Stephen P. Arold

Variable stretch pattern enhances surfactant secretion in alveolar type II cells in culture

Secretion of pulmonary surfactant that maintains low surface tension within the lung is primarily mediated by mechanical stretching of alveolar epithelial type II (AEII) cells. We have shown that guinea pigs ventilated with random variations in frequency and tidal volume had significantly larger pools of surfactant in the lung than animals ventilated in a monotonous manner. Here, we test the hypothesis that variable stretch patterns imparted on the AEII cells results in enhanced surfactant secretion. AEII cells isolated from rat lungs were exposed to equibiaxial strains of 12.5, 25, or 50% change in surface area (DeltaSA) at 3 cycles/min for 15, 30, or 60 min. (3)H-labeled phosphatidylcholine release and cell viability were measured 60 min following the onset of stretch. Whereas secretion increased following 15-min stretch at 50% DeltaSA and 30-min stretch at 12.5% DeltaSA, 60 min of cyclic stretch diminished surfactant secretion regardless of strain. When cells were stretched using a variable strain profile in which the amplitude of each stretch was randomly pulled from a uniform distribution, surfactant secretion was enhanced both at 25 and 50% mean DeltaSA with no additional cell injury. Furthermore, at 50% mean DeltaSA, there was an optimum level of variability that maximized secretion implying that mechanotransduction in these cells exhibits a phenomenon similar to stochastic resonance. These results suggest that application of variable stretch may enhance surfactant secretion, possibly reducing the risk of ventilator-induced lung injury. Variable stretch-induced mechanotransduction may also have implications for other areas of mechanobiology.

Comparison of variable and conventional ventilation in a sheep saline lavage lung injury model.

Objective:There has recently been considerable interest in alternative lung-protective ventilation strategies such as variable ventilation (VV). We aimed at testing VV in a large animal lung injury model and exploring the mechanism of improvement in gas exchange seen with VV. Design:Randomized, controlled comparative ventilation study. Setting:Research laboratory at a veterinary hospital. Subjects:Female sheep weighing 59.8 ± 10.57 kg and excised calf lungs. Interventions:In a sheep saline lavage model of lung injury, we applied VV, whereby tidal volume (VT) and frequency (f) varied on each breath. Sheep were randomized into one of two groups (VV, n = 7; or control, n = 6) and ventilated for 4 hrs with all mean ventilation settings matched. Measurements and Main Results:Gas exchange, lung mechanics, and hemodynamic measures were recorded over the 4 hrs. VV sheep showed improvement in gas exchange (i.e., oxygenation and carbon dioxide elimination) and ventilation pressures (i.e., reduced mean and peak airway pressures) but control sheep did not. VV sheep also displayed lower-lung elastance and mechanical heterogeneity in comparison with control sheep from 2 to 4 hrs of ventilation. To study the mechanism behind improvements seen with VV, we examined the time course associated with the enhanced recruitment occurring during VV in eight saline-lavaged excised calf lungs. We found that the recruitment associated with a larger VT during VV lasted over 200 secs, nearly an order of magnitude greater than the average time interval between large VT deliveries during VV. Conclusions:The application of VV in a large animal model of lung injury results in improved gas exchange and superior lung mechanics in comparison with CV that can be explained at least partially by the long-lasting effects of the recruitments occurring during VV.

Jamming dynamics of stretch-induced surfactant release by alveolar type II cells

Secretion of pulmonary surfactant by alveolar epithelial type II cells is vital for the reduction of interfacial surface tension, thus preventing lung collapse. To study secretion dynamics, rat alveolar epithelial type II cells were cultured on elastic membranes and cyclically stretched. The amounts of phosphatidylcholine, the primary lipid component of surfactant, inside and outside the cells, were measured using radiolabeled choline. During and immediately after stretch, cells secreted less surfactant than unstretched cells; however, stretched cells secreted significantly more surfactant than unstretched cells after an extended lag period. We developed a model based on the hypothesis that stretching leads to jamming of surfactant traffic escaping the cell, similar to vehicular traffic jams. In the model, stretch increases surfactant transport from the interior to the exterior of the cell. This transport is mediated by a surface layer with a finite capacity due to the limited number of fusion pores through which secretion occurs. When the amount of surfactant in the surface layer approaches this capacity, interference among lamellar bodies carrying surfactant reduces the rate of secretion, effectively creating a jam. When the stretch stops, the jam takes an extended time to clear, and subsequently the amount of secreted surfactant increases. We solved the model analytically and show that its dynamics are consistent with experimental observations, implying that surfactant secretion is a fundamentally nonlinear process with memory representing collective behavior at the level of single cells. Our results thus highlight the importance of a jamming dynamics in stretch-induced cellular secretory processes.

Noisy Ventilation Improves Lung Function

It has been shown that mechanical ventilation in the setting of acute lung injury may propagate additional injury within the lung and numerous studies have been carried out to determine the optimal method of minimizing ventilator induced lung injury while still maintaining life‐sustaining gas exchange. We have found that noise added to tidal volume and frequency, called noisy ventilation, during mechanical ventilation improves both lung mechanics and oxygenation in a rodent model of acute lung injury. Additionally, the standard deviation of the noise appears to be directly related to the magnitude of improvements seen with this ventilation modality in a manner similar to stochastic resonance. Furthermore, healthy guinea pigs that underwent with noisy ventilation exhibited increased surfactant content and reduced plasma proteins than their conventionally ventilated counterparts within the alveolar space of the lung. This suggests that not only did noisy ventilation induce endogenous surfactant release, but...

Noise added to mechanical ventilation improves gas exchange in acute lung injury

Noise can be added to tidal volume (V/sub /spl tau//) to vary the depth of inspiration from cycle to cycle, called noisy volume ventilation (NVV), or noise can be added to peak inspiratory pressure from breath to breath, called noisy pressure ventilation (NPV). Experiments were done in two groups of guinea pigs. Guinea pigs with acute lung injury induced by endotoxin (LPS) inhalation or saline lavage. Both groups were mechanically ventilated alternating between periods of conventional ventilation (CV) or different degrees of noisy ventilation (NV). The authors found that the animals consistently showed significant improvement in gas exchange (increased PaO/sub 2/) and lung mechanics (decreased elastance) after NV. The NPV mode was the most efficient, and the degree of improvement was dependent on the level of noise applied, with an optimal level of 30-40%. These results are in agreement with the possibility of mechanical stochastic resonance in the gas exchange mechanism of the injured lung.