Fetal Lung Development: Overview and Practice Questions

Fetal lung development is a vital process that sets the foundation for a newborn’s ability to breathe independently upon entering the world. The journey from a simple bud in the early weeks of gestation to fully developed, functional lungs involves an intricate sequence of stages, each contributing to the formation of airways, alveoli, and essential support structures.

Understanding these phases provides insight into how the lungs prepare for the transition from a fluid-filled environment in the womb to air breathing after birth.

This article explores the key stages of fetal lung development and their significance in ensuring healthy respiratory function.

What is Fetal Lung Development?

Fetal lung development is the complex process through which a fetus’s lungs grow and mature, preparing them for life outside the womb. This process occurs in five distinct stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar.

Each stage is essential for forming the airways, blood vessels, and the tiny air sacs (alveoli) needed for effective gas exchange after birth. During the embryonic and pseudoglandular stages, the basic lung structure forms, followed by more complex tissue differentiation and development of the bronchi and bronchioles.

By the saccular and alveolar stages, surfactant production begins, helping reduce surface tension and preventing lung collapse. Proper lung development is crucial for newborns to take their first breaths and sustain independent breathing.

Phases of Lung Development

The development of the human lung is a complex, multi-stage process that occurs throughout gestation and continues after birth. This process ensures the formation of a fully functional respiratory system capable of gas exchange.

Lung development is traditionally divided into five distinct phases:

1. Embryonic Phase (Weeks 3-7)

During this initial phase, the lung begins as a simple bud that forms from the foregut endoderm. This bud elongates and branches into two primary bronchial tubes, which will eventually become the left and right main bronchi.

The surrounding mesoderm contributes to the formation of the supportive tissue and vasculature.

2. Pseudoglandular Phase (Weeks 7-17)

In this phase, the branching of the bronchial tree continues as the airways become more defined. The lung resembles a gland-like structure, hence the name.

The conducting airways are developed, but gas exchange structures are not yet formed. This phase marks the differentiation of various cell types that will later be part of the respiratory system.

3. Canalicular Phase (Weeks 17-26)

This critical phase involves significant vascular development and the formation of the respiratory bronchioles. The airways become larger, and the epithelial cells begin to thin, which is essential for gas exchange.

Differentiation into type I and type II pneumocytes also occurs during this phase, with type II cells starting to produce surfactant—an essential substance that reduces surface tension in the alveoli.

4. Saccular Phase (Weeks 26-36)

During this period, the terminal sacs (primitive alveoli) develop. These sacs are lined with type I and type II pneumocytes, and the production of surfactant increases significantly.

This phase prepares the lungs for the transition from a fluid-filled environment to air breathing. The capillaries move closer to the epithelial lining, facilitating the initial capability for gas exchange.

5. Alveolar Phase (Week 36 to 8 Years Post-Birth)

This phase begins before birth and extends into early childhood. The alveoli continue to mature and multiply, increasing the surface area available for gas exchange.

The lung tissue undergoes further thinning, and alveolar septation results in the formation of new alveolar structures. By the end of this phase, the lungs have the structural capability to perform efficient gas exchange.

Note: Each phase of lung development plays an essential role in forming the intricate architecture and functionality of the respiratory system. The proper progression through these stages ensures that the newborn is equipped for the demands of independent breathing at birth and that lung growth continues into early childhood to accommodate growth and increased metabolic needs.

Fetal Lung Development Practice Questions

1. When does the pseudoglandular period occur?
It takes place from the 5th to the 16th week of gestation. Goblet cells appear in the trachea and bronchi, and mucous glands develop. By the 16th week, approximately 20 generations of airways are present.

2. What are the periods of fetal lung development?
The periods are Embryonic, Pseudoglandular, Canalicular, and Terminal Sac.

3. When does the first lung bud develop?
The first lung bud develops by the 24th day during the embryonic stage as small buds branching from the esophagus.

