Alveolar Dynamics and Beyond – The Importance of Surfactant Protein C and Cholesterol in Lung Homeostasis and Fibrosis

Surfactant protein C (SP-C) is an important player in enhancing the interfacial adsorption of lung surfactant lipid films to the alveolar air-liquid interface. Doing so, surface tension drops down enough to stabilize alveoli and the lung, reducing the work of breathing. In addition, it has been shown that SP-C counteracts the deleterious effect of high amounts of cholesterol in the surfactant lipid films. On its side, cholesterol is a wellknown modulator of the biophysical properties of biological membranes and it has been proven that it activates the inflammasome pathways in the lung. Even though the molecular mechanism is not known, there are evidences suggesting that these two molecules may interplay with each other in order to keep the proper function of the lung. This review focuses in the role of SP-C and cholesterol in the development of lung fibrosis and the potential pathways in which impairment of both molecules leads to aberrant lung repair, and therefore impaired alveolar dynamics. From molecular to cellular mechanisms to evidences in animal models and human diseases. The evidences revised here highlight a potential SP-C/cholesterol axis as target for the treatment of lung fibrosis

The Effects of Free Radical-induced Epoxidation and Peroxidation of Unsaturated Phospholipids on the Self-assembly of Functional Surfactant Film

The pulmonary surfactant is a protein-lipid mixture that covers the air-water interface. It lowers the alveolar surface tension to near zero values. Surfactant dysfunction has been reported in acute lung injury, acute respiratory distress syndrome, and cystic fibrosis, among other inflammatory lung diseases. Surfactant achieves low surface tension by forming a tightly packed uniform film at the air-water interface and thus, eliminates the electrostatic forces between liquid molecules. As the film pressure (π) increase, surfactant explores a third dimension or multilayers. Monolayer-Multilayer interactions provide additional stability to resist the varying high film pressure at the air-water interface, therefore, preventing premature buckling of the interfacial film. The surfactant may become impaired during pulmonary inflammation, where free radicals degrade its components, whether by introducing epoxides and hydroperoxides to the tightly packed hydrocarbon tails of surfactant phospholipids or by fatty acyl tail fragmentation. In this thesis, we show that oxidation mediated surfactant inhibition is cholesterol dependent. We study surfactant film thermodynamic changes as a result of oxidation and cholesterol. Additionally, we show the structure-function relationship and the underlying importance of monolayer-multilayer anchoring. Moreover, we show that multilayer distribution and arrangements due to oxidized cholesterol species do not alter surfactant film function. Further, we modeled the surfactant film via mechanical finite element analysis software (ANSYS) to examine the role of multilayers. We predict that the mechanism of surfactant dysfunction demonstrated in vitro is relevant to disease state