Fetal lung growth, development, and lung fluid

doi:10.1017/CBO9780511997778.030

15.1 - Fetal lung growth, development, and lung fluid

Physiology and pathophysiology

from Section 2 - Fetal disease

Published online by Cambridge University Press: 05 February 2013

Takushi Hanita and

Edited by

Anthony Johnson and

Mark D. Kilby: Affiliation:
Department of Fetal Medicine, University of Birmingham
Anthony Johnson: Affiliation:
Baylor College of Medicine, Texas
Dick Oepkes: Affiliation:
Department of Obstetrics, Leiden University Medical Center

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Summary

Introduction

The lung develops in utero as a secretory, gland-like organ, and for normal growth and development to occur the lung must be maintained in an expanded state during at least the latter half of gestation. A considerable amount of research in recent years has gone into understanding how lung development is regulated at the molecular level, and also how the lung’s physicochemical environment affects its development. In this chapter we focus on how normal lung development is regulated before birth, and how it is affected by the intrauterine environment. Indeed, there is now a large body of evidence indicating that alterations in lung development that occur during fetal and early postnatal life can persist throughout life, and can impair adult lung function and accelerate the age-related decline in lung function. Lung development is completed during early postnatal life; therefore, after infancy there is limited scope for repairing abnormal lung development. Thus, it is important to be able to detect alterations in lung development early in life, and to understand the processes involved in normal lung development in order to be able to devise therapies to normalize any major alterations. We begin by presenting a brief overview of fetal lung development.

Normal lung development

In order to understand how the lung can be affected by intrauterine conditions, it is important to appreciate how the lung develops. The lung develops as an essentially tubular structure of increasing complexity due to complex interactions between cells of endodermal and mesenchymal origin. At least four or five distinct stages of lung development are recognized, based on microscopic appearance: these are the embryonic, pseudoglandular, canalicular, and saccular-alveolar stages [1]. A final stage of microvascular maturation can also be recognized [2]. These stages of lung development overlap and are conserved between species, although the timing of each stage differs [3].

Keywords

lung liquid lung expansion lung hyperplasia lung hypoplasia lung development fetal breathing movements intrauterine environment

Information

Type: Chapter
Information: Fetal Therapy
Scientific Basis and Critical Appraisal of Clinical Benefits
, pp. 271 - 281
DOI: https://doi.org/10.1017/CBO9780511997778.030 [Opens in a new window]
Publisher: Cambridge University Press
Print publication year: 2012

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References

Hooper, S. Respiratory system. In: Harding, R, Bocking, AD, eds. Fetal Growth and Development. Cambridge, Cambridge University Press. 2001; 114–36.

Burri, PH. Structural aspects of postnatal lung development – alveolar formation and growth. Biol Neonate 2006;89(4):313–22.Google Scholar

Pinkerton, KE, Joad, JP. The mammalian respiratory system and critical windows of exposure for children’s health. Environ Health Perspect 2000;108 Suppl 3:457–62.Google Scholar

Cardoso, W. Lung morphogenesis, role of growth factors and transcription factors. In: Harding, R, Pinkerton, K, Plopper, CG, eds. The Lung: Development, Aging and the Environment. London, Elsevier Academic Press. 2004; 3–11.

Morrisey, EE, Hogan, BL. Preparing for the first breath: genetic and cellular mechanisms in lung development. Develop Cell 2010;18(1):8–23.Google Scholar

Harding, R, Hooper, SB, Wallace, MJ. Lung development: overview. In: Laurent, G, Shapiro, D, eds. Encyclopedia of Respiratory Medicine. Oxford, Elsevier. 2006; 613–18.

