Project Details
Description
Acute respiratory distress syndrome (ARDS) is a diffuse, inflammatory lung disease characterized by
increased vascular permeability, decreased lung compliance, and loss of aerated tissue affecting 200,000 in the
US annually with 40% mortality. Covid-19 infections have significantly increased these numbers over the past
year. The mechanisms through which ARDS arises and how host factors confer an increased risk of developing
severe disease remain unclear. It is known that inflammation due to underlying disease is linked to ARDS
progression and severity. We hypothesize that lipase-catalyzed degradation of pathogen phospholipids to
soluble lysolipids and free fatty acids can lead to a mechanical lung instability known as the “Laplace Instability
by inactivating healthy lung surfactant. The Laplace Instability occurs because the intra-alveolar pressure is
increased by the Laplace pressure, ∆d443; = 2d6fe;⁄d445; ; ∆d443; is higher in alveoli with smaller radii, d445;, than larger alveoli if
d6fe;, the surface tension, is constant. This would cause smaller alveoli to deflate and fill with fluid, while the larger
alveolar become distended, both symptoms of ARDS. To prevent this, d6fe; must decrease with decreasing alveolar
radius such that 2d438;∗(d714;) − d6fe; > 0 in which d438;∗(d714;) = d434;(d714;)(d715;d6fe;⁄d715;d434;) is the dilatational modulus. For healthy lung
surfactant 2d438;∗(d714;) -g >> 0. However, during inflammation, lysolipid concentrations increase by orders of
magnitude in the alveolar fluids due to lipases acting on pathogen membranes. We find that
lysopalmitoylphosphatidylcholine concentrations above its critical micelle concentration (CMC) cause d438;∗(d714;) of
lung surfactant monolayers to decrease dramatically leading to 2d438;∗(d714;) − d6fe; ≤ 0 at breathing frequencies, which
can lead to the Laplace Instability and compromise uniform lung inflation. Theoretical models show d438;∗
decreases due to diffusive exchange of lysolipids between the monolayer and the micelles in the adjacent fluid.
This project will use a combined experimental and theoretical approach to understand how pathogen derived
lysolipids with widely varying CMC’s influence d438;∗(d714;) so that chemical or physical interventions might be
developed to reverse the Laplace Instability. In Aim 1, we will use the unique experimental techniques developed
in our labs to establish how the dilatational properties of lung surfactant change due to contact with lysolipids
representative of various pathogens at concentrations above and below the CMC. We will determine the impact
of d438;∗(d714;) on the dynamics of model alveolar surfaces, and how this leads to physiological dysfunction. In Aim 2,
we will examine the liquid-solid domain morphology of clinical and model lung surfactants to understand the role
of cholesterol and interfacial curvature in modifying domain shapes and sizes to maximize LS respreading during
inhalation and minimize lysolipid adsorption. These first of their kind experiments and fundamental theoretical
approaches should determine the optimal lung surfactant composition that is resistant to lysolipid adsorption and
provide a new way of stabilizing the ARDS lung.
Status | Active |
---|---|
Effective start/end date | 7/1/94 → 6/30/24 |
Funding
- National Heart, Lung, and Blood Institute: $234,247.00
- National Heart, Lung, and Blood Institute: $493,705.00
- National Heart, Lung, and Blood Institute: $251,505.00
- National Heart, Lung, and Blood Institute: $495,664.00
- National Heart, Lung, and Blood Institute: $357,896.00
- National Heart, Lung, and Blood Institute: $351,501.00
- National Heart, Lung, and Blood Institute: $164,906.00
- National Heart, Lung, and Blood Institute: $371,291.00
- National Heart, Lung, and Blood Institute: $234,707.00
- National Heart, Lung, and Blood Institute: $395,426.00
- National Heart, Lung, and Blood Institute: $352,282.00
- National Heart, Lung, and Blood Institute: $299,711.00
- National Heart, Lung, and Blood Institute: $399,021.00
- National Heart, Lung, and Blood Institute: $234,707.00
- National Heart, Lung, and Blood Institute: $342,346.00
- National Heart, Lung, and Blood Institute: $259,484.00
- National Heart, Lung, and Blood Institute: $401,382.00
- National Heart, Lung, and Blood Institute: $245,517.00
- National Heart, Lung, and Blood Institute: $472,133.00
- National Heart, Lung, and Blood Institute: $354,829.00
- National Heart, Lung, and Blood Institute: $429,512.00
- National Heart, Lung, and Blood Institute: $251,008.00
- National Heart, Lung, and Blood Institute: $144,972.00
- National Heart, Lung, and Blood Institute: $361,051.00
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