ARDS Research Area Summary: The Biochemistry and Biophysics of Acute Respiratory Distress

Background and Significance: Surfactant inactivation is an important contributor to acute respiratory distress syndrome (ARDS) in both children and adults (1-3). Surfactant inactivation is a qualitative term for the inability of normally sufficient amounts of surfactant to lower surface tension to levels necessary for lung function (4, 5). The pathophysiology of ARDS begins with events such as gastric content aspiration, pneumonia, near-drowning, toxic gas inhalation, chest/lung trauma, sepsis, acute pancreatitis, major surgery, multiple blood transfusions, fat embolism, or shock, leading to inflammation, increased permeability of the alveolar-capillary barrier, extravasation of serum proteins, followed by surfactant inactivation (Fig. 1). ARDS has an incidence of 150,000 cases per year (U.S.) and a mortality rate of ~ 40% (6-8). How lung injury triggers ARDS is unknown, and there is no generally effective therapy currently available.

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Effects of Interfacial Curvature on Morphology and Dynamics

Monolayers have been studied on flat interfaces since the pioneering work of Agnes Pockels, who published the first observations of the relationships between molecular area and surface pressure in 1891. This led to the development of Langmuir-Blodgett troughs in the 1930’s, which are still the instrument of choice for surface science laboratories today (1). On flat interfaces, lipid and fatty acid monolayers are known to phase separate into domains of different local ordering (2, 3); we are particularly interested in the coexistence of ordered “solid-like” domains in a continuous, disordered, “liquid-like” matrix as shown in Fig. 1. Grazing incidence X-ray diffraction reveals a short-range positional order of 10 – 100 lattice repeats with nearest neighbor tilt, while confocal fluorescence microscopy shows that the chiral orientation of the domains extends for tens of microns (4). On flat interfaces, these solid-like domains have a long-range electrostatic dipole-dipole repulsion (3, 5-8) and do not coalesce, even at high area fractions, even though there is a measurable “line tension” that acts to minimize the domain perimeter (7-11) (Fig. 1).

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Research Vignette
Relating Monolayer Morphology to Monolayer Shear Rheology

Phospholipid monolayers form a plethora of liquid-crystalline phases, in which the molecules pack into hexagonal and pseudo-hexagonal lattices, and the tail groups tilt to accommodate the mismatch in projected area between the headgroup and the close-packed chains (1). Complicating this packing, natural lipids such as 1,2-dipalmitoyl-sn-glycero-3-sn-phosphocholine (r-DPPC) have an exclusively r-enantiomer chiral carbon. This induces a chiral orientational ordering in liquid-condensed (LC) domains that persists over tens of microns (Fig. 1). The chiral twist demands that r-DPPC, and hence the chain tilt, rotate from the domain center to the periphery, which is incompatible with a regular lattice (2). One solution is to localize this required twist to defects. In r-DPPC monolayers, this frustration between tilt and twist leads to “tilt gradient lines” across which tilt rapidly changes orientation, (yellow dotted lines in Fig. 1a). These discontinuous changes in tilt direction allow the chiral precession, while maintaining a constant nearest-neighbor-directed tilt orientation. We combine surface pressure-area isotherms (Fig. 1b) with fluorescence imaging to visualize the monolayer organization. For DPPC, the domains spiral counter-clockwise, which is a mesoscopic manifestation of molecular chirality. We have found that shearing these domains using a microbutton rheometer gives a different viscoelastic response depending on the rotation direction. Fig. 1c shows that domains (e.g. highlighted green example) are compacted when microbutton is CC-torqued (C-shear), but extended when C-torqued (CC-shear). O represents monolayer morphology before shear. The limiting rotational strain, Δθ is greater for the same ~ 440 nN/m torque applied in the C direction than the CC direction, reflecting the chirality of the rheology at the 100 μm length scale in response to molecular chirality (2).

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ARDS Feedback Loop

  Fig. 1. The ARDS Feedback
An initial injury or 
  disease induces
  inflammation, which
  increases capillary
  permeability to serum
  proteins and PLA2
  degradation of
  phospholipids to lysolipids and fatty acids...More




Fig. 1A-C.


Area fraction of solid phase domains (black) in continuous liquid phase (red) increases with π up to ~ 12 mN/m (3:1 DPPC:PA with 3 mol% cholesterol). For π > 12 mN/m, the fraction of solid phase remains constant, and the continuous phase is converted to a tilted condensed phase.



                  Fig. 1