Alveolar development and disease - PubMed (original) (raw)

Review

Alveolar development and disease

Jeffrey A Whitsett et al. Am J Respir Cell Mol Biol. 2015 Jul.

Abstract

Gas exchange after birth is entirely dependent on the remarkable architecture of the alveolus, its formation and function being mediated by the interactions of numerous cell types whose precise positions and activities are controlled by a diversity of signaling and transcriptional networks. In the later stages of gestation, alveolar epithelial cells lining the peripheral lung saccules produce increasing amounts of surfactant lipids and proteins that are secreted into the airspaces at birth. The lack of lung maturation and the associated lack of pulmonary surfactant in preterm infants causes respiratory distress syndrome, a common cause of morbidity and mortality associated with premature birth. At the time of birth, surfactant homeostasis begins to be established by balanced processes involved in surfactant production, storage, secretion, recycling, and catabolism. Insights from physiology and engineering made in the 20th century enabled survival of newborn infants requiring mechanical ventilation for the first time. Thereafter, advances in biochemistry, biophysics, and molecular biology led to an understanding of the pulmonary surfactant system that made possible exogenous surfactant replacement for the treatment of preterm infants. Identification of surfactant proteins, cloning of the genes encoding them, and elucidation of their roles in the regulation of surfactant synthesis, structure, and function have provided increasing understanding of alveolar homeostasis in health and disease. This Perspective seeks to consider developmental aspects of the pulmonary surfactant system and its importance in the pathogenesis of acute and chronic lung diseases related to alveolar homeostasis.

Keywords: lung development; maturation; pulmonary; surfactant.

PubMed Disclaimer

Figures

Figure 1.

Maturation of the alveolar epithelium. Subsets of cells from the anterior foregut endoderm expressing NKX2–1 (TTF-1) (green) form tubules that evaginate into the splanchnic mesenchyme to begin the process of branching morphogenesis (shown at embryonic day [E]10–E12). Sacculation and alveolarization create the alveolar structures seen at Postnatal Day (PND) 7. SOX2 and SOX9 are transcription factors defining the conducting versus peripheral progenitor cells of the respiratory epithelium, respectively. During mouse and human lung development, alveolarization, mediated by the process of septation, begins near the time of birth and continues during the postnatal period. Maturation of the peripheral respiratory epithelium is associated with differentiation of the airway epithelial cells (alveolar type II cells) and increased expression of genes associated with surfactant synthesis and homeostasis (e.g., Abca3, Sftpa, Sftpb, Sftpc, Sftpd, Napsa, and Gpr116). Continued septation subdivides the peripheral saccules into alveolar sacs that are highly vascularized (shown at PND7). Septa (PND7) are stained with homeodomain-only protein (HOPX) (green, alveolar type I), endomucin (red, endothelium), and α-smooth muscle actin (α-SMA; white, myofibroblasts). Lamellar bodies are secreted into the airways, unraveling to form tubular myelin as shown by electron microscopy (bottom right panel). Images provided by John Shannon, Susan Wert, and Joseph Kitzmiller.

Figure 2.

Immunofluorescence staining of HOPX (red; A and B), surfactant protein C (SFTPC) (green; A and B), smooth muscle action (ACTA2) (white; A_–_D), endomucin (EMCN) (red; C and D), and CSPG4 (green; C and D). CSPG4 is a pericyte marker. Lung images from E16.5 (A and C) and Postnatal Day 7 (B and D) mice are shown. Dramatic changes in peripheral lung architecture occur in the perinatal period.

Figure 3.

Immunofluorescence staining of HOPX (green, alveolar type I cell), endomucin (red, endothelium), and α-SMA (white, myofibroblasts) is shown in alveolar septa from Postnatal Day 7 mouse lung. Note the double capillary network and α-SMA staining at the septal tip.

Figure 4.

Surfactant metabolism. NKX2–1 (TTF-1) is a transcription factor critical for differentiation of type II epithelial cells and regulation of expression of Abca3, Slc34a2 (a phosphate transporter), and the surfactant proteins. Newly translated surfactant proteins (SPs) (proSP-B and proSP-C) and lamellar body proteins (ABCA3) traffic from the endoplasmic reticulum (ER) to the Golgi and subsequently to the multivesicular body (MVB); in contrast, SP-A and SP-D are constitutively secreted by the type II epithelial cells (dotted green arrows). Fusion of the MVB with the lamellar body (LB) is accompanied by proteolytic processing of SP-B and SP-C proproteins to their mature peptides. Newly synthesized surfactant phospholipids (DPPC, PG) are likely transported directly from the ER to the LB by lipid transfer proteins. The contents of the LB are secreted into the alveolar space, where they interact with SP-A to form tubular myelin and, ultimately, a phospholipid-rich film (surfactant) at the air–liquid interface. Cyclical expansion and compression of the bioactive film result in incorporation (green arrow) and loss (red arrows) of lipids/proteins from the multilayered surface film. Alveolar surfactant lipids and proteins are cleared through a granulocyte/macrophage colony-stimulating factor–dependent pathway that regulates alveolar macrophage differentiation and function. Surfactant remnants are also taken up by the type II epithelial cell and recycled to the LB via the MVB for resecretion, and a portion is degraded in lysosomes. SP-D plays an important role in regulating alveolar surfactant pool size, likely by enhancing its reuptake by type II epithelial cells; Gpr116 also regulates alveolar surfactant pool size by an unknown mechanism. The MVB integrates surfactant synthesis, secretion, recycling, and degradation pathways in the type II cell. Green arrows indicate biosynthetic pathways; red arrows indicate degradation and recycling pathways. Dotted arrows represent trafficking routes of proteins and lipids.

Figure 5.

Interstitial lung disorders caused by mutations in genes regulating surfactant homeostasis. Histology (hematoxylin and eosin) of lung tissue from patients with genetic disorders of the surfactant system. Neonatal lung tissue from patients with (A) SFTPB, (B) SFTPC, (C) ABCA3, (D) CSF2RA, and (E and F) NKX2–1 gene mutations. Scale bars: 200 μm. Reprinted by permission from Ref. .

References

1. Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child. 1959;97:517–523. - PubMed
1. Rawlins EL, Perl AK. The a“MAZE”ing world of lung-specific transgenic mice. Am J Respir Cell Mol Biol. 2012;46:269–282. - PMC - PubMed
1. Perl AK, Wert SE, Nagy A, Lobe CG, Whitsett JA. Early restriction of peripheral and proximal cell lineages during formation of the lung. Proc Natl Acad Sci USA. 2002;99:10482–10487. - PMC - PubMed
1. Kimura S, Hara Y, Pineau T, Fernandez-Salguero P, Fox CH, Ward JM, Gonzalez FJ. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev. 1996;10:60–69. - PubMed
1. Lazzaro D, Price M, de Felice M, Di Lauro R. The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development. 1991;113:1093–1104. - PubMed

Alveolar development and disease - PubMed (original) (raw)