The role of the pulmonary sodium-glucose cotransport is unknown. We hypothesized that altering glucose balance (the level of passive vs. active transport) across the airspace epithelium might affect luminal liquid clearance (Jw). A mathematical model was developed to calculate Jw from the rate of epithelial glucose uptake and paracellular permeability. The model predicted that steady-state luminal glucose concentration in fluid-filled lungs should be very low (< 0.5 mM, plasma concentration being 10 mM) and that selective changes in paracellular permeability might affect Jw. Protamine was used to increase paracellular permeability in fluid-filled isolated rat lungs. Protamine modified the glucose equilibrium across the epithelium and increased Jw (P < 0.001) in lungs instilled with fluid that contained no glucose. This increase was accurately described by the model (R2 = 0.92). Jw increased because the entry into airspaces of one glucose molecule and its reuptake results in the net absorption of four osmolytes as long as the cotransport has Na-to-glucose stoichiometry of 2:1, operates below saturation, and the barrier selectivity is preserved. Thus modulating paracellular permeability to small solutes might aid in the removal of edema fluid and participate in the regulation of epithelial lining fluid volume and composition.