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Lung growth for beginners
PAEDIATRIC RESPIRATORY REVIEWS (2000) 1, 308–313 doi:10.1053/prrv.2000.0069, available online at http://www.idealibrary.com on
MINI-SYMPOSIUM: GROWTH OF THE LUNG
Lung growth for beginners S. Kotecha Department of Child Health, University of Leicester, Leicester LE2 7LX, UK KEYWORDS lung development, fetal breathing movements, fetal lung liquid, preterm birth
Summary Lung growth occurs as a series of tightly regulated events commencing in the embryo and continuing post-natally. It depends on a number of factors, including developmental, genetic and environment ones.Abnormalities of any of these factors may have a profound influence on lung growth.The causes of developmental abnormalities of the lung such as lung cysts and congenital diaphragmatic hernia are poorly understood, but may result from a combination of genetic and environmental factors. Normal fetal breathing movements and an adequate balance between the production of fetal lung fluid and drainage of this fluid are both essential for normal fetal lung growth. It seems that fetal breathing movements are necessary to maintain sufficient pressure within the airways and perhaps to directly stimulate lung growth via induction of mitogenic activity. The volume of intra-pulmonary fluid is regulated by the resistance of the upper airway and by contractions of the diaphragm. Increased drainage of the amniotic fluid, another essential factor for normal lung growth and development, will result in marked pulmonary hypoplasia as may occur with pre-term rupture of the membranes and with fetal renal disease. Perhaps the most important factor for adverse lung growth is preterm delivery of the infant from any cause including intra-uterine infection. Both anteand post-natal factors, including mechanical ventilation and oxygen therapy, will affect normal alveolization. In this review, particular attention is paid to breathing movements and the balance between fluid production and drainage. © 2000 Harcourt Publishers Ltd
INTRODUCTION For the newborn infant to adapt to the post-natal environment, a number of inter-related factors are important: the lung fluid needs to be absorbed, the lungs need to fill with air and there has to be an adequate gas-exchanging surface area. Most attention has focused on the surfactant system which ensures the lungs remain expanded by decreasing the alveolar surface tension and on the factors which are important in lung development. Both the surfactant system1 and fluid clearance from the lung2 have been reviewed recently. The molecular and cellular mechanisms contributing to normal lung growth have also been extensively reviewed.3 Discussed in this article are aspects of lung growth which may be of relevance to practising
clinicians. In the articles which follow, the consequences in the neonatal period (Anne Greenough) and longer-term (Colin Wallis) are discussed. For normal lung development to occur, normal fetal breathing movements, an adequate intra-thoracic space, sufficient extra- and intra-pulmonary fluid volume and pulmonary blood flow appear to be of particular importance.4 Maternal health, including nutrition, endocrine factors, smoking and disease, may also contribute to abnormal lung development. This article concentrates on the role of breathing movements, the intra-thoracic space and amniotic fluid in their importance to normal lung growth and development.
NORMAL LUNG DEVELOPMENT Correspondence to: Sailesh Kotecha. Department of Child Health, University of Leicester, Leicester LE2 7LX, U.K. 1526–0550/00/040308 + 06 $35.00/0
The development of the lung can be divided into five stages (Fig. 1): © 2000 Harcourt Publishers Ltd
LUNG GROWTH FOR BEGINNERS
● ● ● ● ●
Embryonic Pseudoglandular Canalicular Saccular Alveolar
309
Table 1 congenital malformations or diseases associated with abnormal lung development and the stage of their development.
0–7 weeks in utero 7–17 weeks in utero 17–27 weeks in utero 28–36 weeks in utero 36 weeks in utero–2 years post-natal
During the embryonic phase the lung develops as an outgrowth of the ventral wall of the primitive foregut endoderm. Epithelial cells of the primitive foregut invade the surrounding mesenchyme and undergo repetitive, dichotomous branching to form the proximal structures of the tracheo-bronchial tree. The pulmonary arteries are derived from the sixth aortic arches and accompany the developing airways. The embryonic phase is followed by the pseudoglandular stage, during which branching of the airways and blood vessels continues. The terminal bronchiolus is formed by the end of this stage at approximately 17 weeks gestation. Thus, all precinar airways have developed by 17 weeks of gestation. The acinar structures which comprise the respiratory bronchiolus, alveolar ducts and primitive alveoli are formed during the canalicular stage, which is completed by 27 weeks gestation. During the saccular phase the peripheral airways enlarge and the gas-exchanging surface area increases as the airway walls thin. The alveolar phase is characterized by the recognition of secondary septa and the formation of definitive alveoli. The process continues in humans beyond birth, possibly being completed by 2–3 years of age. The final numbers of alveoli in the fully developed lung range from 300–600 million, which is approximately 1000 per acinus.5 At any of the above stages abnormalities may occur due to feto-maternal factors, (e.g. oligohydramnios), genetic factors (surfactant protein B deficiency) or developmental abnormalities (Table 1).
