Normal Development of the Lung and Premature Birth
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Paediatric Respiratory Reviews 11 (2010) 135–142 Contents lists available at ScienceDirect Paediatric Respiratory Reviews Mini-Symposium: Chronic Neonatal Lung Disease CNLD/BPD Normal Development of the Lung and Premature Birth Lucia J. Smith 1,2, Karen O. McKay 1,2, Peter P. van Asperen 1,2, Hiran Selvadurai 1,2, Dominic A. Fitzgerald 1,2,* 1 Department of Respiratory Medicine, The Children’s Hospital at Westmead, Locked Bag 4001 Westmead NSW Australia 2145 2 Discipline of Paediatrics and Child Health, Faculty of Medicine, The University of Sydney, Sydney NSW Australia ARTICLE INFO SUMMARY Keywords: The following review focuses on the normal development of the lung from conception to birth. The alveoli defined periods of lung development–Embryonic, Pseudoglandular, Canalicular, Saccular and Alveolar– bronchopulmonary dysplasia will be explored in detail in relation to gestational age. Cellular differentiation, formation of the lung development conducting airways and respiratory zone and development of the alveoli will be reviewed. Pulmonary premature birth vascular development will also be examined within these periods to relate the formation of the blood-air barrier to the lungs for their essential function of gas exchange after birth. The development of the surfactant and cortisol systems will also be discussed as these need to be mature before the lungs are able to take on their role of respiration following birth. It is clear that premature birth interrupts normal lung development so the effect of preterm birth on lung development will be examined and the respiratory consequences of very preterm birth will be briefly explored. Crown Copyright ß 2009 Elsevier Ltd. All rights reserved. INTRODUCTION of lung growth were confirmed by the International Congress of Anatomists meeting in Leningrad, 1970 (Nomina Embryologica).1 Investigations into the structure and function of the lung began While it is agreed there is some overlap of the beginning and end of over a century ago. These investigations led to detailed descrip- each of these periods, it is generally accepted that weeks 0 to 6 of tions of each period of lung development and the realisation that gestation comprise the embryonic period, weeks 6 to 16 the the lung is a complex structure in which steady development pseudoglandular period, weeks 16 to 24 the canalicular period and begins during the embryonic period at 0 to 7 weeks gestation and weeks 24 to term (40 weeks) the saccular period.2 continues into early childhood. In fact, there is still great debate as Development of the pulmonary circulation occurs in parallel to when lung development is complete. with lung development (Figure 1). During foetal life there is an It has become clear from these investigations that premature increase in vessel length and diameter but no change in density.3 birth interrupts the normal development of the lung. Infants born By the 20th week of gestation the full number of pre-acinar prematurely have underdeveloped lungs and often require pulmonary vessels is present in each segment. During each period assistance to maintain adequate respiration. While many strate- of gestation structural remodelling and changes in growth and gies that accelerate lung development and assist in providing maturation take place. Lung vascular growth involves two basic adequate gas exchange have benefited a large number of infants, processes, vasculogenesis–formation of new blood vessels from the smallest and most preterm infants are still at the greatest risk endothelial cells4 and angiogenesis–formation of new vessels from of developing Bronchopulmonary Dysplasia capillaries via sprouting.5 The following review explores normal development of the lung and the effect premature birth has on this development. Embryonic Period (weeks 0 to 6) PRENATAL LUNG DEVELOPMENT This is the period of organ development–organogenesis. At the end of the fourth week of gestation the lung appears as a ventral The growth and development of the lung is divided into four bud of the oesophagus.6 By the end of the sixth week lobar and characteristic periods (Figure 1). The nomenclature of the periods segmental portions of the airway tree are preformed as tubes of ‘‘high columnar epithelium’’.6 By seven weeks subsegmental branching is evident.7 Alescio and Cassini8 originally documented, * Corresponding author. Department of Respiratory Medicine, The Children’s in mouse lung, that the branching pattern is driven by signals from Hospital at Westmead, Locked Bag 4001 Westmead NSW Australia. 