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Genetic disorders of alveolar formation and homeostasis
Key points
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Lung morphogenesis begins with the formation of the tracheal and bronchial buds. Subsequent branching morphogenesis forms the respiratory tubules, the acini, and the alveolar regions of the lung required for gas exchange after birth.
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Lung morphogenesis is dependent upon precise paracrine signaling among pulmonary progenitor cells controlling gene transcription, which determines the precise numbers, positions, and functions of pulmonary cells.
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Interactions between the mesenchymal and endodermally derived pulmonary cells direct branching morphogenesis, sacculation, and alveolarization before birth.
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Mutations in genes expressed in pulmonary mesenchymal progenitors, including FOXF1 and TBX4 , disrupt lung morphogenesis and the formation and function of the pulmonary circulation.
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Mutations in genes expressed in endodermally derived cells, including NKX2-1 , ABCA3 , SFTPB , and SFTPC , cause respiratory failure after birth and childhood interstitial lung disorder in infancy.
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Lack of differentiation of the alveolar epithelium in preterm infants is associated with decreased production of surfactant lipids and proteins, resulting in respiratory distress after birth.
Genetic disorders of lung formation
The human lung is comprised of more than 50 distinct cell types that differentiate from subsets of endodermal and mesodermally derived progenitors during embryogenesis. Precisely orchestrated signaling pathways and transcriptional programs regulate cell proliferation, migration, and differentiation during morphogenesis of the lung. Epithelial cells from the foregut endoderm invade the splanchnic mesenchyme and are first distinguished from other foregut derivatives by the expression of NKX2-1 or thyroid transcription factor 1 (TTF-1), a nuclear transcription factor expressed in the earliest lung progenitors ( Fig. 19.1 A). Epithelial cells lining conducting (airway) regions of the lung express SOX2, distinguishing them from the peripheral epithelial cells lining the acinar buds which express SOX9 and high levels of NKX2-1; the latter progenitors form the alveolar regions of the lung later in development. Paracrine signaling among epithelial cells lining the lung tubules and mesodermally derived cells of the splanchnic mesenchyme control the growth of differentiation of the embryonic lung during formation of the tracheal, bronchial, and pulmonary lung buds. The pulmonary vasculature and stromal cells including pericytes, fibroblasts, endothelial, mesothelial, and smooth muscle cells are derived from the splanchnic mesenchyme. Paracrine and juxtacrine interactions among the cells direct branching morphogenesis, sacculation, and alveolarization required for the formation and function of the lung at birth. Identification of several genes critical for lung formation enables genetic diagnosis of respiratory disorders causing respiratory failure in newborn infants. Since lung organogenesis depends on precise cell–cell interactions, mutations in genes regulating critical processes in both epithelial and mesenchymal compartments of the lung cause severe lung dysfunction after birth.
Mutations in genes in pulmonary mesenchyme
Epithelial cells of the lung tubules express and secrete sonic hedgehog (SHH), a signaling molecule which binds to smoothened (SMO) in subsets of pulmonary mesenchymal cells. This activates Gli2/3, which is required for the expression of TBX4 and FOXF-1, which in turn mediate the expression of FGF-10 and FGF-9. These FGFs activate their cognate receptor FGFR2 in epithelial cells in the acinar bud to control cell proliferation and migration during branching morphogenesis ( Fig. 19.1 B). Expression of SOX2 in conducting airways and SOX9 in the peripheral acinar buds controls regiospecific proliferation and differentiation along the cephalocaudal axis of the lung. Mutations in the SHH, FOXF1, and TBX-FGF signaling networks cause acinar/alveolar hypoplasia resulting in a respiratory failure at birth ( Fig. 19.2 ). Loss of SHH signaling, either caused by defects in the cholesterol esterification of SHH (Smith-Lemli-Opitz syndrome) or mutations in Gli3 (Pallister Hall syndrome), causes pulmonary malformations in humans. Likewise, mutations disrupting normal FOXF-1 expression in the splanchnic mesenchyme cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Newborn infants with ACDMVP develop respiratory failure and cyanosis after birth as a result of lung hypoplasia and severe defects in pulmonary vasculogenesis. A majority of ACDMPV patients have point mutations or deletions (typically de novo) in the FOXF-1 gene or in noncoding regions of the genome that impair expression of FOXF-1. The diagnosis of ACDMPV is made by gene sequencing or copy number analysis or by histopathological analysis of lung tissue. FOXF1 regulates TBX transcription factors expression in the splanchnic mesenchyme during lung formation. Mutations in the TBX4 gene (MIM# 601719) cause acinar dysplasia/hypoplasia. Less deleterious mutations in TBX4 cause the “small patellar syndrome” associated with pulmonary hypertension presenting in childhood. Together TBX4 and FOXF1 regulate the expression of FGF-10 in lung mesenchyme, activating FGFR-2 in epithelial cells of the acinar buds required for branching of the lung tubules. Disruption of FGF-10 signaling caused by mutations in FGFR-2 is a rare cause of pulmonary hypoplasia and is associated with other organ malformations. ,
Mutations in genes expressed in the embryonic epithelium (NKX2-1/TTF-1)
Mutations in genes critical for growth and differentiation of the embryonic respiratory epithelium cause respiratory disorders presenting in the newborn period. NKX2-1 is a master transcription factor critical for growth and differentiation of the lung and is expressed in epithelial cells of the primordial lung buds as they invaginate into the splanchnic mesenchyme. Later in lung development, NKX2-1 controls lung maturation and surfactant protein and lipids synthesis. NKX2-1 is also expressed in the central nervous system and thyroid epithelium, thus mutations in the NKX2-1 may influence both CNS and thyroid function. While there is variability affecting each organ, most patients with heterozygous mutations in NKX2-1 have clinical findings in the brain, thyroid, and lung. Diffuse lung disease, associated with primary hypothyroidism in newborn infants, supports the diagnosis of brain-thyroid-lung syndrome. Approximately 60% of infants with TTF-1 mutations have alterations in lung function, often accompanied by altered expression of genes regulating surfactant homeostasis. Severely affected infants may present with respiratory failure caused by surfactant deficiency at birth. Hypothyroidism, ectopic or absent thyroid tissue, in concert with diffuse lung disease supports the diagnosis in newborn infants. The definitive diagnosis of brain-thyroid-lung syndrome is made by genetic analysis of the NKX2-1 gene.
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