Betamethasone Worsens Chorioamnionitis-Related Lung Development Impairment in Rabbits

ABSTRACT

Although chorioamnionitis and glucocorticoids (GC) are both known to have potential adverse effects on alveolar development, the use of GC is generalized because of their demonstrated benefits in premature newborns. The objective of this study was to analyze the cumulative effects of GC and chorioamnionitis on lung development and infectious process. In a model of Escherichia coli chorioamnionitis controlled by antibiotics, pregnant rabbits were randomized among five groups: (1) E. coli infection alone, (2) infection plus one betamethasone injection (0.1 mg.kg⁻¹), (3) infection plus two betamethasone injections, (4) betamethasone alone, (5) control. Lung morphometric analysis, bronchoalveolar lavage, and bacteriologic tissue cultures were performed after spontaneous delivery. In the context of chorioamnionitis, one betamethasone treatment significantly decreased birth weight and lung volume versus controls (30 ± 1.40 versus 52.40 ± 2.54 g, and 1.92 ± 0.67 versus 2.15 ± 0.74 cm³, respectively, p < 0.05). Two betamethasone treatments significantly decreased specific alveolar area (279.8 ± 46 cm²/100 g versus 510.90 ± 54.1 cm²/100 g), specific interstitium volume (0.98 ± 0.09 cm³/100 g versus 1.78 ± 0.16 cm³/100 g), and specific elastin fiber length (57.4 ± 10.5 versus 183.6 ± 8.1 cm/100 g). These results suggest that glucocorticoid treatment might represent an additional risk factor for lung development in the instance of prenatal infection.

