Pathogenesis-driven treatment of primary pulmonary alveolar proteinosis

Abstract

Pulmonary alveolar proteinosis (PAP) is a syndrome that results from the accumulation of lipoproteinaceous material in the alveolar space. According to the underlying pathogenetic mechanisms, three different forms have been identified, namely primary, secondary and congenital. Primary PAP is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling due to the presence of neutralising autoantibodies (autoimmune PAP) or GM-CSF receptor genetic defects (hereditary PAP), which results in dysfunctional alveolar macrophages with reduced phagocytic clearance of particles, cholesterol and surfactant. The serum level of GM-CSF autoantibody is the only disease-specific biomarker of autoimmune PAP, although it does not correlate with disease severity. In PAP patients with normal serum GM-CSF autoantibody levels, elevated serum GM-CSF levels is highly suspicious for hereditary PAP. Several biomarkers have been correlated with disease severity, although they are not specific for PAP. These include lactate dehydrogenase, cytokeratin 19 fragment 21.1, carcinoembryonic antigen, neuron-specific enolase, surfactant proteins, Krebs von Lungen 6, chitinase-3-like protein 1 and monocyte chemotactic proteins. Finally, increased awareness of the disease mechanisms has led to the development of pathogenesis-based treatments, such as GM-CSF augmentation and cholesterol-targeting therapies.

FIGURE 1

Typical high-resolution computed tomography appearance of pulmonary alveolar proteinosis, characterised by diffuse and geographically distributed ground glass opacifications with thickening of the septa (crazy paving aspect).

FIGURE 2

Periodic acid–Schiff stain. The optical microscopy evaluation of bronchoalveolar lavage fluid reveals foamy macrophages (solid arrow), cell debris and diffuse periodic acid–Schiff-positive material (dashed arrow). Magnification: ×100.

FIGURE 3

a) During normal homeostasis, pulmonary surfactant is synthesised, packaged and secreted by type II pneumocytes, then migrates to the air–liquid interface. Granulocyte−macrophage colony-stimulating factor (GM-CSF) secreted from type II pneumocytes binds to GM-CSF receptors on immature alveolar macrophages (AMs) promoting maturation, as well as regulating phagocytosis, immune and other nonimmune functions in mature AMs. Clearance of surfactant occurs via uptake and recycling in type II pneumocytes (Pn) and via phagocytosis and catabolism in AMs. b) In autoimmune pulmonary alveolar proteinosis (PAP), anti-GM-CSF antibodies disrupt maturation and activation of AMs, leading to intracellular build-up of lipid, impaired clearance and accumulation of surfactant in the alveolus. c) Conversely, in hereditary PAP, mutations in the α and β chains of the GM-CSF receptor results in conformational changes and reduced receptor function or cell surface expression, again leading to impaired AM function and accumulation of surfactant in the alveolus.