Studies using this micro-system demonstrated significant morphological differences between alveolar epithelial cells (transformed human alveolar epithelial cell line, A549 and primary murine alveolar epithelial cells, AECs) exposed to combination of solid mechanical and surface-tension stresses (cyclic propagation of air-liquid interface and wall stretch) compared to cell populations exposed solely to cyclic stretch. We have also measured significant differences in both cell death and cell detachment rates in cell monolayers experiencing combination of stresses. This research describes new tools for studying the combined effects of fluid mechanical and solid mechanical stress on alveolar cells. It also highlights the role that surface tension forces may play in the development of clinical pathology, especially under conditions of surfactant dysfunction. The results support the need for further research and improved understanding on techniques to reduce and eliminate fluid stresses in clinical settings.

Surfactant replacement therapy (SRT) involves instillation of a liquid-surfactant mixture directly into the lung airway tree. It is widely successful for treating surfactant deficiency in premature neonates who develop neonatal respiratory distress syndrome (NRDS). However, when applied to adults with acute respiratory distress syndrome (ARDS), early successes were followed by failures. This unexpected and puzzling situation is a vexing issue in the pulmonary community. A pressing question is whether the instilled surfactant mixture actually reaches the adult alveoli/acinus in therapeutic amounts. In this study, to our knowledge, we present the first mathematical model of SRT in a 3D lung structure to provide insight into answering this and other questions. The delivery is computed from fluid mechanical principals for 3D models of the lung airway tree for neonates and adults. A liquid plug propagates through the tree from forced inspiration. In two separate modeling steps, the plug deposits a coating film on the airway wall and then splits unevenly at the bifurcation due to gravity. The model generates 3D images of the resulting acinar distribution and calculates two global indexes, efficiency and homogeneity. Simulating published procedural methods, we show the neonatal lung is a well-mixed compartment, whereas the adult lung is not. The earlier, successful adult SRT studies show comparatively good index values implying adequate delivery. The later, failed studies used different protocols resulting in very low values of both indexes, consistent with inadequate acinar delivery. Reasons for these differences and the evolution of failure from success are outlined and potential remedies discussed.surfactant replacement therapy | pulmonary drug delivery | biological fluid mechanics | respiratory distress syndrome | biological transport processes S ince the early 1980s, surfactant replacement therapy (SRT) has been successful in applications to prematurely born neonates to treat their lack of surfactant production, which normally initiates late in gestation (1). Because surfactant reduces the surface tension between the air and the lung's liquid lining, its deficiency creates high surface tensions and collapsed, stiff lungs making them difficult to inflate. The resulting clinical entity of labored breathing and poor oxygenation is called neonatal respiratory distress syndrome (NRDS), or hyaline membrane disease, and is a risk of premature birth increasing with decreasing gestational age. The incidence is ∼1% of all births, equating to 40,000 cases annually in the United States (2). The mortality associated with NRDS dropped from 4,997 deaths in 1980 to 861 in 2005, and SRT played an important role in this success (3).SRT has also been tried in adults whose surfactant systems are compromised by acute respiratory distress syndrome (ARDS). ARDS results from overwhelming infections, mechanical injuries, and other insults either directly or indirectly to the lung. ARDS cases in the United States total 190,600 annually wit...

The liquid lining in small human airways can become unstable and form liquid plugs that close off the airways. Bench-top experiments have been performed in a glass capillary tube as a model airway to study the airway instability and the flow-induced stresses on the airway walls. A microscale particle image velocimetry system is used to visualize quantitatively the flow fields during the dynamic process of airway closure. An annular film is formed by injecting low-viscosity Si-oil into the glycerol-filled capillary tube. The viscosity ratio between these two fluids is similar to that between water and air. The thickness of the film varies with the infusion rate of the core fluid, which is controlled by a syringe pump. After a uniform film is formed, the syringe pump is shut off so that the core flow speed is close to zero during closure. Instantaneous velocity fields in the annular film at various stages of airway closure are computed from the images and analysed. The wall shear stress at the instant when a liquid plug forms is found to be approximately one order of magnitude higher than the exponential growth period before closure. Within the short time span of the closure process, there are large wall shear stress fluctuations. Furthermore, dramatic velocity changes in the film flow during closure indicate a steep normal stress gradient on the airway wall. The experimental results show that the wall shear stress during closure can be high enough to injure airway epithelial cells. An airway that experiences closure and reopening cyclically during breathing could be injured from fluid forces during both phases of the cycle (i.e. inspiration and expiration).

No abstract

The liquid lining in small human airways can become unstable and form liquid plugs that close off the airways. Direct numerical simulations are carried out on an airway model to study this airway instability and the flow-induced stresses on the airway walls. The equations governing the fluid motion and the interfacial boundary conditions are solved using the finite-volume method coupled with the sharp interface method for the free surface. The dynamics of the closure process is simulated for a viscous Newtonian film with constant surface tension and a passive core gas phase. In addition, a special case is examined that considers the core dynamics so that comparisons can be made with the experiments of Bian et al. (J. Fluid Mech., vol. 647, 2010, p. 391). The computed flow fields and stress distributions are consistent with the experimental findings. Within the short time span of the closure process, there are large fluctuations in the wall shear stress. Furthermore, dramatic velocity changes in the film during closure indicate a steep normal stress gradient on the airway wall. The computational results show that the wall shear stress, normal stress and their gradients during closure can be high enough to injure airway epithelial cells.