A Freeze-Fracture Transmission Electron Microscopy and Small Angle X-Ray Diffraction Study of the Effects of Albumin, Serum, and Polymers on Clinical Lung Surfactant Microstructure

Braun, Andreas; Stenger, Patrick C.; Warriner, Heidi E.; Zasadzinski, Joseph A.; Lu, Karen W.; Taeusch, H. William

doi:10.1529/biophysj.106.095513

Cited by 49 publications

(71 citation statements)

References 103 publications

(169 reference statements)

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“…Unfortunately, surfactant replacement therapy has had limited clinical success, 52,53 since the leak of plasma proteins into the airway/alveolar space often deactivates surfactant. 54 Instead of trying to reduce these forces via altered ventilator settings or surfactant therapy, our laboratory is actively pursuing alternative strategies to reduce the cellular injury associated with atelectrauma. In our approach, changes in the epithelial cell's cytoskeletal and biomechanical properties are used to make these cells less susceptible to the hydrodynamics forces associated with airway reopening and atelectrauma.…”

Section: Introductionmentioning

confidence: 99%

Role of Airway Recruitment and Derecruitment in Lung Injury

Ghadiali

Huang

2011

Crit Rev Biomed Eng

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The mechanical forces generated during the ventilation of patients with acute lung injury causes significant lung damage and inflammation. Low-volume ventilation protocols are commonly used to prevent stretch-related injury that occurs at high lung volumes. However, the cyclic closure and reopening of pulmonary airways at low lung volumes, i.e., derecruitment and recruitment, also causes significant lung damage and inflammation. In this review, we provide an overview of how biomedical engineering techniques are being used to elucidate the complex physiological and biomechanical mechanisms responsible for cellular injury during recruitment/derecruitment. We focus on the development of multiscale, multiphysics computational models of cell deformation and injury during airway reopening. These models, and the corresponding in vitro experiments, have been used to both elucidate the basic mechanisms responsible for recruitment/derecruitment injury and to develop alternative therapies that make the epithelium more resistant to injury. For example, models and experiments indicate that fluidization of the cytoskeleton is cytoprotective and that changes in cytoskeletal structure and cell mechanics can be used to mitigate the mechanotransduction of oscillatory pressure into inflammatory signaling. The continued application of biomedical engineering techniques to the problem of recruitment/derecruitment injury may therefore lead to novel and more effective therapies.

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Section: Introductionmentioning

confidence: 99%

Role of Airway Recruitment and Derecruitment in Lung Injury

Ghadiali

Huang

2011

Crit Rev Biomed Eng

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“…Survanta and Curosurf, two clinically approved animalextract replacement surfactants for treatment of NRDS, have all cholesterol removed after harvesting. Infasurf, the third clinically approved surfactant, retains 4-5 wt% cholesterol (Table S1) (7,8).Resolving this controversy is difficult, because there is little information on the effects of small mole fractions of cholesterol on the organization and dynamics of phospholipid monolayers at the molecular, monolayer, or cell-membrane scale [mitochondrial membranes have ∼5 mol% cholesterol and endoplasmic reticulum ∼10 mol% (9)]. Cholesterol is also implicated in the formation of stable, 10-to 100-nm "rafts" within the plasma membrane of cells (10, 11), which may serve as platforms for organizing proteins responsible for cell signaling or membrane trafficking.…”

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confidence: 99%

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Effect of cholesterol nanodomains on monolayer morphology and dynamics