Lung structure
Fetal stage Embryonic 0-7 weeks
Pseudoglandular 7-17 weeks
Trachea
24 days
Extrapulmonary Main Bronchus
28 days
Bronchi 8-13 generations
4-12 weeks
Bronchioli 3-10 generations
12-16 weeks
Terminal Bronchiolus 16-17 weeks 1 generation Respiratory bronchioli 18-25 weeks 1 generation
Saccular/Alveolar 28 weeks–term pleura
Alveolar ducts 2-3 generations
25 wk-1yr
Alveoli 1 generation ie 1000/acinus
30 wk-2-3yr
Acinus
Canalicular 17-27 weeks
Figure 1 Stages of normal lung development with the airway structure developing within each stage. (Adapted from that used by Dr Alison Hislop, personal communication).
Embryonic Pulmonary agenesis Tracheal or laryngeal agenesis or stenosis Tracheo- or broncho–malacia Bronchial malformations Ectopic lobes A-V malformations Congenital lobar cysts Pseudoglandular Cystic adenomatoid malformation Pulmonary sequestration Lung hypoplasia Lung cysts Congenital pulmonary lymphangiectasia Congenital diaphragmatic hernia Canalicular Lung hypoplasia Respiratory distress syndrome Acinar dysplasia Saccular/Alveolar Pulmonary hypoplasia Respiratory distress syndrome/Chronic Lung disease of prematurity Acinar dysplasia Alveolar capillary dysplasia
FETAL BREATHING MOVEMENTS The classic experiments by Desai and Wigglesworth6 have elegantly demonstrated the importance of fetal breathing movements for normal lung growth and development. Abolishing these movements by transecting the spinal cord at the level of the phrenic nerve, they were able to demonstrate decreased lung growth in newborn rabbits. If the transection was performed at the C1–C3 level, i.e. above the phrenic nerve, hypoplastic lungs with decreased lung weight and poorly expanded, thin-walled terminal sacs were seen. When transection took place below the phrenic nerve at the C5–C8 level, although some weight reduction was seen, the terminal sacs were very similar to control animals. Since no abnormalities were noted in any other organs, the abnormal lung development was attributed to absent breathing movements. Additional experiments on pregnant ewes by Kitterman’s group7 confirmed these findings by ablation of the phrenic nerve but also reported decreased airway fluid, lung weight and total lung DNA. Production of lung fluid was, however, not affected. Although these experiments strongly implicate fetal breathing to be important in normal lung development, abolishing diaphragmatic movement will also decrease intra-thoracic volume as organs in the abdomen encroach on the thoracic cavity.
310
Table 2 Factors that may affect fetal breathing movements. Increased breathing movement Hypercapnia Hyperglycaemia Acidosis Increased temperature Indomethacin Caffeine Theophyllines Decreased breathing movements Hypoxia Hypoglycaemia Prostaglandin E2 Maternal smoking Maternal alcohol Intra-uterine infection Diazepam Morphine
In humans, breathing movements are detected by 11 weeks’ gestation but by 30–40 weeks occur 30% of the time.8 They increase following a maternal meal, presumably due to increased blood glucose and there is a circadian rhythm with minimum movements between 7 pm and midnight and heightened movements between 4 and 7 am. During labour, breathing movements decrease from 25% at the onset to 8% during late labour and <1% during active labour.9 Ash et al. have reported fetal breathing activity increasing from 76% in early labour to 90% in advanced labour.10 Fetal breathing appears to be related to the behavioural state of the fetus.11 As the fetus approaches term, the incidence of these movements is considerably greater during active periods than during periods of quiet activity.12 Besides a circadian rhythm and a relationship to sleep, many other factors can influence breathing movements (Table 2). Fetal breathing movements increase after a maternal meal and after infusions of glucose. Increase in carbon dioxide increases fetal breathing movements in both animals and humans and the opposite is seen with hypocapnia.13 These observations suggest that the central chemoreceptors are active in fetal life. Similarly, hypoxia depresses fetal motor activity, including limb movements, random eye movements, swallowing and fetal breathing. Hyperoxia, in contrast, appears to have minimal effect on fetal breathing. Prostaglandin E2 increases during labour and has been shown to decrease fetal breathing. With induced labour decreased breathing movements have been noted, although in spontaneous labour Ash et al. have observed increased breathing movements.10 Maternal ingestion of alcohol or drugs including sedatives have all been shown to decrease breathing movements but drugs such as caffeine increase them. Maternal smoking also decreases fetal breathing movements by several
S. KOTECHA
mechanisms including decreased uterine blood flow and hypoxia. The importance of breathing movements lies in maintaining an adequate lung volume.14 During apnoeic phases the relatively high resistance of the upper airways prevents efflux of the lung fluid, thus maintaining a satisfactory pressure within the lungs. During fetal breathing the upper airways relax and the diaphragmatic contractions continue to maintain the lung expansion since ablation of the diaphragmatic activity by phrenic nerve ablation decreases the lung fluid volume.15 Lung expansion, together with rhythmic contraction of the diaphragm during fetal breathing, appear to be important contributors to lung growth, since mitogenic growth factors have been shown to be released during rhythmic stretch.16 Many groups have attempted to study breathing movements in the fetus approaching term to identify high-risk infants, especially the hypoxic fetus. Besinger et al. observed fetal breathing movements in 50 pregnancies between 26 and 34 weeks and found that if the movements were absent during a 20-minute observation period labour occurred in 16 out of 17 women.17 In 29 of the remaining 33 in whom fetal breathing was observed, labour did not occur for at least 48 hours after the observation. Fetal breathing movements have also been used to predict pulmonary hypoplasia in pregnant women with oligohydramnios. Blott et al. reported a lethal outcome in five of 20 pregnancies complicated by oligohydramnios when fetal breathing movements were absent.18 As breathing movements are episodic, such methodology to detect breathing movements is not accurate unless performed for prolonged periods and is thus not applied clinically.
