Peroxynitrite inhibits amiloride-sensitive Na+ currents in Xenopus oocytes expressing -rENaC. of the -subunit. K+ ions exit the cells via basolateral K+ channels (KC). Ciliated cells secrete Cl? ions through cystic fibrosis transmembrane conductance regulator (CFTR), as well as Ca2+- triggered Cl? channels (CaCC) and SCL26A9. Cl? ions enter the cells via the basolateral Na+/K+/2Cl? (NKCC) symporter, down an electrochemical gradient produced from the Na+/K+-ATPase. In alveolar cells, Cl? transport across CFTR is likely bidirectional and depends on the concentration gradient. In ATII and ATI cells, Cl? enters cells through CFTR or crosses across the paracellular junctions to keep up electroneutrality. PCL, pericilary fluid; ASL, airway surface fluid; ALF, alveolar lining fluid; AEC, airway epithelial cell. In utero, fetal lung epithelial cells also secrete Cl? by mechanisms much like those of airway epithelial cells. The vectorial transport of NaCl produces an osmotic gradient, which contributes to fetal Radicicol lung fluid formation, which fills the bronchial and alveolar spaces. Shortly before birth, Cl? secretion ceases, and Na+ absorption is initiated through the upregulated amiloride-sensitive ENaCs (68, 78, 101) (Fig. 1). Disturbances of Na+ reabsorption and Cl? secretion may have significant effect in airway fluid homeostasis and may lead to alveolar edema or dehydrated PCL in the conducting airways, excessive mucus build up, and infections by opportunistic pathogens (2, 92, 106). We review fundamental mechanisms of ion transport across airway and alveolar lung epithelia and discuss how influenza disease infection (30) may lead to significant alterations in ion transport and fluid homeostasis across the airways and alveoli, which may contribute to the medical symptoms of influenza. Ion Transport Across Lung Epithelial Cells Early experiments shown that inhibition of the lung epithelial Na+/K+-ATPase with ouabain blocks all active cation and anion transport across lung epithelia. In addition, inhibition of ENaC by amiloride or its structural analogs, benzamil and phenamil, blocked a significant Radicicol portion of reabsorption of alveolar lung fluid, especially following injury to the alveolar epithelium (68C70, 114, 115). ENaC is definitely a highly selective unidirectional Na+ transporter, having a single-channel conductance of ~4C5 pS. It is composed of at least three subunits (, , and ) (7) and indicated in the apical membrane of epithelial cells; an additional subunit () has been identified in human being alveolar epithelial cells (45, 116). The alveolar epithelium makes up 99% of the respiratory surface area of the lung with alveolar type I (ATI) cells, accounting for ~95% of the alveolar space but only 30% of the total alveolar cells. ATII cells constitute the remaining 5% of the surface area (69) and may act as progenitor cells that form Rabbit polyclonal to HYAL2 a new epithelial surface following injury to ATI cells (50, 74) (Fig. 1). Originally, it Radicicol was thought that ion transport occurred only across ATII cells. However, the studies of Johnson et al. (47) and Lazrak et al. (55) showed that rodent ATI and ATII cells communicate similar channel densities of Radicicol highly selective Na+ channels, having a unitary conductance of ~4 pS, most likely composed of the -, -, -ENaC subunits, and nonselective ENaC cation channels, having a conductance of 16C21 pS, composed of -subunits only (42). It has also been reported the nonselective channels consist of a combination of the -ENaC subunit and one or more acid-sensing ion channel 1 (ASIC1a) proteins (103). Human being alveolar cells also communicate ENaC (23) and actively transport Na+, albeit at rates lower than in rodent lungs (89). ENaCs symbolize the rate-limiting step in Na+ absorption as only a small fraction of the basolateral Na+/K+-ATPase activity necessary for normal Na+ transport across the Radicicol alveolar epithelium; indeed, mice having a 50% decrease in Na+/K+-ATPase.