Defective respiratory amiloride‐sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice

Egli, Marc; Duplain, Hervé; Lepori, Mattia; Cook, Stéphane; Nicod, Pascal; Hummler, Edith; Sartori, Cláudio; Scherrer, Urs

doi:10.1113/jphysiol.2004.066704

Cited by 82 publications

(87 citation statements)

References 37 publications

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“…The physiological importance of α-ENaC in the lung has been demonstrated in a study of α-ENaC-knockout mice, where respiratory distress and mortality were observed ≤40 h after birth, as a consequence of an inability to clear fluid from the lungs (5). Furthermore, experimental evidence has indicated that a reduction in α-ENaC expression may impair the resolution of pulmonary edema in patients with ALI (6).…”

Section: Introductionmentioning

confidence: 99%

Biphasic modulation of α-ENaC expression by lipopolysaccharide in vitro and in vivo

Sheng

Nie

et al. 2014

Molecular Medicine Reports

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Abstract. Acute lung injury (ALI) is characterized by pulmonary edema, in which the epithelial sodium channel (ENaC) has a critical role in the clearance of edema fluid from the alveolar space. Lipopolysaccharide (LPS), frequently employed to induce ALI in experimental animal models, has been reported to regulate ENaC expression and alveolar fluid clearance. The role of LPS in regulating ENaC expression is currently controversial, with increases and decreases reported in ENaC expression in response to LPS treatment, as well as reports that ENaC expression is not affected by LPS induction. The present study aimed to systematically analyze the regulation of α-ENaC expression in LPS models of ALI at different pathological stages in vitro and in vivo. ENaC expression was observed to increase ≤8 h after LPS treatment, and to decrease thereafter. This finding may explain the contradictory data regarding α-ENaC expression in response to LPS in the lung. The results of the present study, in combination with those of previous studies, indicate that the modulation of α-ENaC expression may not be a direct genetic response to LPS exposure, but a general response of the lung to the pathological changes associated with inflammation, hypoxia and endothelial and epithelial damage involved in the development of ALI. The findings of this study may have potential clinical significance for understanding the pathogenesis of ALI and improving patient outcome. IntroductionAcute lung injury (ALI) is a clinical syndrome characterized by pulmonary edema and associated with a high mortality rate (1).The pathogenesis of ALI is poorly understood; however, clinical studies have demonstrated that the regulation of epithelial sodium channel (ENaC)-mediated alveolar fluid clearance may represent an effective treatment strategy to improve the outcome for patients with ALI (2,3). ENaC is composed of three homologous subunits, α, β and γ (4). The α subunit is essential for the functional transport of Na + and H 2 O out of the airway lumen. The physiological importance of α-ENaC in the lung has been demonstrated in a study of α-ENaC-knockout mice, where respiratory distress and mortality were observed ≤40 h after birth, as a consequence of an inability to clear fluid from the lungs (5). Furthermore, experimental evidence has indicated that a reduction in α-ENaC expression may impair the resolution of pulmonary edema in patients with ALI (6).To investigate the molecular mechanisms associated with ALI, a variety of experimental models have been used. The induction of lung injury using intra-tracheal administration of lipopolysaccharide (LPS) has represented a useful model for studying ALI, as it avoids multi-organ failure (7). LPS is a prototypical endotoxin that is a key component of the outer membrane of gram-negative bacteria, including Pseudomonas aeruginosa. LPS has been demonstrated to modify Na + transport in the airway epithelium by regulating either ENaC mRNA expression (8) or the ENaC channel current (9). The effect of LPS on α-ENaC express...

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Section: Introductionmentioning

confidence: 99%

Biphasic modulation of α-ENaC expression by lipopolysaccharide in vitro and in vivo

Sheng

Nie

et al. 2014

Molecular Medicine Reports

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“…Rescuing ␣ENaC (Ϫ/Ϫ) KO by ␣ENaC expression driven by the cytomegalovirus promoter leads to viable mice but with reduced ENaC expression in the kidney, colon, and lung (37,61). These mice present increased lung edema and diminished lung liquid clearance in lung injury produced by thiourea or hyperoxia (22). In humans, respiratory distress syndrome has been reported in premature babies with type 1 pseudohypoaldosteronism, a rare genetic disease where ENaC is defective (1,53).…”

