title: An elevated level of cholesterol impairs self-assembly of pulmonary surfactant into a functional film.
abstract: In adult respiratory distress syndrome, the primary function of pulmonary surfactant to strongly reduce the surface tension of the air-alveolar interface is impaired, resulting in diminished lung compliance, a decreased lung volume, and severe hypoxemia. Dysfunction coincides with an increased level of cholesterol in surfactant which on its own or together with other factors causes surfactant failure. In the current study, we investigated by atomic force microscopy and Kelvin-probe force microscopy how the increased level of cholesterol disrupts the assembly of an efficient film. Functional surfactant films underwent a monolayer-bilayer conversion upon contraction and resulted in a film with lipid bilayer stacks, scattered over a lipid monolayer. Large stacks were at positive electrical potential, small stacks at negative potential with respect to the surrounding monolayer areas. Dysfunctional films formed only few stacks. The surface potential of the occasional stacks was also not different from the surrounding monolayer. Based on film topology and potential distribution, we propose a mechanism for formation of stacked bilayer patches whereby the helical surfactant-associated protein SP-C becomes inserted into the bilayers with defined polarity. We discuss the functional role of the stacks as mechanically reinforcing elements and how an elevated level of cholesterol inhibits the formation of the stacks. This offers a simple biophysical explanation for surfactant inhibition in adult respiratory distress syndrome and possible targets for treatment.
authors.affiliation: Department of Cell Biology and Anatomy, Faculty of Medicine, Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Leonenko
authors.forename: Simardeep
authors.initials: S
authors.lastname: Gill
authors.forename: Svetlana
authors.initials: S
authors.lastname: Baoukina
authors.forename: Luca
authors.initials: L
authors.lastname: Monticelli
authors.forename: Jana
authors.initials: J
authors.lastname: Doehner
authors.forename: Lasantha
authors.initials: L
authors.lastname: Gunasekara
authors.forename: Florian
authors.initials: F
authors.lastname: Felderer
authors.forename: Mathias
authors.initials: M
authors.lastname: Rodenstein
authors.forename: Lukas M
authors.initials: LM
authors.lastname: Eng
authors.forename: Matthias
authors.initials: M
authors.lastname: Amrein
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D002417:Cattle; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008170:Lung Compliance / Q000502:physiology; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D011663:Pulmonary Surfactants / Q000737:chemistry* / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000378:metabolism / Q000503:physiopathology; D013500:Surface Tension
chemical_list: D008051:Lipid Bilayers; D011663:Pulmonary Surfactants; D015060:1,2-Dipalmitoylphosphatidylcholine; D002784:Cholesterol