Figure 1.

Schematic illustration of mechanisms that regulate alveolar surfactant metabolism and the disruption of these mechanisms in pulmonary alveolar proteinosis (PAP), the change in the cholesterol/phospholipid ratio in PAP, and the fold increase in various lipid species in PAP. (A) The various PAP-causing diseases classified as primary, secondary, or congenital PAP, and represented by the pathogenic mechanism (red text), can also be grouped as disorders of surfactant production or clearance (indicated) (see also Reference 2). (B) Recently, the ratio of surfactant cholesterol to phospholipids was found to be increased in PAP caused by disruption of GM-CSF (granulocyte–macrophage colony–stimulating factor) signaling in humans and mice (see References 14 and 15). (C) By carefully examining the composition of surfactant from patients with PAP and healthy control subjects collected by BAL, Griese and colleagues found that PAP caused by distinct mechanisms (including GM-CSF autoantibodies; genetic mutations in CSF2RA, MARS, FARSB, and NPC2; and myeloid leukemia) shared a similar pattern of altered surfactant composition, which is characterized by a large increase in the amount of free and esterified cholesterol and large fold increases in the normally small fraction of ceramide and other sphingolipids (16). See text for further details. SP = surfactant protein.