Hepatic Steatosis Accompanies Pulmonary Alveolar Proteinosis.

Maintenance of tissue-specific organ lipid compositions characterizes mammalian lipid homeostasis. The lungs and liver synthesize mixed phosphatidylcholine (PC) molecular species that are subsequently tailored for function. The lungs progressively enrich disaturated PC directed to lamellar body surfactant stores before secretion. The liver accumulates polyunsaturated PC directed to very-low-density lipoprotein assembly and secretion, or to triglyceride stores. In each tissue, selective PC species enrichment mechanisms lie at the heart of effective homeostasis. We tested for potential coordination between these spatially separated but possibly complementary phenomena under a major derangement of lung PC metabolism, pulmonary alveolar proteinosis (PAP), which overwhelms homeostasis and leads to excessive surfactant accumulation. Using static and dynamic lipidomics techniques, we compared (1) tissue PC compositions and contents, and (2) in lungs, the absolute rates of synthesis in both control mice and the granulocyte-macrophage colony-stimulating factor knockout model of PAP. Significant disaturated PC accumulation in bronchoalveolar lavage fluid, alveolar macrophage, and lavaged lung tissue occurred alongside increased PC synthesis, consistent with reported defects in alveolar macrophage surfactant turnover. However, microscopy using oil red O staining, coherent anti-Stokes Raman scattering, second harmonic generation, and transmission electron microscopy also revealed neutral-lipid droplet accumulations in alveolar lipofibroblasts of granular macrophage colony-stimulating factor knockout animals, suggesting that lipid homeostasis deficits extend beyond alveolar macrophages. PAP plasma PC composition was significantly polyunsaturated fatty acid enriched, but the content was unchanged and hepatic polyunsaturated fatty acid-enriched PC content increased by 50% with an accompanying micro/macrovesicular steatosis and a fibrotic damage pattern consistent with nonalcoholic fatty liver disease. These data suggest a hepatopulmonary axis of PC metabolism coordination, with wider implications for understanding and managing lipid pathologies in which compromise of one organ has unexpected consequences for another.

An open-label trial of granulocyte macrophage colony stimulating factor therapy for moderate symptomatic pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare idiopathic autoimmune lung disease in adults characterized by the accumulation of lipoproteinaceous material within the alveoli of the lung. The natural history of this disease is poorly defined. Current therapy of bilateral whole-lung lavage (WLL) under general anesthesia is invasive and has its limitations. Data suggest that relative granulocyte macrophage colony stimulating factor (GM-CSF) deficiency may be involved in the pathogenesis of this disease. There have been several case series that have described clinical improvement with exogenous GM-CSF therapy in a subset of patients with PAP. We describe the results of a prospective, open-label clinical trial of daily subcutaneous GM-CSF therapy in a group of adult patients with idiopathic PAP. In this series of 25 patients, the largest reported to date, administration of GM-CSF improved oxygenation as assessed by a 10 mm Hg decrease in alveolar-arterial oxygen gradient, as well as improvement in other clinical and quality of life parameters in 12 of 25 patients (48%) with moderate symptomatic disease who completed the trial. In addition, the serum anti-GM-CSF antibody titer correlated with lung disease activity and was a predictor for responsiveness to therapy. These data indicate that subcutaneous GM-CSF therapy is a promising alternative to WLL for symptomatic patients with PAP.