Groenman, F, Unger, S, Post, M. The molecular basis for abnormal human lung development. Biol Neonate 2005;87(3):164–77.Google Scholar

Warburton, D, El-Hashash, A, Carraro, G, et al. Lung organogenesis. Curr Top Dev Biol 2010;90:73–158.Google Scholar

Flecknoe, SJ, Wallace, MJ, Cock, ML, Harding, R, Hooper, SB. Changes in alveolar epithelial cell proportions during fetal and postnatal development in sheep. Am J Physiol 2003;285(3):L664–70.Google Scholar

Flecknoe, SJ, Wallace, MJ, Harding, R, Hooper, SB. Determination of alveolar epithelial cell phenotypes in fetal sheep: evidence for the involvement of basal lung expansion. J Physiol 2002;542 (Pt 1):245–53.Google Scholar

Gonzalez, RF, Allen, L, Dobbs, LG. Rat alveolar type I cells proliferate, express OCT-4, and exhibit phenotypic plasticity in vitro. Am J PhysiolAm J Physiol 2009;297(6):L1045–55.Google Scholar

Adamson, TM, Boyd, RD, Platt, HS, Strang, LB. Composition of alveolar liquid in the foetal lamb. J Physiol 1969;204(1):159–68.Google Scholar

Hooper, SB, Harding, R. Fetal lung liquid: a major determinant of the growth and functional development of the fetal lung. Clin Exp Pharm Physiol 1995;22(4):235–47.Google Scholar

Harding, R, Hooper, SB. Regulation of lung expansion and lung growth before birth. J Appl Physiol 1996;81(1):209–24.Google Scholar

Alcorn, D, Adamson, TM, Lambert, TF, et al. Morphological effects of chronic tracheal ligation and drainage in the fetal lamb lung. J Anat 1977;123(3):649–60.Google Scholar

Moessinger, AC, Harding, R, Adamson, TM, Singh, M, Kiu, GT. Role of lung fluid volume in growth and maturation of the fetal sheep lung. J Clin Invest 1990;86(4):1270–7.Google Scholar

Boland, RE, Nardo, L, Hooper, SB. Cortisol pretreatment enhances the lung growth response to tracheal obstruction in fetal sheep. Am J Physiol 1997;273(6 Pt 1):L1126–31.Google Scholar

Nardo, L, Hooper, SB, Harding, R. Stimulation of lung growth by tracheal obstruction in fetal sheep: relation to luminal pressure and lung liquid volume. Pediatr Res 1998; 43(2):184–90.Google Scholar

Sozo, F, Wallace, MJ, Zahra, VA, Filby, CE, Hooper, SB. Gene expression profiling during increased fetal lung expansion identifies genes likely to regulate development of the distal airways. Physiol Genomics 2006;24(2):105–13.Google Scholar

Mesas-Burgos, C, Nord, M, Didon, L, Eklof, AC, Frenckner, B. Gene expression analysis after prenatal tracheal ligation in fetal rat as a model of stimulated lung growth. J Pediatr Surg 2009;44(4):720–8.Google Scholar

Boucherat, O, Franco-Montoya, ML, Thibault, C, et al. Gene expression profiling in lung fibroblasts reveals new players in alveolarization. Physiol Genomics 2007;32(1):128–41.Google Scholar

Gillett, AM, Wallace, MJ, Gillespie, MT, Hooper, SB. Increased expansion of the lung stimulates calmodulin 2 expression in fetal sheep. Am J Physiol 2002;282(3):L440–7.Google Scholar

Liu, M, Xu, J, Tanswell, AK, Post, M. Inhibition of mechanical strain-induced fetal rat lung cell proliferation by gadolinium, a stretch-activated channel blocker. J Cell Physiol 1994;161(3):501–7.Google Scholar

Bolt, RJ, van Weissenbruch, MM, Lafeber, HN, Delemarre-van de Waal, HA. Glucocorticoids and lung development in the fetus and preterm infant. Pediatr Pulmonol 2001;32(1):76–91.Google Scholar

Boland, R, Joyce, BJ, Wallace, MJ, et al. Cortisol enhances structural maturation of the hypoplastic fetal lung in sheep. J Physiol 2004;554(Pt 2):505–17.Google Scholar

Dickson, KA, Harding, R. Restoration of lung liquid volume following its acute alteration in fetal sheep. J Physiol 1987;385:531–43.Google Scholar

