Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease

Abstract

The alveolar region of the lung creates an extensive epithelial surface that mediates the transfer of oxygen and carbon dioxide required for respiration after birth. Maintenance of pulmonary function depends on the function of type II epithelial cells that synthesize and secrete pulmonary surfactant lipids and proteins, reducing the collapsing forces created at the air-liquid interface in the alveoli. Genetic and acquired disorders associated with the surfactant system cause both acute and chronic lung disease. Mutations in the ABCA3, SFTPA, SFTPB, SFTPC, SCL34A2, and TERT genes disrupt type II cell function and/or surfactant homeostasis, causing neonatal respiratory failure and chronic interstitial lung disease. Defects in GM-CSF receptor function disrupt surfactant clearance, causing pulmonary alveolar proteinosis. Abnormalities in the surfactant system and disruption of type II cell homeostasis underlie the pathogenesis of pulmonary disorders previously considered idiopathic, providing the basis for improved diagnosis and therapies of these rare lung diseases.

Figure 1

Surfactant metabolism. The contents of the lamellar body, including surfactant proteins and lipids, are secreted into the alveoli, where they form a phospholipid-rich film that is essential for preventing alveolar collapse. Approximately half of the alveolar surfactant pool is cleared through a GM-CSF-dependent alveolar macrophage pathway. Most of the remaining surfactant is taken up by the type II epithelial cell and recycled to the lamellar body, via the multivesicular body/late endosome (MVB/LE), for resecretion, while a portion is degraded in lysosomes. Biosynthesis of surfactant proteins and lipids is integrated with the recycling/degradation pathways to maintain intracellular and alveolar surfactant pool size. Mutations resulting in decreased GM-CSF (granulocyte macrophage colony-stimulating factor) signaling lead to increased alveolar surfactant pool size. Mutations in genes encoding SP-B and ABCA3 lead to altered lamellar body structure and loss of surfactant function. Mutations in genes encoding SP-C and possibly SP-A lead to misfolded protein that is degraded by the proteasome; failure to clear misfolded protein causes cytotoxicity and, ultimately, interstitial lung disease (ILD). Mutations in the gene encoding telomerase are also associated with cell death and ILD. Mutations in the gene SCL34A2 disrupt phosphate transport and are associated with formation of microliths in the alveolar airspaces. Biosynthetic pathways are shown in blue and catabolic pathways are colored red; the width of the arrow indicates the relative contribution of each pathway to metabolism.

Figure 2

Histopathology and ultrastructural features of genetic disorders of surfactant homeostasis. (a) Normal pediatric lung, demonstrating multiple alveoli with thin alveolar septa and normal airspaces. (b) Electron micrograph (EM) of a typical alveolar type II cell from a normal pediatric lung, demonstrating well-developed lamellar bodies (blue arrows). (c) Lung from a neonate with a lethal SFTPB mutation, demonstrating the typical pattern of congenital alveolar proteinosis (CAP) with thickened alveolar septa. The alveolar proteinosis material is composed of foamy, eosinophilic, lipoproteinaceous secretions rich in SP-A, SP-D, and partially processed proSP-C, as well as surfactant phospholipids. (d) EM of an alveolar type II cell from a neonate with a lethal SFTPB mutation, demonstrating disorganized multivesicular bodies (blue arrows) in lieu of well-developed, organized lamellar bodies. (e) Lung from a neonate with a lethal ABCA3 mutation, exhibiting granular, eosinophilic, alveolar proteinosis material mixed with macrophages characteristic of CAP. The alveolar proteinosis material is rich in surfactant phospholipids, SP-A, SP-C, SP-B, and proSP-B, but not proSP-C. (f) EM of an alveolar type II cell from a neonate with a lethal ABCA3 mutation, demonstrating abnormally small lamellar bodies (blue arrows) with eccentrically placed, electron-dense inclusions and tightly packed phospholipid lamellae. (g) Lung from an infant with an SFTPC mutation, demonstrating chronic interstitial lung disease (chronic pneumonitis of infancy) with thickening of alveolar septa and alveolar proteinosis material in the airspaces. (h) Lung from a child with a mutation in the alpha chain of the GM-CSF receptor, demonstrating foamy alveolar proteinosis material [pulmonary alveolar proteinosis (PAP) is discussed in text] but normal-appearing, thin alveolar septa. H&E stains, original magnification = 10× for panels a, c, e, g, and h. EM, original magnification = 15,000× for panel b and 30,000× for panels d and f.