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confidence: 99%

Dexamethasone inhibits the action of TNF on ENaC expression and activity

Dagenais

Fréchette²,

Clermont³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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We have reported that TNF, a proinflammatory cytokine present in several lung pathologies, decreases the expression and activity of the epithelial Na+channel (ENaC) by ∼70% in alveolar epithelial cells. Because dexamethasone has been shown to upregulate ENaC mRNA expression and is well known to downregulate proinflammatory genes, we tested if it could alleviate the effect of TNF on ENaC expression and activity. In cotreatment with TNF, we found that dexamethasone reversed the inhibitory effect of TNF and upregulated α, β, and γENaC mRNA expression. When the cells were pretreated for 24 h with TNF before cotreatment, dexamethasone was still able to increase αENaC mRNA expression to 1.8-fold above control values. However, in these conditions, β and γENaC mRNA expression was reduced to 47% and 14%, respectively. The potential role of TNF and dexamethasone on αENaC promoter activity was tested in A549 alveolar epithelial cells. TNF decreased luciferase (Luc) expression by ∼25% in these cells, indicating that the strong diminution of αENaC mRNA must be related to posttranscriptional events. Dexamethasone raised Luc expression by fivefold in the cells and augmented promoter activity by 2.77-fold in cotreatment with TNF. In addition to its effect on αENaC gene expression, dexamethasone was able to maintain amiloride-sensitive current as well as the liquid clearance abilities of TNF-treated cells within the normal range. All these results suggest that dexamethasone alleviates the downregulation of ENaC expression and activity in TNF-treated alveolar epithelial cells.

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“…PQ uptake is significantly prevented when extracellular sodium is reduced (Dinis-Oliveira et al, 2006). The amiloride-sensitive cation channel is a major sodium channel, and Na + /K + -ATPase is important for its activation (Dada and Sznajder, 2003;Eaton et al, 2004;Egli et al, 2004;Folkesson and Matthay, 2006;Kemp and Kim, 2004;Planès, et al, 2005;Matalon et al, 2002), as are potassium channels (O'Grady and Lee, 2003). The gene expression alterations of the Na + /Cl − -dependent neurotransmitter transporter gene, Slc17a1, Kcne1, Kcna1, Kcna4, Scn4a, Scn2b, Atp1a2, Accn2, and Accn3 could indicate changes in these functions.…”

Section: Discussionmentioning

confidence: 99%

Novel and Extensive Aspects of Paraquat-Induced Pulmonary Fibrogenesis: Comparative and Time-Course Microarray Analyses in Fibrogenic and Non-Fibrogenic Rats

et al. 2007

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-Although paraquat (PQ) is widely known to induce pulmonary fibrosis, the molecular mechanisms are poorly understood. Therefore, to bring a new dimension to the elucidation of the mechanisms, we conducted microarray experiments to investigate the expression profiles of 1,090 genes in the lungs during the progressive phase of PQ-induced pulmonary fibrosis in rats. After several s.c. injections of PQ, rats were divided into a fibrogenic group and a non-fibrogenic group. Time-course gene expression analysis of the fibrogenic group showed altered gene regulation throughout the experimental period. The expression levels of many cell membrane channel, transporter, and receptor genes were substantially altered. These genes were classified into two categories: polyamine transporter-and electrolyte/fluid balance-related genes. Moreover, comparative analysis of the fibrogenic and the non-fibrogenic group revealed 36 genes with significantly different patterns of expression, including the pro-apoptotic gene Bad. This indicates that Bad is a key factor in apoptosis and that apoptosis provides a major turning point in PQ-induced pulmonary fibrosis. Notably, subtypes of transforming growth factor (TGF)-β genes that are considered to play a pivotal role in fibrogenesis showed no differences in expression between the two groups, though TGF-β3 was markedly induced in both groups. These results provide novel and extensive insights into the molecular mechanisms that lead to pulmonary fibrosis after exposure to PQ.

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Defective respiratory amiloride‐sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice

Cited by 82 publications

References 37 publications

Biphasic modulation of α-ENaC expression by lipopolysaccharide in vitro and in vivo

Biphasic modulation of α-ENaC expression by lipopolysaccharide in vitro and in vivo

Dexamethasone inhibits the action of TNF on ENaC expression and activity

Novel and Extensive Aspects of Paraquat-Induced Pulmonary Fibrogenesis: Comparative and Time-Course Microarray Analyses in Fibrogenic and Non-Fibrogenic Rats

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