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.

Relationship Between Diffuse Pulmonary Fibrosis, Alveolar Proteinosis, and Granulocyte-Macrophage Colony Stimulating Factor Autoantibodies

“…For example, it is recognized that some inherited forms of surfactant homeostasis dysfunction, namely those related to ABCA3, SFTPA, and SFTPC gene variants, are associated with chronic interstitial lung disease. 5 Evolution of idiopathic (or autoimmune, as more recently defined) pulmonary alveolar proteinosis to fibrosis, such as that described as patient 1, is a rare but not exceptional occurrence. 6 However, patient 2 posed an intriguing situation: pulmonary fibrosis and GM-CSF autoantibodies, but absence of milky BAL fluid.…”

Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3

“…characterized subgroups of ILD (3)(4)(5), and among these, variants in the ATP-binding cassette sub-family A member 3 (ABCA3) are the most frequent cause (6)(7)(8).…”

Modeling human lung development and disease using pluripotent stem cells

“…These develop through a tightly regulated branching process, guided by surrounding mesoderm, into proximal airways and distal alveoli. Alveolar maturation occurs late in development and continues after birth, with the generation of alveolar epithelial type I (ATI), essential for gas exchange, and type II (ATII) cells, which produce surfactant, crucial for the maintenance of alveolar integrity (Herriges and Morrisey, 2014;Morrisey and Hogan, 2010;Whitsett et al, 2010).…”

“…A subset of almost universally lethal pediatric lung diseases are due to surfactant deficiency, caused by mutations in genes encoding surfactant proteins (SP-C, SP-B) or factors required for surfactant trafficking (ABCA3). The clinical and pathological features of these diseases vary, however, and no therapy is available (Whitsett et al, 2010). Mouse models generated by deletion of the genes involved recapitulate the most severe forms of the disease and do not reproduce the clinical spectrum associated with the multitude of mutations observed in human populations (Ban et al, 2007;Clark et al, 1995;Fitzgerald et al, 2007;Glasser et al, 2001;Hammel et al, 2007).…”