Abstract 172: Abcg1 Regulates Pulmonary Surfactant Metabolism in Mice and Men

Abstract

Inflammation is a hallmark characteristic of many diseases, including atherosclerosis and respiratory distress, and it is also a stereotypical response of the innate immune system to pathogens. Given the central role both inflammation and lipid homeostasis play in disease progression, defining the immune and lipid signaling pathways is key in identifying new strategies for therapeutic intervention. The ATP Binding Cassette (ABC) transporter ABCG1 is highly expressed in pulmonary type 2 cells, alveolar macrophages and immune cells. We, and others, have demonstrated that loss of ABCG1 attenuates atherosclerotic lesion progression, and profoundly impacts B cell and natural antibody homeostasis. ABCG1-deficient mice accumulate pulmonary surfactant, lamellar-body loaded type 2 cells, lipid-loaded macrophages, B-1 lymphocytes and immunoglobulins, clearly demonstrating the ABCG1 has a critical role in pulmonary homeostasis. We have identified a variant in the ABCG1 promoter in patients with pulmonary alveolar proteinosis, that results in impaired activation of ABCG1 by the liver X receptor alpha. We have generated mice that lack ABCG1 specifically in either type 2 cells or macrophages, and show that loss of ABCG1 from both cell types has specific effects on pulmonary lipid and immune homeostasis. These results establish a critical role for type 2 cell ABCG1 in controlling surfactant and lipid homeostasis in the lung and in the pathogenesis of human lung disease.