FETAL LUNG FLUID Maintenance of fluid within the fetal lung is essential for normal lung growth and development.19 Fetal breathing movements, together with the resistance of the upper airway, appear to be responsible for maintaining the fluid within the fetal lung (see above). This has been elegantly demonstrated in a series of experiments by Harding’s group.20 When one lobe (in fetal lambs) is allowed to drain freely and the other ligated to permit increased fetal lung fluid, the drained lobe shows marked hypoplasia and the ligated lobe shows hyperplasia. Similarly, if the pressure within the fetal lung is allowed to decrease without loss of the total lung fluid, the lungs fail to develop adequately.21 The lung fluid is formed by the epithelial cells, especially of the distal airways and flows through to the upper airway where it is either swallowed or released into the amniotic space. The fluid is rich in chloride and low in bicarbonate and proteins. It is the balance between production and drainage of the fluid from the lung which appears to be important in normal lung development.22 The rate of fluid production increases in fetal lambs from approximately
LUNG GROWTH FOR BEGINNERS
311
hypoplastic lungs. Abnormalities of the thoracic wall or diseases of the muscles may adversely affect lung growth and development. In the former, as in oligohydramnios there is restricted space for the lungs to grow and in the latter poor breathing movement results in poor lung development. Any conditions that affect intrathoracic lung space adversely affect lung development, one of the most important being congenital diaphragmatic herina. Here there is abnormal development of airway branching and of the alveoli, suggesting an early but continuing effect on lung growth (see article by Greenough in this issue). Figure 2 A model depicting the factors which may contribute to normal and abnormal lung growth. Please note the importance of both pre- and post-natal factors to lung growth.
5 ml/kg at mid-gestation to greater than 20 ml/kg near term with hourly rates increasing from 2 ml/kg/h to 5 ml/kg/h, respectively. Chloride is extruded into the luminal space via the apical surface in association with sodium which is reabsorbed in exchange for potassium. As the fetus approaches term, the rate and volume of fluid production decreases. It has been suggested that neonatal respiratory distress may not only be due to surfactant deficiency but also to inadequate fluid clearance from the lungs of susceptible infants.23 Beta-adrenergic agonists stimulate sodium uptake by the epithelial cells, with consequent reabsorption of water from the extracellular space, thereby decreasing the volume of fetal lung fluid.24 Vasopressin also decreases the production of fetal lung fluid. At birth, beta-adrenergic agonists and vasopressin may act synergistically to decrease lung fluid so that the newborn infant can adapt to the post-natal environment. Other factors, such as prostaglandin E2, aldosterone and atrial naturetic hormone, may all decrease fetal lung fluid in late gestation.25
IMPORTANCE OF FLUID BALANCE AND THORACIC WALL TO NORMAL LUNG GROWTH It is not surprising that any condition which affects the balance of formation and drainage of fetal lung fluid will adversely affect the development of the fetal lung. The production of the fluid, however, appears to be unaffected by fetal breathing movements since ablation of the phrenic nerves does not affect fluid production.7 In practice, it is the drainage of the fluid that tends to affect lung growth. Oligohydramnios occurs following spontaneous rupture of the membranes or in association with uterine infection. By failing to maintain adequate extrathoracic fluid volume, the lung development is impeded with resultant hypoplasia. Similarly, Potter’s syndrome with absent kidneys results in lack of amniotic fluid and
PRETERM DELIVERY Perhaps the most important factor that adversely affects lung growth is being born too early. Decreased and dysregulated alveolization has been observed in infants who develop chronic lung disease of prematurity26. Poor alveolization may simply reflect postnatal events, including mechanical ventilation 27, oxygen therapy, patent ductus arteriosus and infection or it may have antenatal origins (Fig. 2). Animal models have elegantly demonstrated the role of each of these risk factors in the development of lung injury and their subsequent effect on lung growth. Coalson in the baboon model has shown that hyperoxia and barotrauma contribute to lung injury with subsequent decrease in alveolization28. Similar results have been observed in a wide range of animal models exposed to both hyperoxia and mechanical ventilation. Despite newer technology to decrease the effects of these risk factors, chronic lung disease of prematurity remains a major cause of morbidity and mortality. Attention has therefore turned towards antenatal factors. Romero’s group has reported the association between proinflammatory cytokines in the uterus and the subsequent development of chronic lung disease of prematurity29. An important trigger is intra-uterine infection, including Ureaplasma urealyticum. There is some clinical evidence to suggest that chorioamnionitis may predispose the fetus to subsequent lung disease and disordered lung growth30. The cascade leading to decreased alveolization may consist of an insult such as an antenatal infection leading to an inflammatory response in the fetal lungs. Resolution of the insult involves growth factors which are also important normal lung growth. It is likely that overexpression of growth factors adversely affects lung growth otherwise progressing simultaneously.
