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This review analyses the mechanisms by which lung fluid balance is strictly controlled in the air-blood barrier (ABB). Relatively large trans-endothelial and trans-epithelial Starling pressure gradients result in a minimal flow across the ABB thanks to low microvascular permeability aided by the macromolecular structure of the interstitial matrix. These edema safety factors are lost when the integrity of the interstitial matrix is damaged. The result is that small Starling pressure gradients, acting on a progressively expanding alveolar barrier with high permeability, generate a high transvascular flow that causes alveolar flooding in minutes. We modeled the trans-endothelial and trans-epithelial Starling pressure gradients under control conditions, as well as under increasing alveolar pressure (Palv) conditions of up to 25 cmH2O. We referred to the wet-to-dry weight (W/D) ratio, a specific index of lung water balance, to be correlated with the functional state of the interstitial structure. W/D averages ∼5 in control and might increase by up to ∼9 in severe edema, corresponding to ∼70% loss in the integrity of the native matrix. Factors buffering edemagenic conditions include: (i) an interstitial capacity for fluid accumulation located in the thick portion of ABB, (ii) the increase in interstitial pressure due to water binding by hyaluronan (the “safety factor” opposing the filtration gradient), and (iii) increased lymphatic flow. Inflammatory factors causing lung tissue damage include those of bacterial/viral and those of sterile nature. Production of reactive oxygen species (ROS) during hypoxia or hyperoxia, or excessive parenchymal stress/strain [lung overdistension caused by patient self-induced lung injury (P-SILI)] can all cause excessive inflammation. We discuss the heterogeneity of intrapulmonary distribution of W/D ratios. A W/D ∼6.5 has been identified as being critical for the transition to severe edema formation. Increasing Palv for W/D > 6.5, both t

Capillary instability of a two-layer liquid film lining a rigid tube is studied computationally as a model for liquid plug formation and closure of human airways. The two-layer liquid consists of a serous layer, also called the periciliary liquid layer, at the inner side and a mucus layer at the outer side. Together, they form the airway surface liquid lining the airway wall and surrounding an air core. Liquid plug formation occurs due to Plateau-Rayleigh instability when the liquid film thickness exceeds a critical value. Numerical simulations are performed for the entire closure process, including the pre- and post-coalescence phases. The mechanical stresses and their gradients on the airway wall are investigated for physiologically relevant ranges of the mucus-to-serous thickness ratio, the viscosity ratio, and the air-mucus and serous-mucus surface tensions encompassing healthy and pathological conditions of a typical adult human lung. The growth rate of the two-layer model is found to be higher in comparison with a one-layer equivalent configuration. This leads to a much sooner closure in the two-layer model than that in the corresponding one-layer model. Moreover, it is found that the serous layer generally provides an effective protection to the pulmonary epithelium against high shear stress excursions and their gradients. A linear stability analysis is also performed, and the results are found to be in good qualitative agreement with the simulations. Finally, a secondary coalescence that may occur during the post-closure phase is investigated., Scientific and Technical Research Council of Turkey (TÜBİTAK); National Institutes of Health (NIH)

The closure of a human lung airway is modelled as a pipe coated internally with a liquid that takes into account the viscoelastic properties of mucus. For a thick-enough coating, the Plateau-Rayleigh instability blocks the airway by the creation of a liquid plug, and the preclosure phase is dominated by the Newtonian behaviour of the liquid. Our previous study with a Newtonian-liquid model demonstrated that the bifrontal plug growth consequent to airway closure induces a high level of stress and stress gradients on the airway wall, which is large enough to damage the epithelial cells, causing sublethal or lethal responses. In this study, we explore the effect of the viscoelastic properties of mucus by means of the Oldroyd-B and FENE-CR model. Viscoelasticity is shown to be very relevant in the postcoalescence process, introducing a second peak of the wall shear stresses. This second peak is related to an elastic instability due to the presence of the polymeric extra stresses. For high-enough Weissenberg and Laplace numbers, this second shear stress peak is as severe as the first one. Consequently, a second lethal or sublethal response of the epithelial cells is induced.

The closure of a human lung airway is modelled as a pipe coated internally with a liquid that takes into account the viscoelastic properties of mucus. For a thick-enough coating, the Plateau-Rayleigh instability blocks the airway by the creation of a liquid plug, and the preclosure phase is dominated by the Newtonian behaviour of the liquid. Our previous study with a Newtonian-liquid model demonstrated that the bifrontal plug growth consequent to airway closure induces a high level of stress and stress gradients on the airway wall, which is large enough to damage the epithelial cells, causing sublethal or lethal responses. In this study, we explore the effect of the viscoelastic properties of mucus by means of the Oldroyd-B and FENE-CR model. Viscoelasticity is shown to be very relevant in the postcoalescence process, introducing a second peak of the wall shear stresses. This second peak is related to an elastic instability due to the presence of the polymeric extra stresses. For high-enough Weissenberg and Laplace numbers, this second shear stress peak is as severe as the first one. Consequently, a second lethal or sublethal response of the epithelial cells is induced., Scientific and Technological Research Council of Turkey (TÜBİTAK); National Institutes of Health (NIH)

Both theoretical and experimental studies of pleural fluid dynamics and lung buoyancy during steady-state, apneic conditions are presented. The theory, shows that steady-state, top-to-bottom pleural-liquid flow, creates a pressure distribution that opposes lung buoyancy. These two forces may, balance, permitting dynamic lung floating, but when they, do not, pleural-pleural contact is required. The animal experiments examine pleural-liquid pressure distributions in response to simulated reduced gravity, achieved by, lung inflation with perfluorocarbon liquid as compared to air The resulting decrease in lung buoyancy modifies the force balance in the pleural fluid, which is reflected in its vertical pressure gradient. The data and model show that the decrease in buoyancy with perfluorocarbon inflation causes the vertical pressure gradient to approach hydrostatic. In the microgravity analogue, the pleural pressures would be toward a more uniform distribution, consistent with ventilation studies during spaceflight. The pleural liquid turnover predicted by the model is computed and found to be comparable to experimental values from the literature. The model provides the flow field, which can be used to develop a full transport theory for molecular and cellular constituents that are found in pleural fluid.