Kim

Choi

Zell

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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At low mole fractions, cholesterol segregates into 10-to 100-nmdiameter nanodomains dispersed throughout primarily dipalmitoylphosphatidylcholine (DPPC) domains in mixed DPPC:cholesterol monolayers. The nanodomains consist of 6:1 DPPC:cholesterol "complexes" that decorate and lengthen DPPC domain boundaries, consistent with a reduced line tension, λ. The surface viscosity of the monolayer, η s , decreases exponentially with the area fraction of the nanodomains at fixed surface pressure over the 0.1-to 10-Hz range of frequencies common to respiration. At fixed cholesterol fraction, the surface viscosity increases exponentially with surface pressure in similar ways for all cholesterol fractions. This increase can be explained with a free-area model that relates η s to the pure DPPC monolayer compressibility and collapse pressure. The elastic modulus, G′, initially decreases with cholesterol fraction, consistent with the decrease in λ expected from the line-active nanodomains, in analogy to 3D emulsions. However, increasing cholesterol further causes a sharp increase in G′ between 4 and 5 mol% cholesterol owing to an evolution in the domain morphology, so that the monolayer is elastic rather than viscous over 0.1-10 Hz. Understanding the effects of small mole fractions of cholesterol should help resolve the controversial role cholesterol plays in human lung surfactants and may give clues as to how cholesterol influences raft formation in cell membranes.surface rheology | isotherms | free-volume model | AFM M inute fractions of cholesterol lead to dramatic changes in dipalmitoylphosphatidylcholine (DPPC) monolayer morphology (Figs. 1-3) (1, 2) and have equally dramatic effects on monolayer dynamic properties. One weight percent cholesterol reduces the surface viscosity, η s , of DPPC monolayers by an order of magnitude, and 2 wt% reduces η s by two orders of magnitude . Atomic force microscopy (AFM) images and microrheological data show that the cholesterol is segregated to lineactive, locally disordered nanodomains that are dispersed in and separate ordered, primarily DPPC domains. As a result, the monolayer retains many of the features of pure DPPC monolayers including a high collapse pressure, high compressibility, and so on, while having significantly lower surface viscosity. This surface viscosity effect suggests a role for cholesterol in lung surfactant (LS), a lipid-protein monolayer necessary to reduce the surface tension in the lung alveoli during respiration (Fig. S1) (3, 4). At present, even the existence of cholesterol in native LS is questioned, because the lung lavage required to harvest LS inevitably causes blood and cell debris to be coextracted, potentially contaminating LS with cholesterol (5). This lack of consensus over the role of cholesterol is reflected in the composition of replacement lung surfactants for neonatal respiratory distress syndrome (NRDS), which occurs in 20,000-30,000 premature births each year (6). Survanta and Curosurf, two clinically approved animalextract replacement surfact...

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“…In vitro studies (4) have suggested that the use of exogenous surfactants, which decreases surface tension forces, may result in decreased cell necrosis. However, surfactant replacement therapy for ARDS has had limited clinical success (24,31) potentially due to the deactivation of surfactant by plasma proteins (5). As a result, there is a pressing need for new therapies to address ventilator-induced lung injury during low volume ventilation.…”

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confidence: 99%

Influence of cytoskeletal structure and mechanics on epithelial cell injury during cyclic airway reopening

Yalcin

Hallow

Wang

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Although patients with acute respiratory distress syndrome require mechanical ventilation, these ventilators often exacerbate the existing lung injury. For example, the cyclic closure and reopening of fluid-filled airways during ventilation can cause epithelial cell (EpC) necrosis and barrier disruption. Although much work has focused on minimizing the injurious mechanical forces generated during ventilation, an alternative approach is to make the EpC less susceptible to injury by altering the cell's intrinsic biomechanical/biostructural properties. In this study, we hypothesized that alterations in cytoskeletal structure and mechanics can be used to reduce the cell's susceptibility to injury during airway reopening. EpC were treated with jasplakinolide to stabilize actin filaments or latrunculin A to depolymerize actin and then exposed to cyclic airway reopening conditions at room temperature using a previously developed in vitro cell culture model. Actin stabilization did not affect cell viability but significantly improved cell adhesion primarily due to the development of more numerous focal adhesions. Surprisingly, actin depolymerization significantly improved both cell viability and cell adhesion but weakened focal adhesions. Optical tweezer based measurements of the EpC's micromechanical properties indicate that although latrunculin-treated cells are softer, they also have increased viscous damping properties. To further investigate the effect of "fluidization" on cell injury, experiments were also conducted at 37 degrees C. Although cells held at 37 degrees C exhibited no changes in cytoskeletal structure, they did exhibit increased viscous damping properties and improved cell viability. We conclude that fluidization of the actin cytoskeleton makes the EpC less susceptible to the injurious mechanical forces generated during cyclic airway reopening.

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A Freeze-Fracture Transmission Electron Microscopy and Small Angle X-Ray Diffraction Study of the Effects of Albumin, Serum, and Polymers on Clinical Lung Surfactant Microstructure

Cited by 49 publications

References 103 publications

Role of Airway Recruitment and Derecruitment in Lung Injury

Role of Airway Recruitment and Derecruitment in Lung Injury

Effect of cholesterol nanodomains on monolayer morphology and dynamics

Influence of cytoskeletal structure and mechanics on epithelial cell injury during cyclic airway reopening

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