4. When does the terminal sac period begin?
It begins at 24 weeks and continues until term.

5. What time frame is considered the postnatal alveolar period?
From birth to approximately 12 years of age, when alveoli increase to around 200 million.

6. What develops or continues to develop during the postnatal alveolar period?
Alveoli continue to develop and mature.

7. How many alveoli does a baby have at birth?
Approximately 24 million alveoli.

8. In what three ways is fluid eliminated from a neonate’s lungs during childbirth?
One-third is squeezed out through the birth canal, one-third is removed by lymphatic drainage, and one-third is absorbed by the pulmonary capillaries.

9. What is surface tension?
It is the force present on the surface of a liquid that causes the surface area to become as small as possible.

10. What is surfactant?
A mixture of phospholipids and proteins that lines the alveolar walls. It consists of two main phospholipids: sphingomyelin and lecithin.

11. What is the purpose of surfactant?
It reduces surface tension within the alveoli.

12. What type of cells produce surfactant?
Surfactant is produced by alveolar type II cells.

13. What happens in the placenta?
The exchange of gases, nutrients, and waste products occurs in the placenta.

14. How many arteries and veins are present in the umbilical cord?
There are two arteries and one vein.

15. What is the purpose of the umbilical arteries?
They carry deoxygenated blood from the fetus to the placenta.

16. What is the purpose of the umbilical vein?
It carries oxygenated blood and nutrients from the placenta to the fetus.

17. What is the partial pressure of oxygen (PaO2) in the placenta?
Approximately 20 mmHg.

18. What is the partial pressure of carbon dioxide (PaCO2) in the placenta?
Approximately 55 mmHg.

19. What is the partial pressure of oxygen (PaO2) in the fetus?
Approximately 30 mmHg.

20. What is the partial pressure of carbon dioxide (PaCO2) in the fetus?
Approximately 40 mmHg.

21. Why is there a difference between maternal and fetal oxygen levels?
The differences are due to shunting in the placenta, oxygen metabolism in the placenta, and the permeability of the gas exchange membrane in the placenta.

22. What is compliance?
It refers to the ability of the alveoli in the lungs to expand and accept volume for gas exchange.

23. How long and thick is the placenta?
The placenta is approximately 20 cm long and 2.5 cm (1 inch) thick.

24. How many segments are in the placenta?
There are 15-20 segments, known as cotyledons.

25. How is fetal waste and oxygen transferred between the fetus and placenta?
Through diffusion.

26. What is the maternal PaO2?
It ranges between 80-100 mmHg.

27. What is the maternal PaCO2?
Approximately 33 mmHg.

28. How does oxygen transfer from maternal to fetal blood?
Through the maternal-fetal PO2 gradient, where oxygen moves from an area of higher pressure to lower pressure. This process is supported by higher fetal hemoglobin levels and greater oxygen affinity.

29. What is Functional Residual Capacity (FRC)?
The volume of air remaining in a newborn’s lungs after a normal exhalation. The lungs are partially inflated at birth, with fluid originating from alveolar cells during fetal development. This fluid is cleared during the first 24 hours by three mechanisms: expulsion during birth, absorption by pulmonary capillaries, and drainage via the lymphatic system.

30. What is the compliance of a newborn’s lungs?
Approximately 0.0005 L/cm H2O.

31. What is the airway resistance in a newborn?
Approximately 30 cm H2O/L/sec.

32. What percentage of babies born between 26-28 weeks develop Respiratory Distress Syndrome (RDS)?
Around 50%.

33. What percentage of babies born between 30-31 weeks develop RDS?
Approximately 25%.

34. What is the procedure used to diagnose fetal abnormalities?
Amniocentesis.

35. What can amniocentesis reveal?
It can indicate lung maturity, bilirubin levels, creatinine levels (for kidney function), genetic disorders, and the presence of meconium.

