A Surface Phase Model of the Alveolar Lining: Ultrastructural Analysis and in vivo Applications

Abstract: In this thesis the relation between lung surfactant structure and functional properties have been studied. Experimental results show that the alveolar surface is formed by a coherent surface phase with a structure equal to tubular myelin. The properties of this phase may explain certain unresolved issues in lung physiology, e.g., mechanical stability of surfactant during the breathing cycle, the question of free water in the alveolus, and uptake kinetics of pulmonary administered drugs. A surface phase has important consequences in general for the barrier function of the lung, and for host defense. This surface phase is modeled with a biomathematical approach and is proposed to have a bilayer structure of a minimal surface type, the so-called CLP surface. This structure corresponds to a surfactant bilayer without self-intersections. The functional and structural properties of the CLP surface may explain e.g., the ultra low surface energy of surfactant in vivo, and rapid deformability of the surface phase during breathing. The role of cholesterol in lung surfactant was studied by X-ray diffraction. It was shown that the presence of cholesterol lowers the crystallization temperature of the surfactant significantly. During work with a pharmacy-grade lung surfactant, a novel dynamic swelling behavior was observed. During swelling in electrolyte containing water solutions, a dramatic increase of the air-water surface area was seen. In vivo evaluation of this process in an ARDS model was performed, showing significantly higher arterial oxygen levels in rats treated with surfactant in dynamic swelling compared to normal surfactant therapy.