SUMMARY Lung growth is highly dependent on developmental, genetic and environmental factors. Fetal breathing movements and the balance between the production and removal of the fetal lung fluid appear to be
312
S. KOTECHA
essential. In addition, an adequate extra-uterine fluid volume is also necessary for normal lung growth. Maternal and intra-uterine factors are important and may contribute directly or indirectly to growth and development of the fetal lung. These include maternal smoking and ingestion of alcohol or sedative drugs such as benzodiazepines. Maternal health and nutrition, and the intra-uterine environment, also contribute to fetal lung growth. The commonest cause of lung injury with subsequent reduced lung growth is preterm delivery, exposing the infant to noxious agents both ante- and post-natally.
PRACTICE POINTS Normal lung growth depends on a number of inter-related factors, including: • • • • • • • • •
Normal embryonic and fetal development Genetic constitution Maternal and fetal nutrition Endocrine factors Fetal breathing movements Normal fetal lung fluid production Adequate intra-thoracic space Adequate extra-throacic space Normal post-natal adaptation The above list is not exhaustive. Lung growth depends on many factors which may directly or indirectly affect lung growth.
RESEARCH ISSUES Very little information is available on lung growth in the human fetus and infant. There are many areas which need to be studied to better understand the mechanisms that lead to lung growth. The following are some of these: • A better understanding of the embryonic development • The contribution of genetics to normal lung development is poorly understood • Regulatory growth factors need to be more clearly defined • The role of the intra-uterine environment and normal fetal development needs to be understood more accurately • Better imaging systems are needed to assess lung growth and development
REFERENCES 1. Griese M. Pulmonary surfactant in health and human lung disease: state of the art. Eur Respir J 1999; 13: 1455–1476. 2. Jain L. Alveolar fluid clearance in developing lungs and its role in neonatal transition. Clin Perinatol 1999; 26: 585–599. 3. Kotecha S. Lung growth: implications for the newborn infant. Arch Dis Child Fetal Neonatal Ed 2000; 82: F69–F74. 4. McDonald JA. Lung Growth and Development. New York: Marcel Dekker, Inc.; 1997. 5. Thurlbeck WM. Postnatal human lung growth. Thorax 1982; 37: 564–571. 6. Wigglesworth JS, Desai R. Effect on lung growth of cervical cord section in the rabbit fetus. Early Hum Dev 1979; 3: 51–65. 7. Fewell JE, Lee CC, Kitterman JA. Effects of phrenic nerve section on the respiratory system of fetal lambs. J Appl Physiol 1981; 51: 293–297. 8. Patrick J, Campbell K, Carmichael L, Natale R, Richardson B. Patterns of human fetal breathing during the last 10 weeks of pregnancy. Obstet Gynecol 1980; 56: 24–30. 9. Richardson B, Natale R, Patrick J. Human fetal breathing activity during electively induced labor at term. Am J Obstet Gynecol 1979; 133: 247–255. 10. Ash KM, Morrison I, Manning FA. Observations of intrapartum fetal activities. Am J Obstet Gynecol 1993; 168: 760–764. 11. Mulder EJ, Boersma M, Meeuse M, van der WM, van de WE, Visser GH. Patterns of breathing movements in the near-term human fetus: relationship to behavioural states. Early Hum Dev 1994; 36: 127–135. 12. van Vliet MA, Martin CB, Jr., Nijhuis JG, Prechtl HF. The relationship between fetal activity and behavioral states and fetal breathing movements in normal and growth-retarded fetuses. Am J Obstet Gynecol 1985; 153: 582–588. 13. Jansen AH, Chernick V. Respiratory control in the fetus. In: Chernick V, Mellins RB (eds). Basic mechanisms of pediatric respiratory disease: cellular and integrative. Philadelphia: BC Decker Inc; 1991. p. 273–287. 14. Hooper SB, Harding R. Fetal lung liquid: a major determinant of the growth and functional development of the fetal lung. Clin Exp Pharmacol Physiol 1995; 22: 235–247. 15. Miller AA, Hooper SB, Harding R. Role of fetal breathing movements in control of fetal lung distension. J Appl Physiol 1993; 75: 2711–2717. 16. Smith PG, Janiga KE, Bruce MC. Strain increases airway smooth muscle cell proliferation. Am J Respir Cell Mol Biol 1994; 10: 85–90. 17. Besinger RE, Compton AA, Hayashi RH. The presence or absence of fetal breathing movements as a predictor of outcome in preterm labor. Am J Obstet Gynecol 1987; 157: 753–757. 18. Blott M, Greenough A, Nicolaides KH, Campbell S. The ultrasonographic assessment of the fetal thorax and fetal breathing movements in the prediction of pulmonary hypoplasia. Early Hum Dev 1990; 21: 143–151. 19. Blott M, Greenough A, Nicolaides KH. Fetal breathing movements in pregnancies complicated by premature membrane rupture in the second trimester. Early Hum Dev 1990; 21: 41–48. 20. 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: 1270–1277. 21. Kizilcan F, Tanyel FC, Cakar N, Buyukpamukcu N, Hicsonmez A. The effect of low amniotic pressure without oligohydramnios on fetal lung development in a rabbit model. Am J Obstet Gynecol 1995; 173: 36–41. 22. Bland RD. Fetal lung liquid and its removal near term. In: Crystal RG, West JB, Weibel ER, Barnes PJ, (eds). The Lung: Scientific Foundations, second ed. Philadelphia: Lippincott-Raven Publishers; 1997. p. 2115–2127. 23. O’Brodovich HM. Immature epithelial Na+ channel expression is one of the pathogenetic mechanisms leading to human neonatal respiratory distress syndrome. Proc Assoc Am Physicians 1996; 108: 345–355.