36. Why is there a higher occurrence of deaths in premature infants, with a decrease in mortality rates closer to term?
The respiratory system matures slowly, so infants born closer to term have more developed lungs, leading to a higher chance of survival.

37. What is the path of air during breathing?
Air travels from the nose/mouth to the pharynx, then to the larynx and trachea, followed by the primary bronchi, secondary bronchi, bronchioles, ducts, and finally to the alveolar sacs and alveoli where gas exchange occurs.

38. What are the two types of cells in the alveoli?
Type I and Type II cells.

39. What are Type I alveolar cells?
These cells form the structure of the alveolar wall and are responsible for gas exchange.

40. What are Type II alveolar cells?
These cells produce lamellar bodies that create surfactant, which lines the alveoli to reduce surface tension.

41. What are the three zones of the lung?
Conducting, respiratory, and transitional zones.

42. What is the conducting zone?
This zone includes the pharynx, larynx, and trachea, and is responsible for conducting air to and from the lungs.

43. What is the respiratory zone?
This zone consists of the alveoli, where gas exchange occurs.

44. What is the transitional zone?
It is the area between the conducting and respiratory zones.

45. When is surfactant initially secreted?
At around 25 weeks of gestation, with an increasing amount produced as the fetus nears term.

46. What are the five stages of lung development?
Embryonic, pseudoglandular, canalicular, saccular, and alveolar/alveologenesis stages.

47. What occurs at 37-38 weeks of gestation?
The interstitial layer of the lung becomes thinner.

48. How would you describe immature lungs?
They have a smaller alveolar surface area, reducing the capacity for efficient gas exchange.

49. What can be adjusted to support premature infants’ respiration?
The concentration of oxygen in the alveoli, which is why preemies with underdeveloped lungs are often given high concentrations of oxygen to enhance diffusion.

50. How is surfactant production in premature infants?
It is insufficient or poor, contributing to respiratory complications.

51. Why is poor surfactant production a problem?
Poor surfactant production leads to high surface tension within the alveoli due to the water content in mucus. This causes the alveoli to pull inward and collapse. Surfactant reduces surface tension by breaking polar bonds, allowing the alveoli to remain open and maintain their shape, facilitating proper lung function.

52. What are some treatments for immature infants with respiratory issues?
Treatments include supplemental oxygen to promote diffusion for respiration, administration of synthetic surfactant derived from animal sources like calf lungs to help alveoli maintain their shape and prevent collapse, and mechanical ventilation, which, although effective, can be taxing on the lungs and potentially lead to long-term complications.

53. What are the consequences of bronchopulmonary dysplasia (BPD)?
BPD results in interrupted alveolar growth, abnormal lung development, inflammation, scarring in the lung tissues, and chronic hypoxia.

54. What is the treatment for bronchopulmonary dysplasia?
Treatment options include the use of low-pressure ventilation systems, bronchodilators, and corticosteroids to reduce inflammation and support lung function.

55. What are the stages of fetal lung development?
The stages are embryonal, canalicular, and saccular.

56. From where does the initial lung bud emerge?
The initial lung bud emerges from the pharynx.

57. At which stage of lung development is the bronchial tree formed?
The bronchial tree is formed during the pseudoglandular stage.

58. What are the minimal developmental features required for an immature fetus to survive outside the uterus?
Sufficient alveolar and vascular surface area for gas exchange, gestational age of 22 to 24 weeks, and nearly complete progression through the canalicular stage of lung development.

59. Why do investigators’ estimates of the number of alveoli at birth vary widely?
The gas exchange surface area increases proportionally with oxygen consumption and body surface area, leading to differing estimates of the exact number of alveoli at birth.

60. Which stage of lung development was previously believed to be the final stage before birth, characterized by cylindrical structures subdivided by secondary crests?
The alveolar stage.

61. What are the clinical associations related to pulmonary hypoplasia, a common lung development abnormality?
Associations include lung tissue compression, oligohydramnios (low amniotic fluid), and maternal diabetes.