Harding, R, Sigger, JN, Wickham, PJ, Bocking, AD. The regulation of flow of pulmonary fluid in fetal sheep. Respir Physiol 1984;57(1):47–59.Google Scholar

Harding, R, Bocking, AD, Sigger, JN. Influence of upper respiratory tract on liquid flow to and from fetal lungs. J Appl Physiol 1986;61(1):68–74.Google Scholar

Miller, AA, Hooper, SB, Harding, R. Role of fetal breathing movements in control of fetal lung distension. J Appl Physiol 1993;75(6):2711–17.Google Scholar

Albuquerque, CA, Smith, KR, Saywers, TE, et al. Relation between oligohydramnios and spinal flexion in the human fetus. Early Hum Development 2002;68(2):119–26.Google Scholar

Harding, R, Hooper, SB, Dickson, KA. A mechanism leading to reduced lung expansion and lung hypoplasia in fetal sheep during oligohydramnios. Am J Obstet Gynecol 1990;163(6 Pt 1):1904–13.Google Scholar

Lines, A, Nardo, L, Phillips, ID, Possmayer, F, Hooper, SB. Alterations in lung expansion affect surfactant protein A, B, and C mRNA levels in fetal sheep. Am J Physiol 1999;276(2 Pt 1):L239–45.Google Scholar

Morin, FC 3rd, Stenmark, KR. Persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med 1995;151(6):2010–32.Google Scholar

Suzuki, K, Hooper, SB, Cock, ML, Harding, R. Effect of lung hypoplasia on birth-related changes in the pulmonary circulation in sheep. Pediatr Res 2005;57(4):530–6.Google Scholar

Suzuki, K, Hooper, SB, Wallace, MJ, Probyn, ME, Harding, R. Effects of antenatal corticosteroid treatment on pulmonary ventilation and circulation in neonatal lambs with hypoplastic lungs. Pediatr Pulmonol 2006;41(9):844–54.Google Scholar

Langer, R, Kaufmann, HJ. Primary (isolated) bilateral pulmonary hypoplasia: a comparative study of radiologic findings and autopsy results. Pediatr Radiol 1986;16(3):175–9.Google Scholar

Gould, S. Pulmonary hypoplasia: hyaline membrane disease and chronic lung disease. In: Hanson, MA, Spencer, JAD, Rodeck, CH, eds. Fetus and Neonate: Breathing. Cambridge, Cambridge University Press. 1994; 214–36.

Sherer, DM, Davis, JM, Woods, JR Jr. Pulmonary hypoplasia: a review. Obstet Gynecol Surv 1990;45(11):792–803.Google Scholar

Thibeault, DW, Beatty, EC Jr, Hall, RT, Bowen, SK, O’Neill, DH. Neonatal pulmonary hypoplasia with premature rupture of fetal membranes and oligohydramnios. J Pediatr 1985;107(2):273–7.Google Scholar

Logan, JW, Rice, HE, Goldberg, RN, Cotten, CM. Congenital diaphragmatic hernia: a systematic review and summary of best-evidence practice strategies. J Perinatol 2007;27(9):535–49.Google Scholar

Lund, DP, Mitchell, J, Kharasch, V, et al. Congenital diaphragmatic hernia: the hidden morbidity. J Pediatric Surg 1994;29(2):258–62; discussion 262–4.Google Scholar

Wung, JT, Sahni, R, Moffitt, ST, Lipsitz, E, Stolar, CJ. Congenital diaphragmatic hernia: survival treated with very delayed surgery, spontaneous respiration, and no chest tube. J Pediatric Surg 1995;30(3):406–9.Google Scholar

Reiss, I, Schaible, T, van den Hout, L, et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Neonatology 98(4):354–64.

