmonary hypertension after surgical repair. J Pediatr. 1985 Sep;107(3):457–464. doi: 10.1016/s0022-3476(85)80534-5. [DOI] [PubMed] [Google Scholar]
  11. Greenholz S. K. Congenital diaphragmatic hernia: an overview. Semin Pediatr Surg. 1996 Nov;5(4):216–223. [PubMed] [Google Scholar]
  12. Gross I., Ballard P. L., Ballard R. A., Jones C. T., Wilson C. M. Corticosteroid stimulation of phosphatidylcholine synthesis in cultured fetal rabbit lung: evidence for de novo protein synthesis mediated by glucocorticoid receptors. Endocrinology. 1983 Mar;112(3):829–837. doi: 10.1210/endo-112-3-829. [DOI] [PubMed] [Google Scholar]
  13. Henneberg S. W., Jepsen S., Andersen P. K., Pedersen S. A. Inhalation of nitric oxide as a treatment of pulmonary hypertension in congenital diaphragmatic hernia. J Pediatr Surg. 1995 Jun;30(6):853–855. doi: 10.1016/0022-3468(95)90763-7. [DOI] [PubMed] [Google Scholar]
  14. Inoue N., Venema R. C., Sayegh H. S., Ohara Y., Murphy T. J., Harrison D. G. Molecular regulation of the bovine endothelial cell nitric oxide synthase by transforming growth factor-beta 1. Arterioscler Thromb Vasc Biol. 1995 Aug;15(8):1255–1261. doi: 10.1161/01.atv.15.8.1255. [DOI] [PubMed] [Google Scholar]
  15. Jaskoll T., Choy H. A., Melnick M. The glucocorticoid-glucocorticoid receptor signal transduction pathway, transforming growth factor-beta, and embryonic mouse lung development in vivo. Pediatr Res. 1996 May;39(5):749–759. doi: 10.1203/00006450-199605000-00002. [DOI] [PubMed] [Google Scholar]
  16. Karamanoukian H. L., Peay T., Love J. E., Abdel-Rahman E., Dandonna P., Azizkhan R. G., Glick P. L. Decreased pulmonary nitric oxide synthase activity in the rat model of congenital diaphragmatic hernia. J Pediatr Surg. 1996 Aug;31(8):1016–1019. doi: 10.1016/s0022-3468(96)90076-7. [DOI] [PubMed] [Google Scholar]
  17. Kitagawa M., Hislop A., Boyden E. A., Reid L. Lung hypoplasia in congenital diaphragmatic hernia. A quantitative study of airway, artery, and alveolar development. Br J Surg. 1971 May;58(5):342–346. doi: 10.1002/bjs.1800580507. [DOI] [PubMed] [Google Scholar]
  18. Kluth D., Kangah R., Reich P., Tenbrinck R., Tibboel D., Lambrecht W. Nitrofen-induced diaphragmatic hernias in rats: an animal model. J Pediatr Surg. 1990 Aug;25(8):850–854. doi: 10.1016/0022-3468(90)90190-k. [DOI] [PubMed] [Google Scholar]
  19. Kostyk S. K., Kourembanas S., Wheeler E. L., Medeiros D., McQuillan L. P., D'Amore P. A., Braunhut S. J. Basic fibroblast growth factor increases nitric oxide synthase production in bovine endothelial cells. Am J Physiol. 1995 Nov;269(5 Pt 2):H1583–H1589. doi: 10.1152/ajpheart.1995.269.5.H1583. [DOI] [PubMed] [Google Scholar]
  20. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  21. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  22. Losty P. D., Pacheco B. A., Manganaro T. F., Donahoe P. K., Jones R. C., Schnitzer J. J. Prenatal hormonal therapy improves pulmonary morphology in rats with congenital diaphragmatic hernia. J Surg Res. 1996 Sep;65(1):42–52. doi: 10.1006/jsre.1996.0341. [DOI] [PubMed] [Google Scholar]
  23. Losty P. D., Suen H. C., Manganaro T. F., Donahoe P. K., Schnitzer J. J. Prenatal hormonal therapy improves pulmonary compliance in the nitrofen-induced CDH rat model. J Pediatr Surg. 1995 Mar;30(3):420–426. doi: 10.1016/0022-3468(95)90046-2. [DOI] [PubMed] [Google Scholar]
  24. MacRitchie A. N., Jun S. S., Chen Z., German Z., Yuhanna I. S., Sherman T. S., Shaul P. W. Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ Res. 1997 Sep;81(3):355–362. doi: 10.1161/01.res.81.3.355. [DOI] [PubMed] [Google Scholar]
  25. Meisinger C., Zeschnigk C., Grothe C. In vivo and in vitro effect of glucocorticoids on fibroblast growth factor (FGF)-2 and FGF receptor 1 expression. J Biol Chem. 1996 Jul 12;271(28):16520–16525. doi: 10.1074/jbc.271.28.16520. [DOI] [PubMed] [Google Scholar]
  26. Minoo P., King R. J. Epithelial-mesenchymal interactions in lung development. Annu Rev Physiol. 1994;56:13–45. doi: 10.1146/annurev.ph.56.030194.000305. [DOI] [PubMed] [Google Scholar]
  27. Mouhieddine O. B., Cazals V., Kuto E., Le Bouc Y., Clement A. Glucocorticoid-induced growth arrest of lung alveolar epithelial cells is associated with increased production of insulin-like growth factor binding protein-2. Endocrinology. 1996 Jan;137(1):287–295. doi: 10.1210/endo.137.1.8536625. [DOI] [PubMed] [Google Scholar]
  28. Nathan C., Xie Q. W. Regulation of biosynthesis of nitric oxide. J Biol Chem. 1994 May 13;269(19):13725–13728. [PubMed] [Google Scholar]