LUNG GROWTH FOR BEGINNERS
24. Olver RE, Ramsden CA, Strang LB, Walters DV. The role of amiloride-blockable sodium transport in adrenaline-induced lung liquid reabsorption in the fetal lamb. J Physiol (Lond) 1986; 376: 321–340. 25. Barker PM, Walters DV, Markiewicz M, Strang LB. Development of the lung liquid reabsorptive mechanism in fetal sheep: synergism of triiodothyronine and hydrocortisone. J Physiol (Lond) 1991; 433: 435–449. 26. Margraf LR, Paciga JE, Balis JU. Surfactant-associated glycoproteins accumulate in alveolar cells and secretions during reparative stage of hyaline membranes disease. Hum Pathol 1990; 21: 329–396. 27. Hislop AA, Wigglesworth JS, Desai R, Aber V. The effects of preterm delivery and mechanical ventilation on human lung growth. Early Hum Dev 1987; 15: 147–164.
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28. Coalson JJ, Winter V, deLemos RA. Decreased alveolarization in baboon survivors with bronchopulmonary dysplasia. Am J Respir Crit Care Med 1995; 152: 640–646. 29. Ghezzi F, Gomez R, Romero R, Yoon BH, Edwin SS, David C et al. Elevated interleukin-8 concentrations in amniotic fluid of mothers whose neonates subsequently develop bronchopulmonary dysplasia. Eur J Obstet Gynecol Reprod Biol 1998; 78: 5–10. 30. Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops [see comments]. Pediatrics 1996; 97: 210–215.
MINI-SYMPOSIUM: GROWTH OF THE LUNG
Lung growth for beginners S. Kotecha Department of Child Health, University of Leicester, Leicester LE2 7LX, UK KEYWORDS lung development, fetal breathing movements, fetal lung liquid, preterm birth
Summary Lung growth occurs as a series of tightly regulated events commencing in the embryo and continuing post-natally. It depends on a number of factors, including developmental, genetic and environment ones.Abnormalities of any of these factors may have a profound influence on lung growth.The causes of developmental abnormalities of the lung such as lung cysts and congenital diaphragmatic hernia are poorly understood, but may result from a combination of genetic and environmental factors. Normal fetal breathing movements and an adequate balance between the production of fetal lung fluid and drainage of this fluid are both essential for normal fetal lung growth. It seems that fetal breathing movements are necessary to maintain sufficient pressure within the airways and perhaps to directly stimulate lung growth via induction of mitogenic activity. The volume of intra-pulmonary fluid is regulated by the resistance of the upper airway and by contractions of the diaphragm. Increased drainage of the amniotic fluid, another essential factor for normal lung growth and development, will result in marked pulmonary hypoplasia as may occur with pre-term rupture of the membranes and with fetal renal disease. Perhaps the most important factor for adverse lung growth is preterm delivery of the infant from any cause including intra-uterine infection. Both anteand post-natal factors, including mechanical ventilation and oxygen therapy, will affect normal alveolization. In this review, particular attention is paid to breathing movements and the balance between fluid production and drainage. © 2000 Harcourt Publishers Ltd
INTRODUCTION For the newborn infant to adapt to the post-natal environment, a number of inter-related factors are important: the lung fluid needs to be absorbed, the lungs need to fill with air and there has to be an adequate gas-exchanging surface area. Most attention has focused on the surfactant system which ensures the lungs remain expanded by decreasing the alveolar surface tension and on the factors which are important in lung development. Both the surfactant system1 and fluid clearance from the lung2 have been reviewed recently. The molecular and cellular mechanisms contributing to normal lung growth have also been extensively reviewed.3 Discussed in this article are aspects of lung growth which may be of relevance to practising
clinicians. In the articles which follow, the consequences in the neonatal period (Anne Greenough) and longer-term (Colin Wallis) are discussed. For normal lung development to occur, normal fetal breathing movements, an adequate intra-thoracic space, sufficient extra- and intra-pulmonary fluid volume and pulmonary blood flow appear to be of particular importance.4 Maternal health, including nutrition, endocrine factors, smoking and disease, may also contribute to abnormal lung development. This article concentrates on the role of breathing movements, the intra-thoracic space and amniotic fluid in their importance to normal lung growth and development.
