Interleukin-1 Decreases Expression of the Epithelial Sodium Channel -Subunit in Alveolar Epithelial Cells via a p38 MAPK-dependent Signaling Pathway*□S

Acute lung injury (ALI) is a devastating syndrome characterized by diffuse alveolar damage, elevated airspace levels of pro-inflammatory cytokines, and flooding of the alveolar spaces with protein-rich edema fluid. Interleukin-1 (IL-1 ) is one of the most biologically active cytokines in the distal airspaces of patients with ALI. IL-1 has been shown to increase lung epithelial and endothelial permeability. In this study, we hypothesized that IL-1 would decrease vectorial ion and water transport across the distal lung epithelium. Therefore, we measured the effects of IL-1 on transepithelial current, resistance, and sodium transport in primary cultures of alveolar epithelial type II (ATII) cells. IL-1 significantly reduced the amiloride-sensitive fraction of the transepithelial current and sodium transport across rat ATII cell monolayers. Moreover, IL-1 decreased basal and dexamethasone-induced epithelial sodium channel -subunit ( ENaC) mRNA levels and total and cellsurface protein expression. The inhibitory effect of IL-1 on ENaC expression was mediated by the activation of p38 MAPK in both rat and human ATII cells and was independent of the activation of v 6 integrin and transforming growth factor. These results indicate that IL-1 may contribute to alveolar edema in ALI by reducing distal lung epithelial sodium absorption. This reduction in ion and water transport across the lung epithelium is in large part due to a decrease in ENaC expression through p38 MAPK-dependent inhibition of ENaC promoter activity and to an alteration in ENaC trafficking to the apical membrane of ATII cells.