62. What are Reid’s laws of human lung development?
Reid’s laws state that the bronchial tree is developed by the 16th week of intrauterine life, pre-acinar vasculature forms after airway development, and intra-acinar vasculature develops after alveoli generation. The esophageal lung bud also arises from the embryonic mesoderm to form the tracheobronchial tree.

63. How are lung and kidney development similar?
Both develop through a process known as branching morphogenesis.

64. From which embryonic layer do the lungs arise?
The lungs develop from the endoderm.

65. Does lung development stop at birth?
No, lung development continues postnatally.

66. What is the first phase of lung development?
The embryonic phase.

67. How do the lungs develop during the embryonic phase?
The lungs begin as an outgrowth of the foregut, with simple epithelial tubes branching into the mesenchyme (connective tissue).

68. What occurs during the embryonic phase?
The laryngotracheal tube forms and develops into buds that give rise to the primary bronchi, which divide unevenly into three lobes on the right and two lobes on the left, eventually forming bronchi and bronchioles.

69. What are lobar bronchi?
Lobar bronchi are the secondary branches formed from the budding of the bronchioles.

70. Where does most division of lung structures occur?
Most of the division takes place during fetal development, but further secondary septation can continue into adulthood.

71. What influences the differentiation of the developing respiratory tube?
The regional specificity of the surrounding mesenchyme determines the differentiation of the respiratory tube.

72. How does the respiratory epithelium develop?
The neck elongates to form the trachea, which branches as it enters the thoracic cavity to create the bronchi and lungs.

73. What is the second stage of lung development?
The pseudoglandular stage.

74. What occurs during the pseudoglandular stage?
Epithelial cells further invade the mesenchyme, and signals from the mesenchyme stimulate the formation of new buds and outgrowths.

75. What is present within the mesenchyme during the pseudoglandular stage?
A loose network of capillaries.

76. What coincides with the development of pulmonary vasculature in the second stage?
The rapid growth and proliferation of primitive airways.

77. What type of epithelium is present during stage 2?
Undifferentiated cuboidal or columnar epithelium.

78. When do initial respiratory ducts form?
During the pseudoglandular stage.

79. What is the 3rd stage of lung development?
The canalicular stage.

80. What do canaliculi branch out from?
Terminal bronchioles.

81. What are the canaliculi?
The early respiratory parts of the lungs.

82. Where do air spaces derive from, and what do they form?
They derive from terminal bronchioles and form an acinus.

83. What is a key aspect of the canalicular phase?
The alteration of epithelium and the invasion of capillaries into the mesenchyme.

84. What happens to the tubule lumens during stage 3?
They widen.

85. How do epithelial cells change in stage 3?
They become flatter.

86. When do respiratory bronchioles form?
During stage 3, the canalicular stage.

87. What happens to lung volume during stage 3?
It increases, along with the expansion of air spaces.

88. Is there any differentiation of cells between stage 3 and stage 4?
Yes, cells differentiate into type I and type II pneumocytes (alveolar cells).

89. What is the difference between type I and type II pneumocytes?
Type I pneumocytes are flat and make up the gas diffusion surface, while type II pneumocytes are round and produce surfactant.

90. When does the airway epithelium start secreting lung fluid?
When type II cells begin producing surfactant.

91. When do capillaries start organizing into a double-layered network around epithelial tubes?
Between stage 3 and stage 4.

