Epithelial organs are almost universally secretory. The lung secretes mucus of extremely variable consistency. In the early prenatal period, the secretions are of largely unknown composition, consistency, and flow rates. In addition to net outflow from secretion, the embryonic lung exhibits transient reversing flows from peristalsis. Airway peristalsis (AP) begins as soon as the smooth muscle forms, and persists until birth. Since the prenatal lung is liquid-filled, smooth muscle action can transport fluid far from the immediately adjacent tissues. The sensation of internal fluid flows has been shown to have potent morphogenetic effects, as has the transport of morphogens. We hypothesize that these effects play an important role in lung morphogenesis. To test these hypotheses in a quantitative framework, we analyzed the fluid-structure interactions between embryonic tissues and lumen fluid resulting from peristaltic waves that partially occlude the airway. We found that if the airway is closed, fluid transport is minimal; by contrast, if the trachea is open, shear rates can be very high, particularly at the stenosis. We performed a parametric analysis of flow characteristics' dependence on tissue stiffnesses, smooth muscle force, geometry, and fluid viscosity, and found that most of these relationships are governed by simple ratios. We measured the viscosity of prenatal lung fluid with passive bead microrheology. This paper reports the first measurements of the viscosity of embryonic lung lumen fluid. In the range tested, lumen fluid can be considered Newtonian, with a viscosity of 0.016 ± 0.008 Pa-s. We analyzed the interaction between the internal flows and diffusion and conclude that AP has a strong effect on flow sensing away from the tip and on transport of morphogens. These effects may be the intermediate mechanisms for the enhancement of branching seen in occluded embryonic lungs.
Peristalsis begins in the lung as soon as the smooth muscle forms, and persists until birth. Since the prenatal lung is liquid-filled, smooth muscle action can deform tissues and transport fluid far from the immediately adjacent tissues. Stretching of embryonic tissues and sensation of internal fluid flows have been shown to have potent morphogenetic effects. We hypothesize that these effects are at work in lung morphogenesis. To place that hypothesis in a quantitative framework, we analyze a model of the fluid-structure interactions between embryonic tissues and lumen fluid resulting from peristaltic waves that partially occlude the airway. We find that if the airway is closed, deformations are synchronized; by contrast, if the trachea is open, maximal occlusion precedes maximal pressure. We perform a parametric analysis of how occlusion, stretch, and flow depend on tissue stiffnesses, smooth muscle force, tissue shape and size, and fluid viscosity. We find that most of these relationships are governed by simple ratios.
Branching in the embryonic lung is controlled by a variety of morphogens. Mechanics is also believed to play a significant role in lung branching. The relative roles and interactions of these two broad factors are challenging to determine. We considered three hypotheses for explaining why tracheal occlusion triples branching with no overall increase in size. Both hypotheses are based on tracheal occlusion blocking the exit of secretions. (H1) Increased lumen pressure stretches tissues; stretch receptors at shoulders of growing tips increase local rate of branching. (H2) Blocking exit of secretions blocks advective transport of morphogens, leading to (H2a) increased overall concentration of morphogens or (H2b) increased flux of morphogens at specific locations. We constructed and analyzed computational models of tissue stretch and solute transport in a 3D lung geometry. Observed tissue stresses and stretches were predominantly in locations unrelated to subsequent branch locations, suggesting that tissue stretch (H1) is not the mechanism of enhancement of branching. Morphogen concentration in the mesenchyme (H2a) increased with tracheal occlusion, consistent with previously reported results. Morphogen flux at the epithelial surface (H2b) completely changed its distribution pattern when the trachea was occluded, tripling the number of locations at which it was elevated. Our results are consistent with the hypothesis that tracheal occlusion blocks outflow of secretions, leading to a higher number of high-flux locations at branching tips, in turn leading to a large increase in number of branching locations.
Peristalsis begins in the lung as soon as the smooth muscle (SM) forms, and persists until birth. As the prenatal lung is filled with liquid, SM action can, through lumen pressure, deform tissues far from the immediately adjacent tissues. Stretching of embryonic tissues has been shown to have potent morphogenetic effects. We hypothesize that these effects are at work in lung morphogenesis. In order to refine that broad hypothesis in a quantitative framework, we geometrically analyse cell shapes in an epithelial tissue, and individual cell deformations resulting from peristaltic waves that completely occlude the airway. Typical distortions can be very large, with opposite orientations in the stalk and tip regions. Apical distortions are always greater than basal distortions. We give a quantitative estimate of the relationship between length of occluded airway and the resulting tissue stretch in the distal tip. We refine our analysis of cell stresses and strains from peristalsis with a simple mechanical model of deformation of cells within an epithelium, which accounts for basic subcellular geometry and material properties. The model identifies likely stress concentrations near the nucleus and at the apical cell -cell junction. The surprisingly large strains of airway peristalsis may serve to rearrange cells and stimulate other mechanosensitive processes by repeatedly aligning cytoskeletal components and/or breaking and reforming lateral cell -cell adhesions. Stress concentrations between nuclei of adjacent cells may serve as a mechanical control mechanism guiding the alignment of nuclei as an epithelium matures.
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