  29. Nobuhara K. K., Wilson J. M. Pathophysiology of congenital diaphragmatic hernia. Semin Pediatr Surg. 1996 Nov;5(4):234–242. [PubMed] [Google Scholar]
  30. North A. J., Moya F. R., Mysore M. R., Thomas V. L., Wells L. B., Wu L. C., Shaul P. W. Pulmonary endothelial nitric oxide synthase gene expression is decreased in a rat model of congenital diaphragmatic hernia. Am J Respir Cell Mol Biol. 1995 Dec;13(6):676–682. doi: 10.1165/ajrcmb.13.6.7576705. [DOI] [PubMed] [Google Scholar]
  31. O'Toole S. J., Irish M. S., Holm B. A., Glick P. L. Pulmonary vascular abnormalities in congenital diaphragmatic hernia. Clin Perinatol. 1996 Dec;23(4):781–794. [PubMed] [Google Scholar]
  32. Okoye B. O., Losty P. D., Fisher M. J., Hughes A. T., Lloyd D. A. Antenatal glucocorticoid therapy suppresses angiotensin-converting enzyme activity in rats with nitrofen-induced congenital diaphragmatic hernia. J Pediatr Surg. 1998 Feb;33(2):286–291. doi: 10.1016/s0022-3468(98)90449-3. [DOI] [PubMed] [Google Scholar]
  33. Okoye B. O., Losty P. D., Lloyd D. A., Gosney J. R. Effect of prenatal glucocorticoids on pulmonary vascular muscularisation in nitrofen-induced congenital diaphragmatic hernia. J Pediatr Surg. 1998 Jan;33(1):76–80. doi: 10.1016/s0022-3468(98)90366-9. [DOI] [PubMed] [Google Scholar]
  34. Rudolph A. M. Fetal and neonatal pulmonary circulation. Annu Rev Physiol. 1979;41:383–395. doi: 10.1146/annurev.ph.41.030179.002123. [DOI] [PubMed] [Google Scholar]
  35. Sadiq H. F., Devaskar U. P. Glucocorticoids increase pulmonary epidermal growth factor receptors in female and male fetal rabbit. Biochem Biophys Res Commun. 1984 Feb 29;119(1):408–414. doi: 10.1016/0006-291x(84)91667-x. [DOI] [PubMed] [Google Scholar]
  36. Schnitzer J. J., Hedrick H. L., Pacheco B. A., Losty P. D., Ryan D. P., Doody D. P., Donahoe P. K. Prenatal glucocorticoid therapy reverses pulmonary immaturity in congenital diaphragmatic hernia in fetal sheep. Ann Surg. 1996 Oct;224(4):430–439. doi: 10.1097/00000658-199610000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Shah N., Jacob T., Exler R., Morrow S., Ford H., Albanese C., Wiener E., Rowe M., Billiar T., Simmons R. Inhaled nitric oxide in congenital diaphragmatic hernia. J Pediatr Surg. 1994 Aug;29(8):1010–1015. doi: 10.1016/0022-3468(94)90269-0. [DOI] [PubMed] [Google Scholar]
  38. Sigalet D. L., Tierney A., Adolph V., Perreault T., Finer N., Hallgren R., Laberge J. M. Timing of repair of congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation support. J Pediatr Surg. 1995 Aug;30(8):1183–1187. doi: 10.1016/0022-3468(95)90017-9. [DOI] [PubMed] [Google Scholar]
  39. Steinhorn R. H., Millard S. L., Morin F. C., 3rd Persistent pulmonary hypertension of the newborn. Role of nitric oxide and endothelin in pathophysiology and treatment. Clin Perinatol. 1995 Jun;22(2):405–428. [PubMed] [Google Scholar]
  40. Suen H. C., Bloch K. D., Donahoe P. K. Antenatal glucocorticoid corrects pulmonary immaturity in experimentally induced congenital diaphragmatic hernia in rats. Pediatr Res. 1994 May;35(5):523–529. doi: 10.1203/00006450-199405000-00002. [DOI] [PubMed] [Google Scholar]
  41. Tenbrinck R., Gaillard J. L., Tibboel D., Kluth D., Lachmann B., Molenaar J. C. Pulmonary vascular abnormalities in experimentally induced congenital diaphragmatic hernia in rats. J Pediatr Surg. 1992 Jul;27(7):862–865. doi: 10.1016/0022-3468(92)90385-k. [DOI] [PubMed] [Google Scholar]
  42. Vyas J., Kotecha S. Effects of antenatal and postnatal corticosteroids on the preterm lung. Arch Dis Child Fetal Neonatal Ed. 1997 Sep;77(2):F147–F150. doi: 10.1136/fn.77.2.f147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wang J., Kuliszewski M., Yee W., Sedlackova L., Xu J., Tseu I., Post M. Cloning and expression of glucocorticoid-induced genes in fetal rat lung fibroblasts. Transforming growth factor-beta 3. J Biol Chem. 1995 Feb 10;270(6):2722–2728. doi: 10.1074/jbc.270.6.2722. [DOI] [PubMed] [Google Scholar]
  44. Xue C., Botkin S. J., Johns R. A. Localization of endothelial NOS at the basal microtubule membrane in ciliated epithelium of rat lung. J Histochem Cytochem. 1996 May;44(5):463–471. doi: 10.1177/44.5.8627003. [DOI] [PubMed] [Google Scholar]
  45. vd Staak F. H., de Haan A. F., Geven W. B., Doesburg W. H., Festen C. Improving survival for patients with high-risk congenital diaphragmatic hernia by using extracorporeal membrane oxygenation. J Pediatr Surg. 1995 Oct;30(10):1463–1467. doi: 10.1016/0022-3468(95)90408-5. [DOI] [PubMed] [Google Scholar]

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