Efficient gas exchange depends on a tight control of the fluid volume covering the respiratory epithelium. This is mainly due to active Na⁺ reabsortion through epithelial Na⁺ channels (ENaCs). Further, pulmonary epithelial cells are permanently exposed to mechanical forces, in particular stretch and shear forces. In our present study we investigated whether stretch and/or shear forces affect the activity of ENaCs in pulmonary epithelia. For this purpose two different strategies were employed: 1) Native lung preparations from Xenopus laevis were used for transepithelial ion transport measurements in Ussing chambers and exposed to hydrostatic pressure (5 cm) at the apical side in order to stretch the epithelial cells. This procedure resulted in a net decreased of the transepithelial short-circuit current. With strategies reducing Na⁺ reabsortion through ENaCs (1 mM amiloride or decreased apical Na⁺ concentrations respectively) we found that this inhibitory effect was more pronounced. These data indicate that hydrostatic pressure - among other effects - activates amiloride-sensitive ENaCs. 2) To further clarify whether lung ENaCs directly respond to mechanical forces, human lung aßgENaCs were exposed to laminar shear stress (LSS). aßgENaCs were expressed in Xenopus oocytes and activity was measured by the two-electrode voltage clamp technique in response to LSS. LSS activated a current, which was fully sensitive to amiloride (10 mM). Further we were able to activate an amiloride-sensitive current in cultured human pulmonary epithelial cell (H441) by exposure to a laminar flow. These data indicate that ENaCs are per se mechano-sensitive ion channels.

Taken together, we have evidence that lung ENaCs are activated by stretch although it is unclear whether this is a direct or a secondary effect. Nevertheless, at least laminar shear stress seems to be an adequate stimulus in order to directly activate lung ENaCs. We hypothesize that mechano-sensitivity of lung ENaCs represents an intrinsic mechanism to control Na⁺ reabsorption in dependence to the mechanical exposure of the epithelium, e.g. as induced by breathing movements.