Modeling the effect of stretch and plasma membrane tension on Na⁺-K⁺-ATPase activity in alveolar epithelial cells

Abstract

Fisher, Jacob L., and Susan S. Margulies. Modeling the effect of stretch and plasma membrane tension on Na ϩ -K ϩ -ATPase activity in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 292: L40-L53, 2007. First published August 4, 2006; doi:10.1152/ajplung.00425.2005.-While a number of whole cell mechanical models have been proposed, few, if any, have focused on the relationship among plasma membrane tension, plasma membrane unfolding, and plasma membrane expansion and relaxation via lipid insertion. The goal of this communication is to develop such a model to better understand how plasma membrane tension, which we propose stimulates Na ϩ -K ϩ -ATPase activity but possibly also causes cell injury, may be generated in alveolar epithelial cells during mechanical ventilation. Assuming basic relationships between plasma membrane unfolding and tension and lipid insertion as the result of tension, we have captured plasma membrane mechanical responses observed in alveolar epithelial cells: fast deformation during fast cyclic stretch, slower, time-dependent deformation via lipid insertion during tonic stretch, and cell recovery after release from stretch. The model estimates plasma membrane tension and predicts Na ϩ -K ϩ -ATPase activation for a specified cell deformation time course. Model parameters were fit to plasma membrane tension, whole cell capacitance, and plasma membrane area data collected from the literature for osmotically swollen and shrunken cells. Predictions of membrane tension and stretch-stimulated Na ϩ -K ϩ -ATPase activity were validated with measurements from previous studies. As a proof of concept, we demonstrate experimentally that tonic stretch and consequent plasma membrane recruitment can be exploited to condition cells against subsequent cyclic stretch and hence mitigate stretchinduced responses, including stretch-induced cell death and stretch-induced modulation of Na ϩ -K ϩ -ATPase activity. Finally, the model was exercised to evaluate plasma membrane tension and potential Na ϩ -K ϩ -ATPase stimulation for an assortment of traditional and novel ventilation techniques.ventilator-induced lung injury; lipid trafficking; edema recovery INVESTIGATORS HAVE FOUND alveolar epithelial stretch magnitude to be related to cell injury in vitro (55, 56) and tidal volume to be related to ventilator-induced lung injury (VILI) in animal models (12-15). Studies have revealed that the frequency of epithelial stretch or ventilation can also be an important factor in cell injury (56, 60). The model developed in this study examines how combinations of amplitude and frequency in ventilation procedures affect Na ϩ -K ϩ -ATPase activity via hypothesized pathways including alveolar epithelial cell plasma membrane tension and stretch-activated channel (SAC) stimulation.To date, numerous models have been proposed to describe cellular mechanical behavior, from early continuum viscoelastic representations for erythrocytes and leukocytes (11,27,65) to more sophisticated variations that modeled cell membrane an...

Epithelium damage and protection during reopening of occluded airways in a physiologic microfluidic pulmonary airway model

“…It is expected that cells at the air-liquid interface of the tip of a propagating liquid plug experience a combination of shear stress and pressure gradients and a more complex and detrimental force profile. Permanent damage of the cell occurs when the resulting pores are large and beyond the capacity of the cell to reseal them through the lipid unfolding and trafficking process (Vlahakis et al 2001;Fisher and Margulies 2007). Similar stress profiles may also occur on cells exposed to propagating air finger in a liquid-filled channel (Bilek et al 2003), although with a smaller magnitude of fluidic stresses (see below) (Huh et al 2007;Ghadiali and Gaver 2008).…”

Lung regional stress and strain as a function of posture and ventilatory mode

“…The conclusion is that macroscopic (spirometry and CT methods) and microscopic strains are coupled as soon as cells are put in tension. The interplaying roles by amplitude, frequency, and basal stretch and its application time (preconditioning) have been overviewed and brought to results compatible to clinical evidence (9,37,40). By this reason, we chose to include in our analysis not only the end-inspiratory strain but also its difference to the end-expiratory strain (EI-EE), which estimates the entity of deformation due to respiratory cycling.…”

Relationship Between Strain Levels and Permeability of the Plasma Membrane in Statically Stretched Myoblasts

“…13,16,19,20 As suggested by these authors when addressing the effects of instantaneous or cyclic loading on PM permeability, it is very likely that in our present experiments, the fluorescent Dextran marker was able to cross the PM barrier through non-specific pores which developed in the PM when cells were distorted. We further surmise, based on the data (Fig.…”

“…29 Additional studies consistently provided evidence for mechanically induced PM permeability disruptions in cells subjected to mechanical stress levels exceeding critical thresholds, such as in aortic endothelial cells 17,50 and cardiomyocytes, 23 as well as in alveolar epithelial cells subjected to cyclic stretches. 13,16 Skeletal muscle tissue was the focus of several other studies, investigating stretch-induced muscle damage due to eccentric contractions, particularly in the presence of muscle dystrophies. 2,5,31,47 In this case, the cell-level injury was also proposed to be caused by dynamic stretching of the PM, as demonstrated experimentally in isolated myotubes.…”