NORMAL LUNG DEVELOPMENT Correspondence to: Sailesh Kotecha. Department of Child Health, University of Leicester, Leicester LE2 7LX, U.K. 1526–0550/00/040308 + 06 $35.00/0
The development of the lung can be divided into five stages (Fig. 1): © 2000 Harcourt Publishers Ltd
LUNG GROWTH FOR BEGINNERS
● ● ● ● ●
Embryonic Pseudoglandular Canalicular Saccular Alveolar
309
Table 1 congenital malformations or diseases associated with abnormal lung development and the stage of their development.
0–7 weeks in utero 7–17 weeks in utero 17–27 weeks in utero 28–36 weeks in utero 36 weeks in utero–2 years post-natal
During the embryonic phase the lung develops as an outgrowth of the ventral wall of the primitive foregut endoderm. Epithelial cells of the primitive foregut invade the surrounding mesenchyme and undergo repetitive, dichotomous branching to form the proximal structures of the tracheo-bronchial tree. The pulmonary arteries are derived from the sixth aortic arches and accompany the developing airways. The embryonic phase is followed by the pseudoglandular stage, during which branching of the airways and blood vessels continues. The terminal bronchiolus is formed by the end of this stage at approximately 17 weeks gestation. Thus, all precinar airways have developed by 17 weeks of gestation. The acinar structures which comprise the respiratory bronchiolus, alveolar ducts and primitive alveoli are formed during the canalicular stage, which is completed by 27 weeks gestation. During the saccular phase the peripheral airways enlarge and the gas-exchanging surface area increases as the airway walls thin. The alveolar phase is characterized by the recognition of secondary septa and the formation of definitive alveoli. The process continues in humans beyond birth, possibly being completed by 2–3 years of age. The final numbers of alveoli in the fully developed lung range from 300–600 million, which is approximately 1000 per acinus.5 At any of the above stages abnormalities may occur due to feto-maternal factors, (e.g. oligohydramnios), genetic factors (surfactant protein B deficiency) or developmental abnormalities (Table 1).
Lung structure
Fetal stage Embryonic 0-7 weeks
Pseudoglandular 7-17 weeks
Trachea
24 days
Extrapulmonary Main Bronchus
28 days
Bronchi 8-13 generations
4-12 weeks
Bronchioli 3-10 generations
12-16 weeks
Terminal Bronchiolus 16-17 weeks 1 generation Respiratory bronchioli 18-25 weeks 1 generation
Saccular/Alveolar 28 weeks–term pleura
Alveolar ducts 2-3 generations
25 wk-1yr
Alveoli 1 generation ie 1000/acinus
30 wk-2-3yr
Acinus
Canalicular 17-27 weeks
Figure 1 Stages of normal lung development with the airway structure developing within each stage. (Adapted from that used by Dr Alison Hislop, personal communication).
Embryonic Pulmonary agenesis Tracheal or laryngeal agenesis or stenosis Tracheo- or broncho–malacia Bronchial malformations Ectopic lobes A-V malformations Congenital lobar cysts Pseudoglandular Cystic adenomatoid malformation Pulmonary sequestration Lung hypoplasia Lung cysts Congenital pulmonary lymphangiectasia Congenital diaphragmatic hernia Canalicular Lung hypoplasia Respiratory distress syndrome Acinar dysplasia Saccular/Alveolar Pulmonary hypoplasia Respiratory distress syndrome/Chronic Lung disease of prematurity Acinar dysplasia Alveolar capillary dysplasia
FETAL BREATHING MOVEMENTS The classic experiments by Desai and Wigglesworth6 have elegantly demonstrated the importance of fetal breathing movements for normal lung growth and development. Abolishing these movements by transecting the spinal cord at the level of the phrenic nerve, they were able to demonstrate decreased lung growth in newborn rabbits. If the transection was performed at the C1–C3 level, i.e. above the phrenic nerve, hypoplastic lungs with decreased lung weight and poorly expanded, thin-walled terminal sacs were seen. When transection took place below the phrenic nerve at the C5–C8 level, although some weight reduction was seen, the terminal sacs were very similar to control animals. Since no abnormalities were noted in any other organs, the abnormal lung development was attributed to absent breathing movements. Additional experiments on pregnant ewes by Kitterman’s group7 confirmed these findings by ablation of the phrenic nerve but also reported decreased airway fluid, lung weight and total lung DNA. Production of lung fluid was, however, not affected. Although these experiments strongly implicate fetal breathing to be important in normal lung development, abolishing diaphragmatic movement will also decrease intra-thoracic volume as organs in the abdomen encroach on the thoracic cavity.
