Pulmonary Alveolar Proteinosis, PAP (NORD)

Pulmonary alveolar proteinosis, also called PAP, is a rare syndrome characterized by progressive accumulation of surfactant in the alveoli. Alveoli are the tiny air sacs in the lungs where gas exchange occurs. Surfactant is a substance produced by alveolar cells that reduces the surface tension in the alveoli and prevents them from collapsing. In PAP, there’s so much surfactant that it blocks air from entering the alveoli, making breathing more difficult and causing other respiratory issues.

Disorders of surfactant production can be divided into primary, secondary, and congenital PAP. 

Primary PAP is characterized by reduced function of the granulocyte-macrophage colony-stimulating factor, also called GM-CSF. GM-CSF stimulates alveolar macrophages to remove excess surfactant from alveoli. When less GM-CSF is present, surfactant builds up in the alveoli. 

Primary PAP can be categorized further as autoimmune or hereditary. In autoimmune PAP, the body creates a protein that attacks GM-CSF and blocks the stimulation of alveolar macrophages. In hereditary PAP, individuals are born with genetic changes that destroy alveolar macrophage proteins, preventing GM-CSF from stimulating the macrophages. 

Secondary PAP can be caused by any underlying condition, such as myelodysplastic syndrome, that reduces the number of working alveolar macrophages, or by breathing in high levels of environmental toxins such as silica and talc. 

Congenital PAP occurs in individuals with inherited changes in genes  that cause the production of abnormal surfactant.  These genes include ABCA3, NKX2.1, SFTPB, and SFTPC, but there are likely other genes yet to be discovered.  The abnormal surfactant not only leads to excess surfactant in the alveoli, but other effects that cause reduced lung function or respiratory failure.