G protein regulation of alveolar ion channels: implications for lung fluid transport.

Vectorial ion flow across the alveolar epithelium provides the driving force for lung fluid secretion in the prenatal lung and for fluid reabsorption at birth and thereafter into adult life. Fluid secretion is dependent upon 'active' accumulation of Cl- into the lumen of the developing lung and any factor which interupts the production of this liquid template results in life-threatening abnormalities in lung growth. The direction of fluid flow is reversed at birth to bring about the reabsorption of the lung fluid so that gaseous exchange can be initated successfully in the neonate. This functional switch at birth involves active Na+ reabsorption; failure of this mechanism to activate adequately contributes to respiratory distress in the newborn. Although beta 2-adrenoceptor-cAMP-protein kinase activation provides a basic model for the switch, it is clear that local regulation of many of the components in the switching cascade are important to the overall efficiency with which it is achieved. Co-localized with apical Cl- and Na+ channels are pertussis toxin-sensitive G proteins, which exert their regulatory effects principally by direct protein-channel interactions. The modulation of channels by local G proteins is finely tuned by negative feedback mechanisms, which may include a novel double-bond specific fatty acid regulation of G protein turnover and the paracrine effects of locally produced eicosanoids. An understanding of how these overlapping pathways integrate to produce the smooth and ordered transition from Cl- secretion to Na+ absorption will allow the design of rational treatments for conditions that are characterized by disfunctional lung fluid homeostasis.