Bronchodysplasia - chorioamnionitis - glucocorticoids - lung development

REFERENCES

• 1 Jobe A H, Bancalari E. Bronchopulmonary dysplasia.  Am J Respir Crit Care Med. 2001;  163 1723-1729
• 2 Watterberg K L, Demers L M, Scott S M, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops.  Pediatrics. 1996;  97 210-215
• 3 Goldenberg R L, Hauth J C, Andrews W W. Intrauterine infection and preterm delivery.  N Engl J Med. 2000;  342 1500-1507
• 4 Kallapur S G, Jobe A H. Contribution of inflammation to lung injury and development.  Arch Dis Child Fetal Neonatal Ed. 2006;  91 F132-F135
• 5 Crowley P. Prophylactic corticosteroids for preterm birth.  Cochrane Database Syst Rev. 2000;  (2) CD000065
• 6 Grier D G, Halliday H L. Effects of glucocorticoids on fetal and neonatal lung development.  Treat Respir Med. 2004;  3 295-306
• 7 Willet K E, McMenamin P, Pinkerton K E et al.. Lung morphometry and collagen and elastin content: changes during normal development and after prenatal hormone exposure in sheep.  Pediatr Res. 1999;  45 (5 Pt 1) 615-625
• 8 Bolt R J, van Weissenbruch M M, Lafeber H N, Delemarre-van de Waal H A. Glucocorticoids and lung development in the fetus and preterm infant.  Pediatr Pulmonol. 2001;  32 76-91
• 9 Roth-Kleiner M, Berger T M, Tarek M R, Burri P H, Schittny J C. Neonatal dexamethasone induces premature microvascular maturation of the alveolar capillary network.  Dev Dyn. 2005;  233 1261-1271
• 10 Massaro D, Teich N, Maxwell S, Massaro G D, Whitney P. Postnatal development of alveoli. Regulation and evidence for a critical period in rats.  J Clin Invest. 1985;  76 1297-1305
• 11 le Cras T D, Markham N E, Morris K G, Ahrens C R, McMurtry I F, Abman S H. Neonatal dexamethasone treatment increases the risk for pulmonary hypertension in adult rats.  Am J Physiol Lung Cell Mol Physiol. 2000;  278 L822-L829
• 12 Eskenasy A, Tapu V, Eskenasy M. The foetal development of the rabbit lung: a cytologic, cytochemical and histoenzymatic study.  Morphol Embryol (Bucur). 1976;  22 237-247
• 13 Fukuda Y, Ishizaki M, Okada Y, Seiki M, Yamanaka N. Matrix metalloproteinases and tissue inhibitor of metalloproteinase-2 in fetal rabbit lung.  Am J Physiol Lung Cell Mol Physiol. 2000;  279 L555-L561
• 14 Gras-Le Guen C, Debillon T, Toquet C et al.. Persistent bacteremia in rabbit fetuses despite maternal antibiotic therapy in a novel intrauterine-infection model.  Antimicrob Agents Chemother. 2003;  47 2125-2130
• 15 Gras-Le Guen C, Denis C, Franco-Montoya M L et al.. Antenatal infection in the rabbit impairs post-natal growth and lung alveolarisation.  Eur Respir J. 2008;  32 1520-1528
• 16 Pratt L, Magness R R, Phernetton T, Hendricks S K, Abbott D H, Bird I M. Repeated use of betamethasone in rabbits: effects of treatment variation on adrenal suppression, pulmonary maturation, and pregnancy outcome.  Am J Obstet Gynecol. 1999;  180 995-1005
• 17 Scherle W. A simple method for volumetry of organs in quantitative stereology.  Mikroskopie. 1970;  26 57-60
• 18 Weibel E R, Cruz-Orive L M. Morphometric methods. In: Crystal R G, West R G, eds. The Lung: Scientific Foundations. 2nd ed. Philadelphia: Raven; 1997: 333-334
• 19 Burri P H, Dbaly J, Weibel E R. The postnatal growth of the rat lung. I. Morphometry.  Anat Rec. 1974;  178 711-730
• 20 Namysłowski G, Scierski W, Nozyński J K, Zembala-Nozyńska E. Morphometric characteristics of cell nuclei of the precancerous lesions and laryngeal cancer.  Med Sci Monit. 2004;  10 CR241-CR245
• 21 Bourbon J, Boucherat O, Chailley-Heu B, Delacourt C. Control mechanisms of lung alveolar development and their disorders in bronchopulmonary dysplasia.  Pediatr Res. 2005;  57 (5 Pt 2) 38R-46R
• 22 Kinsella J P, Greenough A, Abman S H. Bronchopulmonary dysplasia.  Lancet. 2006;  367 1421-1431
• 23 Kallapur S G, Bachurski C J, Le Cras T D, Joshi S N, Ikegami M, Jobe A H. Vascular changes after intra-amniotic endotoxin in preterm lamb lungs.  Am J Physiol Lung Cell Mol Physiol. 2004;  287 L1178-L1185
• 24 Ikegami M, Jobe A H, Newnham J, Polk D H, Willet K E, Sly P. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs.  Am J Respir Crit Care Med. 1997;  156 178-184
• 25 Willet K E, Jobe A H, Ikegami M, Kovar J, Sly P D. Lung morphometry after repetitive antenatal glucocorticoid treatment in preterm sheep.  Am J Respir Crit Care Med. 2001;  163 1437-1443
• 26 Willet K E, Jobe A H, Ikegami M, Newnham J, Brennan S, Sly P D. Antenatal endotoxin and glucocorticoid effects on lung morphometry in preterm lambs.  Pediatr Res. 2000;  48 782-788
• 27 Ueda K, Cho K, Matsuda T et al.. A rat model for arrest of alveolarization induced by antenatal endotoxin administration.  Pediatr Res. 2006;  59 396-400
• 28 Massaro G D, Massaro D. Formation of alveoli in rats: postnatal effect of prenatal dexamethasone.  Am J Physiol. 1992;  263 (1 Pt 1) L37-L41
• 29 Watterberg K L, Scott S M, Naeye R L. Chorioamnionitis, cortisol, and acute lung disease in very low birth weight infants.  Pediatrics. 1997;  99 E6
• 30 Hardie W D, Bruno M D, Huelsman K M et al.. Postnatal lung function and morphology in transgenic mice expressing transforming growth factor-alpha.  Am J Pathol. 1997;  151 1075-1083
• 31 Kovar J, Willet K E, Hislop A, Sly P D. Impact of postnatal glucocorticoids on early lung development.  J Appl Physiol. 2005;  98 881-888
• 32 Crowther C A, Haslam R R, Hiller J E, Doyle L W, Robinson J S. Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group . Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.  Lancet. 2006;  367 1913-1919
• 33 Jobe A H. Glucocorticoids, inflammation and the perinatal lung.  Semin Neonatol. 2001;  6 331-342