Soll, RF. Inhaled nitric oxide in the neonate. J Perinatol 2009;29 Suppl 2:S63–7.Google Scholar

De Luca, D, Zecca, E, Vento, G, De Carolis, MP, Romagnoli, C. Transient effect of epoprostenol and sildenafil combined with iNO for pulmonary hypertension in congenital diaphragmatic hernia. Paediatr Anaesth 2006;16(5):597–8.Google Scholar

Inamura, N, Kubota, A, Nakajima, T, et al. A proposal of new therapeutic strategy for antenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 2005;40(8):1315–19.Google Scholar

Harrison, MR, Adzick, NS, Flake, AW, et al. Correction of congenital diaphragmatic hernia in utero VIII: Response of the hypoplastic lung to tracheal occlusion. J Pediatr Surg 1996;31(10):1339–48.Google Scholar

Hashim, E, Laberge, JM, Chen, MF, Quillen, EW Jr. Reversible tracheal obstruction in the fetal sheep: effects on tracheal fluid pressure and lung growth. J Pediatr Surg 1995;30(8):1172–7.Google Scholar

Bratu, I, Flageole, H, Laberge, JM, Chen, MF, Piedboeuf, B. Pulmonary structural maturation and pulmonary artery remodeling after reversible fetal ovine tracheal occlusion in diaphragmatic hernia. J Pediatr Surg 2001;36(5):739–44.Google Scholar

Baird, R, Khan, N, Flageole, H, et al. The effect of tracheal occlusion on lung branching in the rat nitrofen CDH model. J Surg Res 2008;148(2):224–9.Google Scholar

Probyn, ME, Wallace, MJ, Hooper, SB. Effect of increased lung expansion on lung growth and development near midgestation in fetal sheep. Pediatr Res 2000;47(6):806–12.Google Scholar

Piedboeuf, B, Laberge, JM, Ghitulescu, G, et al. Deleterious effect of tracheal obstruction on type II pneumocytes in fetal sheep. Pediatr Res 1997;41(4 Pt 1):473–9.Google Scholar

Deprest, J, Gratacos, E, Nicolaides, KH. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet Gynecol 2004;24(2):121–6.Google Scholar

Saura, L, Castanon, M, Prat, J, et al. Impact of fetal intervention on postnatal management of congenital diaphragmatic hernia. Eur J Pediatr Surg 2007;17(6):404–7.Google Scholar

Stocker, JT, Madewell, JE, Drake, RM. Congenital cystic adenomatoid malformation of the lung. Classification and morphologic spectrum. Hum Pathol 1977;8(2):155–71.Google Scholar

Harrison, MR, Adzick, NS, Jennings, RW, et al. Antenatal intervention for congenital cystic adenomatoid malformation. Lancet 1990;336(8721):965–7.Google Scholar

Crombleholme, TM, Coleman, B, Hedrick, H, et al. Cystic adenomatoid malformation volume ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformation of the lung. J Pediatr Surg 2002;37(3):331–8.Google Scholar

Wilson, RD, Hedrick, HL, Liechty, KW, et al. Cystic adenomatoid malformation of the lung: review of genetics, prenatal diagnosis, and in utero treatment. Am J Med Genet 2006;140(2):151–5.Google Scholar

Curran, PF, Jelin, EB, Rand, L, et al. Prenatal steroids for microcystic congenital cystic adenomatoid malformations. J Pediatr Surg 2010;45(1):145–50.Google Scholar

Adzick, NS. Management of fetal lung lesions. Clin Perinatol 2003;30(3):481–92.Google Scholar

Bianchi, S, Lista, G, Castoldi, F, Rustico, M. Congenital primary hydrothorax: effect of thoracoamniotic shunting on neonatal clinical outcome. J Matern Fetal Neonatal Med 2010;23(10):1225–9.Google Scholar

Waller, K, Chaithongwongwatthana, S, Yamasmit, W, Donnenfeld AE. Chromosomal abnormalities among 246 fetuses with pleural effusions detected on prenatal ultrasound examination: factors associated with an increased risk of aneuploidy. Genet Med 2005;7(6):417–21.Google Scholar

Patton, MA, Baraitser, M, Nickolaides, K, Rodeck, CH, Gamsu, H. Prenatal treatment of fetal hydrops associated with the hypertelorism-dysphagia syndrome (Opitz-G syndrome). Prenat Diag 1986;6(2):109–15.Google Scholar

Nakamura, Y, Harada, K, Yamamoto, I, et al. Human pulmonary hypoplasia. Statistical, morphological, morphometric, and biochemical study. Arch Path Lab Med 1992;116(6):635–42.Google Scholar

Fukushima, K, Morokuma, S, Fujita, Y, et al. Short-term and long-term outcomes of 214 cases of non-immune hydrops fetalis. Early Hum Dev 87(8):571–5.