92. What is the 4th stage of lung development?
The saccular stage.

93. Where do sacs or saccules form?
At the terminal bronchioles.

94. What do sacs or saccules develop into?
Alveolar ducts and sacs coated with type I and type II pneumocytes.

95. What type of tissue starts to appear in the sacs during the saccular stage?
Elastic tissue.

96. What promotes the final stage of differentiation?
The extracellular matrix (ECM).

97. When does the saccular stage end?
At birth.

98. When do sacculi start developing into alveoli?
Around the end of pregnancy or shortly after birth.

99. What is the last stage of lung development called?
The alveolar stage.

100. How many alveoli are fully developed but immature at birth?
Approximately 20-30%.

101. What happens to the lungs in the alveolar stage?
There is an increase in surface area (SA) and vascular maturation.

102. When does the double capillary network in the alveolar wall remodel into a single layer?
During the alveolar stage.

103. What does the ECM influence during the alveolar stage?
The outgrowth of the secondary septa.

104. What is the ECM composed of?
Collagen, elastin, and proteoglycans.

105. What is the function of the ECM?
It provides structural support and influences cell division, differentiation, and migration.

106. What does the development of the secondary septa accomplish?
It thins the interstitial tissue layer and decreases the diffusion distance for gas exchange.

107. What happens in the last stage after birth?
Alveoli grow and subdivide the sacculi into smaller subunits (alveoli).

108. What do surrounding elastic fibers form?
The interstitial septa between two capillary networks.

109. When does the number of alveoli increase rapidly, and what is this process called? Also, how long does it continue?
Rapid alveolar increase occurs during the first 6 months and is called alveolarization. It continues for about 18 months.

110. What limits alveolar growth?
The formation of secondary septa.

111. What are the main factors influencing lung development?
Intra-thoracic space, intra-uterine space, fetal breathing movements, lung liquid production, and conditions such as oligohydramnios and lack of amniotic fluid that can impair intra-uterine space due to compression.

112. What occurs during ‘practice’ breathing?
Before birth, the fetus activates the respiratory muscles regularly, resulting in little change in lung volume.

113. When is lung liquid produced?
Mid-gestation.

114. What is lung liquid?
A secretory product of the pulmonary epithelium.

115. What can decrease intra-thoracic space?
A congenital diaphragmatic hernia.

116. What is a common cause of pulmonary hypoplasia?
Oligohydramnios.

117. Is lung liquid secretion active or passive?
Active.

118. What is needed for lung liquid secretion?
Chloride ions (Cl-).

119. When Cl- ions move across the epithelium into the lumen, what do they draw from the interstitial fluid (ISF)?
Sodium ions (Na+), creating an osmotic gradient that causes water to follow via the paracellular route.

120. How is Cl- taken up on the basolateral membrane?
Through the Na/K/2Cl cotransporter, a form of secondary active transport.

121. Is the movement of Cl- across the apical membrane into the lumen active or passive?
Passive.

122. Why does lung volume increase with gestational age?
Because secretion increases with the pulmonary surface area.

123. Why is fluid secretion into the lungs essential?
It promotes lung growth, keeps the lungs free of debris, and supports amniotic fluid volume.

124. What is the most important function of lung liquid?
To keep the lungs expanded.

125. Are changes in lung volume induced locally or generally?
Locally.

126. What stimulates the cAMP second messenger system to increase the expression of Na+ channels on the apical surface of the epithelium?
High levels of epinephrine and vasopressin.

127. What does the pulmonary epithelium switch to after cAMP induction?
From a Cl- secreting membrane to a Na+ absorbing membrane.

128. What are the functions of surfactant?
It decreases surface tension, increases lung compliance, decreases the work of breathing, and stabilizes the lungs.

129. What is the composition of surfactant?
Surfactant is composed of 90% lipids (primarily dipalmitoyl phosphatidylcholine) and 10% proteins.

130. What controls surfactant production?
Glucocorticoids, catecholamines (epinephrine), thyroid hormones, and mechanical stretch.

Final Thoughts

Fetal lung development is a complex, multi-phase process that is crucial for survival outside the womb. From the embryonic phase to the alveolar phase, each stage plays a unique role in shaping the lungs into organs capable of effective gas exchange.

By the time a baby is born, their lungs are typically prepared to support independent breathing thanks to the coordinated growth and maturation that occurs throughout gestation.

Understanding these developmental stages can shed light on potential complications and inform better medical care to ensure healthy respiratory outcomes in newborns.