Alveolar dynamics and beyond – The importance of surfactant protein C in cholesterol metabolism and lung homeostasis

Lung surfactant is a complex mixture of lipids and proteins, which reduces surface tension at the air-water alveolar interface, decreasing the work of breathing and avoiding alveolar collapse. The main function of surfactant protein C (SP-C) is highlighted during compression of the interfacial film, where SP-C provides stability to the lipid film allowing lower surface tension. Several mutations in the SP-C gene have been associated with the development of lung fibrosis. Moreover, SP-C has been described to counter-act cholesterol deleterious effect on surfactant film stability at the interface. Animal models with lack of SP-C breathe and live normally, but they show higher susceptibility to chronic lung diseases and induced fibrosis. A detailed structural analysis of the lung over the first 30 weeks of age showed an interesting redistribution pattern of air in distal airspaces in the SP-C deficient mice. Lack of SP-C increases the heterogeneity in alveolar volumes towards bigger over-distended alveolar spaces with age, leading to impaired alveolar dynamics compared to control animals. Western Blot analysis of the other surface-active surfactant protein (SP-B) revealed a compensatory upregulation, which however was not able to compensate for the lack of SP-C on the level of lung dynamics in vivo. Numbers of cells in BAL are elevated in SP-C deficient mice and electron microscope pictures showed foamy alveolar macrophages (AM) loaded with different vesicles and lamellar body (LB)-like structures. Therefore we studied the expression of lipid metabolism genes in these cells. To confirm whether SP-C may have an effect on lipid metabolism and degradation in AM, we performed in vitro endocytosis and gene expression studies using the murine alveolar macrophage cell line MH-S. Addition of cholesterol to surfactant lipids increased the endocytosis ratio of these cells and differentially regulates a set of genes involved in cholesterol transport, regulation and metabolism, such as Abca1, Abcg1, Npc2, Cd36, Pparg, Lal and Dhcr24. SP-C in combination with cholesterol in surfactant membranes further activates genes related to cholesterol transport and regulation. In conclusion, SP-C seems to play an important role not only in surfactant activity and alveolar dynamics, but also in lipid metabolism in alveolar macrophages.

*Both authors contributed equally to this work