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

Abstract

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. Acute lung injury (ALI)1 is a devastating clinical syndrome manifested by diffuse alveolar damage, capillary injury, and disruption of the alveolar epithelium. The acute phase of ALI is characterized by the influx of protein-rich edema fluid that impairs gas exchange, causing arterial hypoxemia and respiratory failure with an overall mortality rate of 30 -40% (1). Along with an increase in lung endothelial and epithelial permeability to protein, this syndrome is associated with abnormal surfactant production and decreased vectorial fluid transport across the lung epithelial barrier (2, 3). A number of inflammatory mediators have been found to be elevated in the alveolar space during the early phase of ALI, including interleukin (IL)-1␤, tumor necrosis factor-␣, IL-6, and IL-8 (4). IL-1␤ is one of the most biologically active cytokines in pulmonary edema and bronchoalveolar lavage fluids of patients with ALI (4 -6). Indeed, IL-1␤ increases microvascular lung epithelial permeability in in vitro and in vivo models of ALI (7). IL-1␤ also enhances alveolar epithelial repair by increasing cell spreading (8) and fibroblast activation and proliferation (5). In contrast, the role of IL-1␤ in distal lung epithelial ion transport remains unclear. In other epithelia such as the colonic epithelium, IL-1␤ inhibits aldosterone-induced electrogenic sodium absorption and attenuates aldosterone-induced up-regulation of ␤-and ␥-subunit ...

Proteomic and Computational Analysis of Bronchoalveolar Proteins during the Course of the Acute Respiratory Distress Syndrome

“…Previous studies showed that TNF-a, IL-1b, IL-6, and LBP are present in the BALF of patients with ARDS and contribute to the pro-inflammatory environment (16)(17)(18)(19)(20). In addition, p38 MAPK has also been shown to regulate key physiologic responses, including neutrophil recruitment and clearance of edema fluid, during the development of lung injury (20)(21)(22)(23). The proteins that were added into the network were predominantly cytokines, intracellular signaling proteins, and transcription factors that exist in extremely low concentrations in the BALF.…”

Role of the pulmonary epithelium and inflammatory signals in acute lung injury

“…IL-1β expression augments neutrophil recruitment and also impairs fluid clearance via down-regulation of the epithelial sodium channel (ENaC) [94]. Early blockage of IL-1β is protective in a murine model of VILI, suggesting that IL-1β may be a potential target in ALI [92].…”

Initial interrogation, confirmation and fine mapping of modifying genes: STAT3, IL1B and IFNGR1 determine cystic fibrosis disease manifestation

“…Several cytokines have been identified to alter secretory properties of epithelial cells [48][49][50][51] resulting in altered ion and fluid transport upon activation of host defense pathways. This has been interpreted as an unspecific host response to pathogens as the surface liquid is increased on the epithelium upon induction of a hypersecretory state by inflammatory stimuli, 49 and consequently mucociliary clearance of the intruding pathogen will be alleviated.…”