Blott, M, Greenough, A. Neonatal outcome after prolonged rupture of the membranes starting in the second trimester. Arch Dis Child 1988;63(10 Spec No):1146–50.Google Scholar

Roberts, AB, Mitchell, JM. Direct ultrasonographic measurement of fetal lung length in normal pregnancies and pregnancies complicated by prolonged rupture of membranes. Am J Obstet Gynecol 1990;163(5 Pt 1):1560–6.Google Scholar

Harding, R, Liggins, GC. The influence of oligohydramnios on thoracic dimensions of fetal sheep. J Dev Physiol 1991;16(6):355–61.Google Scholar

Singla, A, Yadav, P, Vaid, NB, Suneja, A, Faridi, MM. Transabdominal amnioinfusion in preterm premature rupture of membranes. Int J Gynaecol Obstet 2010;108(3):199–202.Google Scholar

Locatelli, A, Ghidini, A, Verderio, M, et al. Predictors of perinatal survival in a cohort of pregnancies with severe oligohydramnios due to premature rupture of membranes at <26 weeks managed with serial amnioinfusions. EurJ Obstet Gynecol Reprod Biol 2006;128(1–2):97–102.Google Scholar

Tchirikov, M, Steetskamp, J, Hohmann, M, Koelbl, H. Long-term amnioinfusion through a subcutaneously implanted amniotic fluid replacement port system for treatment of PPROM in humans. Eur J Obstet Gynecol Reprod Biol 2010;152(1):30–3.Google Scholar

Klaassen, I, Neuhaus, TJ, Mueller-Wiefel, DE, Kemper, MJ. Antenatal oligohydramnios of renal origin: long-term outcome. Nephrol Dial Transplant 2007;22(2):432–9.Google Scholar

Vilos, GA, McLeod, WJ, Carmichael, L, Probert, C, Harding, PG. Absence or impaired response of fetal breathing to intravenous glucose is associated with pulmonary hypoplasia in congenital myotonic dystrophy. Am J Obstet Gynecol 1984;148(5):558–62.Google Scholar

Pena, SD, Shokeir, MH. Syndrome of camptodactyly, multiple ankyloses, facial anomalies, and pulmonary hypoplasia: a lethal condition. J Pediatr 1974;85(3):373–5.Google Scholar

Moessinger, AC. Fetal akinesia deformation sequence: an animal model. Pediatrics 1983;72(6):857–63.Google Scholar

Solopova, A, Wisser, J, Huisman, TA. Osteogenesis imperfecta type II: fetal magnetic resonance imaging findings. Fetal Diagn Ther 2008;24(4):361–7.Google Scholar

Scurry, JP, Adamson, TM, Cussen, LJ. Fetal lung growth in laryngeal atresia and tracheal agenesis. Aust Paediatr J 1989;25(1):47–51.Google Scholar

McDougall, AR, Hooper, SB, Zahra, VA, et al. The oncogene Trop2 regulates fetal lung cell proliferation. Am J Physiol 301(4):L478–89.

Jelin, EB, Etemadi, M, Encinas, J, et al. Dynamic tracheal occlusion improves lung morphometrics and function in the fetal lamb model of congenital diaphragmatic hernia. J Pediatr Surg 2011;46(6):1150–7.Google Scholar

Khan, PA, Cloutier, M, Piedboeuf, B. Tracheal occlusion: a review of obstructing fetal lungs to make them grow and mature. Am J Med Genet C Semin Med Genet 2007;145C(2):125–38.Google Scholar

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