The active transcellular transport of electrolytes across the alveolar epithelium probably plays an important role in alveolar fluid homeostasis by helping to maintain the alveolus relatively free of fluid. To better understand the factors regulating active ion transport across alveolar epithelial cells, we examined the effect of a number of pharmacologically active agents on the bioelectric properties of alveolar type II cells in primary culture. Alveolar type II cells were isolated from adult male rats and cultured on collagen-coated Millipore filters for 6-14 days. The bioelectric properties of these monolayers were determined in Ussing-type chambers. The addition of 10(-3) M 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) increased the short-circuit current (Isc) from 2.9 +/- 0.75 to 6.9 +/- 0.73 microA/cm2 (means +/- SE; n = 8) and decreased the transepithelial resistance. Cholera toxin, 3-isobutyl-1-methylxanthine, and terbutaline sulfate produced similar increases in Isc and decreases in resistance. The Isc stimulated by 8-BrcAMP was Na but not Cl dependent and could be blocked by amiloride but not by furosemide. Thus 8-BrcAMP and agents that increase intracellular cAMP can stimulate a Na-dependent net active ion transport across alveolar type II cell monolayers. Similar regulatory mechanisms may be involved in controlling solute and fluid movement across the alveolar epithelium in vivo.

Quality of life was a sensitive indicator of treatment response and has the potential to be a useful parameter to guide treatment.

Airway inflammation is a consistent finding in asthma, and increased amounts of eosinophil-derived cationic proteins are present in bronchoalveolar lavage fluid from asthmatic subjects. Tracheal instillation of a variety of naturally occurring and synthetic cationic proteins has been shown to induce airway hyperresponsiveness in animal models. Cationic proteins may alter the barrier function of airway epithelium, allowing increased access of agonists to underlying nerves and airway smooth muscle. To examine the effect of cationic proteins on airway epithelial cell function, rabbit tracheal epithelial cells were isolated and cultured on collagen-coated filter membranes. Both apical and basolateral exposure of the cell cultures to poly-L-lysine and poly-L-arginine decreased transepithelial electrical resistance (Rt) over 60 min. There were no discernable light microscopic changes in the morphology of the cultures at 60 min after poly-L-lysine exposure, but permeability to mannitol was increased compared to controls. Evidence for the critical role of cationic charge included the following observations: (1) Poly-L-aspartate, an anionic polyamino acid, had no significant effect on Rt, and (2) the addition of heparin prior to the addition of poly-L-lysine blocked the reduction in Rt. Furthermore, when applied after poly-L-lysine addition, heparin reversed the decrease in Rt in a time-dependent fashion. Increasing the [Ca2+] in the medium from 1 to 10 mM resulted in significant attenuation of the response to polycation addition. These findings suggest that cationic proteins significantly alter the barrier properties of airway epithelium and that cationic charge is a crucial factor. This alteration is not an "all or none" phenomenon, since subsequent addition of heparin resulted in a reversal of the effect. While the precise mechanisms responsible for these observations remain to be elucidated, cationic proteins may be modifying the interaction of extracellular calcium with tight junctions thereby resulting in increased permeability. The barrier function of the epithelium may be perturbed in asthma and a variety of other airway diseases through the presence of cationic proteins derived from inflammatory cells within the airway lumen and/or the subepithelium.

The transition of the fetal lung from a fluid-secreting to a fluid-absorbing organ is dependent on ion transport across the pulmonary epithelium. This study examined the ion transport characteristics of distal pulmonary epithelial cells isolated from rat fetuses in late gestation and maintained in differentiation-arrested monolayer cultures. The response to inhibitors of active ion transport suggested the presence of apical to basolateral Na+ transport in monolayers derived from each gestational age. However, amiloride inhibition of short-circuit current (Isc) varied with gestational age, decreasing Isc by 30% in monolayers derived from day 18 fetuses and by 55% in monolayers from day 21 fetuses. A portion (10%) of the residual Isc remaining after amiloride addition to monolayers from day 18 fetuses could be inhibited by bumetanide, suggesting the induction of net Cl- transport. Ion-substitution experiments confirmed the presence of Na+ and inducible Cl- transport mechanisms in monolayers from day 18 fetuses and only Na+ transport mechanisms in monolayers from day 21 fetuses. beta-Adrenergic stimulation increased Isc but maintained the age-dependent characteristics of Na(+)- and Cl(-)-dependent ion transport. In summary, monolayer cultures of fetal pulmonary epithelial cells exhibit age-dependent differences in ion transport properties that are consistent with a transition or maturation of the distal pulmonary epithelium from an epithelium capable of Na+ absorption and Cl- secretion preterm to one capable of only Na+ absorption at term.