2145. Tel.: +61 2 98453397; Fax: +61 2 98453396. the mesenchyme to the budding airway. Their investigations E-mail address: [email protected] (D.A. Fitzgerald). showed that the pulmonary mesenchyme consists of a bronchial 1526-0542/$ – see front matter. Crown Copyright ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2009.12.006 136 L.J. Smith et al. / Paediatric Respiratory Reviews 11 (2010) 135–142 Figure 1. Overview of Gestation. portion, which induces budding from the epithelium and a tracheal vascular plexus.6 The pulmonary vein appears as a small tubule portion that does not. They also demonstrated that without the growing out from the left atrial portion of the heart.2 By the sixth bronchial mesenchyme, branching of the epithelium does not week of gestation, the adult pattern of central vascular and airway occur.8 structures consisting of lobar and segmental branches is present.9 Vasculogenesis occurs within the immature mesenchyme. The After the age of seven weeks the lung resembles a primitive pulmonary arteries bud off the 6th pair of aortic arches growing small gland (giving the next stage its name) and has so entered the down to the mesenchyme and surround the lung tubules as a Pseudoglandular period of development.6 L.J. Smith et al. / Paediatric Respiratory Reviews 11 (2010) 135–142 137 Pseudoglandular Period (weeks 6 to 16) epithelial cells.13 This stretches the intervening cytoplasm into a flange-like film through which, after birth, gases will be exchanged Detailed examination of human foetal tissue has allowed a between blood and air.1 precise definition of this stage of development. Early investiga- Pulmonary vascular development is characterised in this period tors10,11 shared the view that all conducting airways of the by increased vessel proliferation and organisation into a capillary respiratory tree down to the terminal bronchioles were present at network around airspaces.15 Increasing numbers of capillaries birth with no new airways formed postnatally. It is now accepted accompany the small clusters of short tubules and buds that are that all the conducting airways are created during this stage.12 the acinus with the capillaries forming a loose three-dimensional Investigators in the 1960’s concluded that all non-respiratory network in the mesenchyme. At 12 to 14 weeks the capillary portions of the bronchial tree had been formed by the 16th week.6 network is separated from the acinus by the mesenchyme Thirty five years later Kitaoka and colleagues12 confirmed this view however, by about 23 weeks this network closely approaches with their investigations of foetal airways that had been the alveolar epithelium.16 reconstructed three-dimensionally from serial histologic sections. The formation of the thin blood-air barrier starts peripherally.17 Their results showed that 20 generations of branching were Capillaries induce overlying epithelial cells to flatten and completed by 16 weeks. They concluded that airway branching differentiate into type I alveolar epithelial cells via various reaches the level of the acinus by the late Pseudoglandular period. regulatory factors.18 At this time, formation of the blood-air The acinus is a collective term for the respiratory zone of the barrier does not involve the terminal segment of the last tubule lung. It contains the respiratory bronchiole, which by definition branch because the undifferentiated cuboidal epithelium is needed contains no cartilage in the wall, the alveolar ducts and the alveolar for further growth.6 sacs.7 Flattening of the alveolar epithelium is evident by 20 weeks.19 Vascular development is complete by the end of this stage. The This represents differentiation of cuboidal cells into type I arterial tree branches in accord with the airways3 with the veins epithelial cells7 and type II epithelial cells that contain lamellar running through connective tissue septa. By the end of this period bodies, which are the intracellular storage units of surfactant.17 the pre-acinar vascular pattern corresponds to that of the adult Some investigators have suggested that alveolar type II cells lung.2 Capillaries of a 3 to 4 month old foetus had no ultra- appear initially and then differentiate into alveolar type I cells.17 structural differences from those of adults, apart from a thicker The type II alveolar epithelial cell is crucial for normal lung endothelium.13 development as it is the precursor to surfactant production and During this period cellular differentiation of the conducting secretion which is essential for normal respiration after birth. Early airways commences from the proximal end to the distal end.7 investigations using the electron microscope determined it was Growth also occurs from a proximal to distal direction.14 Airway possible to distinguish two types of epithelial cells from about 24 tubes are lined with high columnar epithelium. By 12 weeks of weeks. Type I cells lined the greater part of the alveolar surface gestation cartilage and smooth muscle