The primary goal of this research is to determine, for the first time, the physiologically optimal surface viscosity of the lung surfactant using an active microrheology technique unique to our lab. We hypothesize that there exists an optimal surface viscosity in an effective lung surfactant that provides both rapid adsorption to the air-water interface and ultra-low surface tensions. Our goal is to determine how best to achieve this optimum by controlling the cholesterol fraction of a synthetic replacement lung surfactant. Three orders of magnitude increased sensitivity of our microrheology technique as compared to macroscopic rheometers allows precise monitoring of changes in the molecular organization of the lung surfactant film in the presence of cholesterol, enabling accurate measurements of surface viscosity of surfactant films. Ultimately, determining the optimal cholesterol concentration will enable a better design of synthetic surfactants to treat Neonatal Respiratory Distress Syndrome (NRDS) and may give insights into the causes of surfactant inactivation in Adult Respiratory Distress Syndrome (ARDS). We hypothesize that small fractions (1-5 wt. %) of cholesterol reduce the crystalline ordering of saturated lipids in lung surfactant monolayers, leading to a reduction in the shear viscosity, which enhances the surfactant's ability to flow and cover the alveolar interface. We also hypothesize that excess cholesterol ( >10 wt %) decreases the effectiveness of lung surfactants in ARDS by increasing the minimum surface tension of the interfacial film. This inability to reach ultra-low surface tensions is hypothesized to be a consequence of significantly reduced interfacial energy of the film (line tension). Low interfacial film energy can influence the mechanical cohesion in the surfactant film and lead to the failure of the film on compression, which ultimately causes the film to become unstable at lower surface tensions. Furthermore, lipid(cholesterol)- protein interactions can also alter these mechanical and structural properties by changing their molecular organization at the interface. By determining the mechanical properties of both model and clinically relevant surfactant film in the presence of physiological and elevated amounts of cholesterol, we can understand how increased cholesterol might lead to surfactant inactivation in ARDS and determine better replacement surfactants for treatment. The mechanical properties thus determined by the active microrheology technique will be correlated with isotherms, fluorescence microscopy, and grazing incidence synchrotron X-ray diffraction to determine how cholesterol alters the molecular packing of lung surfactant lipids, which determines the mechanical properties of monolayers.

Public Health Relevance

A lack of lung surfactant, due to immaturity in premature infants can lead to neonatal respiratory distress syndrome (RDS). It is currently one of the most common lung disorders in premature infants, affecting about 10 of every 100 premature babies in the United States. The ultimate goal of this research is to develop a completely synthetic lung surfactant that should lower costs, decrease contaminations and/or infectious agents and improve efficacy in treatment of NRDS as well as Acute Lung Injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103638-03
Application #
8691920
Study Section
Special Emphasis Panel (ZRR1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Type
DUNS #
City
Lawrence
State
KS
Country
United States
Zip Code
66045
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