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Microbes & Immunity Understanding lung development, health, and diseases

Table 1. Summary of human lung development from the embryonic stage to adulthood
Stage Duration Characteristics
Embryonic 4 – 7 weeks of gestation Organogenesis begins with the formation of the lung anlage, main airways, and pleura.
Pseudoglandular 5 – 17 weeks of gestation Formation of large respiratory parenchyma, development of bronchial trees, formation of
early acinar structures.
Canalicular 16 – 26 weeks of gestation Airway branching is completed, surfactant production begins, and the initial appearance
of the air-blood barrier.
Saccular (terminal sac) 4 – 38 weeks of gestation Characterized by the expansion of future airspaces, followed by differentiation and
preparation for postnatal breathing.
Alveolarization (first phase) 36 weeks of gestation – 3 years Immature alveoli emerge, and the septa contain double-layered capillary networks.
Continued alveolarization 2 years–17 – 21 years Alveolar maturation and the formation of single-layered capillary networks in the
alveolar septa.
Microvascular maturation Term–3 – 21 years Septa remodeling: the capillary beds are transformed into single-layered structures.
Note: Adapted from Schittny 5

Table 2. Development stages and associated signaling
Development stage Key signal and factors References
Lung specification Nkx2.1 expression in the ventral foregut endoderm triggers this process. Wnt/β-catenin signaling 4,6
enhances Nkx2.1, but requires active BMP signaling.
Lung bud initiation Retinoic acid signaling is critical to lung budding. Deficiency of this leads to hypoplasia. 7,8
RAR-γ mutations affect alveolar development.
Airway branching Epithelial branching is important for airway branching, and it is induced by peripheral lung mesenchyme. 9
Branching morphogenesis FGF signaling (FGF10, FGFR2b) regulates branching morphogenesis; FGF10 mutations or FGFR2b 10-12
inactivation prevents branching completely.
FGF10 deficiency or increased Sprouty 2 expression causes tiny, poorly branching lungs.
Histone modifications The balance between HAT and HDAC is essential for proximal cell growth and branching. 13
Vascular development VEGF signaling supports endothelial survival and capillary formation, critical for alveolar development. 11,14,15
Inhibiting VEGF signaling impairs pulmonary endothelial survival and inhibits postnatal alveolarization.
Abbreviations: BMP: Bone morphogenetic protein; FGF: Fibroblast growth factor; HAT: Histone acetyltransferases; HDAC: Histone deacetylase;
SOX2: SRY-box transcription factor 2; RAR: Retinoic acid receptor; VEGF; Vascular endothelial growth factor.
alveolar cells, also referred to as type II pneumocytes, play Also, the clearance of fetal lung fluid commences
an essential role in maintaining lung function. They are before birth and is accelerated by labor, typically
responsible for producing and releasing surfactant to lower completed within 2 h following delivery. Following birth,
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surface tension within the alveoli, thereby preventing newborns establish respiratory patterns that are more
collapse. Moreover, these cells also act as progenitors for regular than in utero. Both term and preterm babies will
alveolar epithelial regeneration following injury. As adult initiate spontaneous breathing unless affected by severe
3
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tissue stem cells, type II alveolar cells also contribute to hypoxemia, which suppresses breathing. Gas exchange
the maintenance, repair, and regeneration of lung tissue to stabilizes in most babies within 2 min after vaginal delivery,
support pulmonary homeostasis. 22 with an improved heart rate serving as the strongest clinical
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indicator of effective breathing. However, preterm babies
Alveolar type II cells play a crucial role in maintaining may experience delays and often require assistance through
the unique microenvironment of the alveoli. They secrete mechanical ventilation.
pulmonary surfactants and collections such as surfactant
protein A and surfactant protein D, along with a range 2.3. Epigenetic regulation of lung development
of substances that possess anti-inflammatory and anti- from early lung development to advanced age
microbial properties, including lysozyme, β-defensin 2, Epigenetic mechanisms such as DNA methylation,
secretory leukocyte proteinase inhibitor, and lipocalin 2. histone modifications, and non-coding RNA activity
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These polar molecules help reduce alveolar surface tension, regulate extracellular processes that are essential for
thereby lowering pressure within the lungs and promoting lung development and remodeling. These processes are
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gas exchange. important in chronic remodeling disorders, including

Volume 2 Issue 3 (2025) 49 doi: 10.36922/mi.7719