310
Table 2 Factors that may affect fetal breathing movements. Increased breathing movement Hypercapnia Hyperglycaemia Acidosis Increased temperature Indomethacin Caffeine Theophyllines Decreased breathing movements Hypoxia Hypoglycaemia Prostaglandin E2 Maternal smoking Maternal alcohol Intra-uterine infection Diazepam Morphine
In humans, breathing movements are detected by 11 weeks’ gestation but by 30–40 weeks occur 30% of the time.8 They increase following a maternal meal, presumably due to increased blood glucose and there is a circadian rhythm with minimum movements between 7 pm and midnight and heightened movements between 4 and 7 am. During labour, breathing movements decrease from 25% at the onset to 8% during late labour and <1% during active labour.9 Ash et al. have reported fetal breathing activity increasing from 76% in early labour to 90% in advanced labour.10 Fetal breathing appears to be related to the behavioural state of the fetus.11 As the fetus approaches term, the incidence of these movements is considerably greater during active periods than during periods of quiet activity.12 Besides a circadian rhythm and a relationship to sleep, many other factors can influence breathing movements (Table 2). Fetal breathing movements increase after a maternal meal and after infusions of glucose. Increase in carbon dioxide increases fetal breathing movements in both animals and humans and the opposite is seen with hypocapnia.13 These observations suggest that the central chemoreceptors are active in fetal life. Similarly, hypoxia depresses fetal motor activity, including limb movements, random eye movements, swallowing and fetal breathing. Hyperoxia, in contrast, appears to have minimal effect on fetal breathing. Prostaglandin E2 increases during labour and has been shown to decrease fetal breathing. With induced labour decreased breathing movements have been noted, although in spontaneous labour Ash et al. have observed increased breathing movements.10 Maternal ingestion of alcohol or drugs including sedatives have all been shown to decrease breathing movements but drugs such as caffeine increase them. Maternal smoking also decreases fetal breathing movements by several
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mechanisms including decreased uterine blood flow and hypoxia. The importance of breathing movements lies in maintaining an adequate lung volume.14 During apnoeic phases the relatively high resistance of the upper airways prevents efflux of the lung fluid, thus maintaining a satisfactory pressure within the lungs. During fetal breathing the upper airways relax and the diaphragmatic contractions continue to maintain the lung expansion since ablation of the diaphragmatic activity by phrenic nerve ablation decreases the lung fluid volume.15 Lung expansion, together with rhythmic contraction of the diaphragm during fetal breathing, appear to be important contributors to lung growth, since mitogenic growth factors have been shown to be released during rhythmic stretch.16 Many groups have attempted to study breathing movements in the fetus approaching term to identify high-risk infants, especially the hypoxic fetus. Besinger et al. observed fetal breathing movements in 50 pregnancies between 26 and 34 weeks and found that if the movements were absent during a 20-minute observation period labour occurred in 16 out of 17 women.17 In 29 of the remaining 33 in whom fetal breathing was observed, labour did not occur for at least 48 hours after the observation. Fetal breathing movements have also been used to predict pulmonary hypoplasia in pregnant women with oligohydramnios. Blott et al. reported a lethal outcome in five of 20 pregnancies complicated by oligohydramnios when fetal breathing movements were absent.18 As breathing movements are episodic, such methodology to detect breathing movements is not accurate unless performed for prolonged periods and is thus not applied clinically.
FETAL LUNG FLUID Maintenance of fluid within the fetal lung is essential for normal lung growth and development.19 Fetal breathing movements, together with the resistance of the upper airway, appear to be responsible for maintaining the fluid within the fetal lung (see above). This has been elegantly demonstrated in a series of experiments by Harding’s group.20 When one lobe (in fetal lambs) is allowed to drain freely and the other ligated to permit increased fetal lung fluid, the drained lobe shows marked hypoplasia and the ligated lobe shows hyperplasia. Similarly, if the pressure within the fetal lung is allowed to decrease without loss of the total lung fluid, the lungs fail to develop adequately.21 The lung fluid is formed by the epithelial cells, especially of the distal airways and flows through to the upper airway where it is either swallowed or released into the amniotic space. The fluid is rich in chloride and low in bicarbonate and proteins. It is the balance between production and drainage of the fluid from the lung which appears to be important in normal lung development.22 The rate of fluid production increases in fetal lambs from approximately
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hypoplastic lungs. Abnormalities of the thoracic wall or diseases of the muscles may adversely affect lung growth and development. In the former, as in oligohydramnios there is restricted space for the lungs to grow and in the latter poor breathing movement results in poor lung development. Any conditions that affect intrathoracic lung space adversely affect lung development, one of the most important being congenital diaphragmatic herina. Here there is abnormal development of airway branching and of the alveoli, suggesting an early but continuing effect on lung growth (see article by Greenough in this issue). Figure 2 A model depicting the factors which may contribute to normal and abnormal lung growth. Please note the importance of both pre- and post-natal factors to lung growth.
