The role of Lung Surfactant (LS) in lowering the surface tension, ?, at the alveolar air-liquid interface is well known. We hypothesize that a second essential function of LS is to prevent the Laplace instability, which drives gas out of smaller alveoli and into larger ones, leading to alveolar de-recruitment, atelectasis and loss of lung compliance. These are the core symptoms of Acute Respiratory Distress Syndrome (ARDS), which afflicts 150,000 people in the US with a 40% mortality rate. We hypothesize that the dynamic resistance of the LS monolayer to changes in area can reverse the Laplace instability. The dilatational modulus, ? = ? ?? ?? , relates the change in surface tension, ?, to the change in interfacial area, A. For 2??? >0, the Laplace pressure decreases with decreasing radius, suppressing the Laplace Instability. However, if 2??? < 0, variations in lung inflation drive collapse of smaller alveoli, leading to the alveolar flooding and decreased lung compliance. Our preliminary work shows that serum proteins and lysolipids, which increase in the alveolar fluids during ARDS-induced inflammation, increase ? by competitively adsorbing to the alveolar interface. These inhibitors also dramatically decrease the dilatational modulus due to their diffusional exchange with the subphase, especially at low interfacial area strain rates (?A(t)/A). Such conditions arise in damaged areas of the lung with poor gas exchange and high levels of inflammation products and provoke the Laplace instability as 2??? < 0. This leads to further damage in injured areas of the lung and a negative feedback loop is established that may be responsible for the ineffectiveness of current ARDS treatments. To address this hypothesis, we have built a novel capillary pressure microtensiometer to measure ?(?) of LS, serum proteins, and lysolipids for the first time. We will map out ?(?) for clinical and model lung surfactants as a function of surfactant composition, morphology, surface pressure and frequency to determine the effects of saturated vs. unsaturated lipid fraction, domain morphology, and lung surfactant proteins SP-B and SP-C, cholesterol and fatty acid fractions. We will examine how ?(?) changes due to subphase compositions of lysolipids, albumin, and fibrinogen, all of which have elevated levels in the ARDS lung. These first of their kind measurements should provide us with a map of the conditions under which the Laplace instability plays a role in the progression of ARDS. Reversing the Laplace instability requires understanding how to prevent inhibitors from reaching the alveolar interface, or removing inhibitors that do adsorb. From our new understanding of ?(?) we will create LS formulations with optimized rheological properties to promote LS respreading. We also propose that minimizing the anionic lipid fraction in LS and adding low concentrations of polyethylene glycol (PEG) and trivalent cations from adjuvants such as alum, will provide an electrostatic and osmotic assist to promote LS adsorption. Minimizing the inhibitor concentration and maximizing LS would lower ?, increase ?(?) and reverse the conditions leading to the Laplace instability, thereby restoring proper lung function.

Public Health Relevance

Attachment) A lack of lung surfactant, often due to premature delivery, is responsible for neonatal respiratory distress syndrome which affects an estimated 30,000 newborns in the US. Our work is also designed to understand the origins of surfactant inhibition in meconium aspiration, acute lung injury, and acute respiratory distress syndrome in children and adults which affect more than 150,000 per year with high mortality rates. Our goal is to develop a fundamental understanding of composition-function relationships to determine the composition of an optimized synthetic replacement lung surfactant to provide better treatments for NRDS and ARDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051177-23
Application #
9432545
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Lin, Sara
Project Start
1994-07-01
Project End
2021-01-31
Budget Start
2018-02-15
Budget End
2019-01-31
Support Year
23
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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