Native lung surfactant (LS) consists of a mixture of lipids and proteins that together posses the ability to lower the alveolar surface tension, and thus is essential for normal breathing. While the exact mechanisms of acute lung injury (ALI), and its more severe form, acute respiratory distress syndrome (ARDS), are currently not well understood, LS inactivation by surface active inhibitory proteins, enzymes, fatty acids and lyso-lipids are believed to play a contributing role. Published and preliminary work reveals that even small fractions of ARDS-implicated components may change the surface viscosity and elasticity of monolayers by orders of magnitude: thousand-fold increases in phospholipid monolayer stiffness when saturated fatty acids are added or albumin adsorbs, whereas 100-1000-fold decreases occur when 1-2% cholesterol is added. These results suggest a plausible mechanical mechanism for ARDS progression, and the central hypothesis of the proposed project: that the rheological (e.g. viscous and elastic) properties of ARDS- inactivated LS play a central, causative role in the ARDS cascade, and in the inability of RS therapies to effectively reverse ARDS progression. An initial insult to the lung introduces blood proteins through permeabilized alveolar walls, and heightened levels of the enzyme PLA2, as part of the inflammatory response. Previous results suggest that either of these situations would create heterogeneous, rheologically elastic domains deep in the lung: PLA2 by digesting phospholipids to produce lyso-lipids and fatty acids, and blood proteins through adsorption. Well-known phenomena in continuum mechanics suggest that elastic heterogeneities within the LS strongly resist the curvature changes that occur naturally during respiration, and may even `crack' or `crumple' rather than deform smoothly. Such abnormal deformations would thus exert strong, localized mechanical stresses on the alveolar epithelium, promoting further tissue damage and inflammation, and ultimately to greater levels of protein and PLA2. Notably, the hypothesized mechanism is physical in origin, and derives from how the organization of these components in the LS monolayer affects their ability to flow and deform. Such a mechanism could not be uncovered from chemical assays alone. To test this hypothesis, the impact of LS-inactivating factors (blood proteins, fatty acids, enzymes) on the rheology of model LS monolayers will be measured with first-of-their-kind techniques, as well components (e.g. natural or synthetic surfactant proteins, mono-unsaturated fatty acids, cholesterol) that may reduce or reverse the inactivation. Using both novel experimental techniques and theory, the molecular composition of inactivated LS will be related to elastic heterogeneities, and elastic heterogeneities to anisotropic alveolar inflation and deflation. Finally, the mixing and evolution of heterogeneous monolayers will be studied to identify strategies to dissolve, disrupt or displace these elastic heterogeneities, and ultimately guiding therapeutic formulations.

Public Health Relevance

Inactivation of lung surfactant (LS) due to trauma or injury results in acute respiratory distress syndrome (ARDS) in both children and adults, affecting 150,000 patients a year with a mortality rate of 30-40%. This project seeks to relate the molecular components of model lung surfactants to their flow and deformation during respiration, focusing on how molecules released during lung injury or inflammation stiffen and de- activate the surfactant, to identify therapeutic strategies that restore LS function in ARDS patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Lin, Sara
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University of California Santa Barbara
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
Santa Barbara
United States
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Kim, KyuHan; Choi, Siyoung Q; Zasadzinski, Joseph A et al. (2018) Nonlinear chiral rheology of phospholipid monolayers. Soft Matter 14:2476-2483
Sachan, Amit Kumar; Zasadzinski, Joseph A (2018) Interfacial curvature effects on the monolayer morphology and dynamics of a clinical lung surfactant. Proc Natl Acad Sci U S A 115:E134-E143