5 ml/kg at mid-gestation to greater than 20 ml/kg near term with hourly rates increasing from 2 ml/kg/h to 5 ml/kg/h, respectively. Chloride is extruded into the luminal space via the apical surface in association with sodium which is reabsorbed in exchange for potassium. As the fetus approaches term, the rate and volume of fluid production decreases. It has been suggested that neonatal respiratory distress may not only be due to surfactant deficiency but also to inadequate fluid clearance from the lungs of susceptible infants.23 Beta-adrenergic agonists stimulate sodium uptake by the epithelial cells, with consequent reabsorption of water from the extracellular space, thereby decreasing the volume of fetal lung fluid.24 Vasopressin also decreases the production of fetal lung fluid. At birth, beta-adrenergic agonists and vasopressin may act synergistically to decrease lung fluid so that the newborn infant can adapt to the post-natal environment. Other factors, such as prostaglandin E2, aldosterone and atrial naturetic hormone, may all decrease fetal lung fluid in late gestation.25
IMPORTANCE OF FLUID BALANCE AND THORACIC WALL TO NORMAL LUNG GROWTH It is not surprising that any condition which affects the balance of formation and drainage of fetal lung fluid will adversely affect the development of the fetal lung. The production of the fluid, however, appears to be unaffected by fetal breathing movements since ablation of the phrenic nerves does not affect fluid production.7 In practice, it is the drainage of the fluid that tends to affect lung growth. Oligohydramnios occurs following spontaneous rupture of the membranes or in association with uterine infection. By failing to maintain adequate extrathoracic fluid volume, the lung development is impeded with resultant hypoplasia. Similarly, Potter’s syndrome with absent kidneys results in lack of amniotic fluid and
PRETERM DELIVERY Perhaps the most important factor that adversely affects lung growth is being born too early. Decreased and dysregulated alveolization has been observed in infants who develop chronic lung disease of prematurity26. Poor alveolization may simply reflect postnatal events, including mechanical ventilation 27, oxygen therapy, patent ductus arteriosus and infection or it may have antenatal origins (Fig. 2). Animal models have elegantly demonstrated the role of each of these risk factors in the development of lung injury and their subsequent effect on lung growth. Coalson in the baboon model has shown that hyperoxia and barotrauma contribute to lung injury with subsequent decrease in alveolization28. Similar results have been observed in a wide range of animal models exposed to both hyperoxia and mechanical ventilation. Despite newer technology to decrease the effects of these risk factors, chronic lung disease of prematurity remains a major cause of morbidity and mortality. Attention has therefore turned towards antenatal factors. Romero’s group has reported the association between proinflammatory cytokines in the uterus and the subsequent development of chronic lung disease of prematurity29. An important trigger is intra-uterine infection, including Ureaplasma urealyticum. There is some clinical evidence to suggest that chorioamnionitis may predispose the fetus to subsequent lung disease and disordered lung growth30. The cascade leading to decreased alveolization may consist of an insult such as an antenatal infection leading to an inflammatory response in the fetal lungs. Resolution of the insult involves growth factors which are also important normal lung growth. It is likely that overexpression of growth factors adversely affects lung growth otherwise progressing simultaneously.
SUMMARY Lung growth is highly dependent on developmental, genetic and environmental factors. Fetal breathing movements and the balance between the production and removal of the fetal lung fluid appear to be
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essential. In addition, an adequate extra-uterine fluid volume is also necessary for normal lung growth. Maternal and intra-uterine factors are important and may contribute directly or indirectly to growth and development of the fetal lung. These include maternal smoking and ingestion of alcohol or sedative drugs such as benzodiazepines. Maternal health and nutrition, and the intra-uterine environment, also contribute to fetal lung growth. The commonest cause of lung injury with subsequent reduced lung growth is preterm delivery, exposing the infant to noxious agents both ante- and post-natally.
PRACTICE POINTS Normal lung growth depends on a number of inter-related factors, including: • • • • • • • • •
Normal embryonic and fetal development Genetic constitution Maternal and fetal nutrition Endocrine factors Fetal breathing movements Normal fetal lung fluid production Adequate intra-thoracic space Adequate extra-throacic space Normal post-natal adaptation The above list is not exhaustive. Lung growth depends on many factors which may directly or indirectly affect lung growth.
RESEARCH ISSUES Very little information is available on lung growth in the human fetus and infant. There are many areas which need to be studied to better understand the mechanisms that lead to lung growth. The following are some of these: • A better understanding of the embryonic development • The contribution of genetics to normal lung development is poorly understood • Regulatory growth factors need to be more clearly defined • The role of the intra-uterine environment and normal fetal development needs to be understood more accurately • Better imaging systems are needed to assess lung growth and development
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