Pulmonary alveolar proteinosis (PAP) is a syndrome of surfactant accumulation, respiratory
failure, and innate immune deficiency for which therapy remains limited to whole lung lavage
(WLL), an invasive physical procedure to remove surfactant unavailable at most medical
centers. While PAP occurs in multiple diseases affecting men, women, and children of all ages
and ethnic origins, in 85% of patients, it occurs as an idiopathic disease associated with
neutralizing GM-CSF autoantibodies. Basic science and translational research has shown that
idiopathic PAP is an autoimmune disease in which disruption of GM-CSF signaling impairs the
ability of alveolar macrophages to clear surfactant and perform host defense functions.
Recently, it has been shown that cholesterol toxicity drives pathogenesis in alveolar
macrophages from GM-CSF deficient (Csf2-/-) mice and patients with autoimmune PAP. Loss of
GM-CSF signaling reduces PU.1/CEBP-mediated expression of PPARĪ³ and its downstream target
ABCG1 (a cholesterol exporter important in macrophages). The cell responds by esterifying and
storing cholesterol in vesicles to reduce toxicity. Eventually, vesicles fill the cell,
impair intracellular transport and reduce uptake and clearance of surfactant from the lung
surface resulting in disease manifestations. Recent data indicates that pioglitazone, a PPARĪ³
agonist currently approved by the FDA for human use, increases cholesterol/surfactant
clearance by alveolar macrophages from autoimmune PAP patients and Csf2-/- mice. Importantly,
pioglitazone significantly reduced the severity of PAP lung disease in Csf2-/- mice after
several months of therapy. Together, these observations suggest pioglitazone could be
'repurposed' as pharmacologic therapy for PAP.