In vitro and in vivo regulation of transepithelial lung alveolar sodium transport by serine proteases

Planès, Carole; Leyvraz, Céline; Uchida, Tatsuo; Angelova, Milena Apostolova; Vuagniaux, Grégoire; Hummler, Edith; Matthay, Michael A.; Clérici, Christine; Rossier, Bernard C.

doi:10.1152/ajplung.00332.2004

Cited by 73 publications

(93 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2A). After digestion with PNGase, both prostasin molecular species migrated faster, consistent with the previous reports of prostasin glycosylation (2,38,39,45). However, differential glycosylation does not account for the difference between the 37-and 40-kDa prostasin bands, because both molecular species were present following N-glycan digestion.…”

Section: Prostasin Is Expressed In a Nonpolarized Distribution But Onsupporting

confidence: 89%

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

Myerburg

McKenna²,

Luke³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Airway surface liquid (ASL) absorption is initiated by Na+ entry via epithelial Na+ channels (ENaC), which establishes an osmotic gradient that drives fluid from the luminal to serosal airway surface. We and others have recently reported that a protease/anti-protease balance regulates ENaC in human airway epithelial cells (HAEC) and provides a mechanism for autoregulation of ASL volume. In cystic fibrosis (CF), this balance is disturbed, leading to constitutive proteolytic activation of ENaC and the pathological Na+ hyperabsorption characteristic of this airway disease. Prostasin is a glycosylphosphatidylinositol-anchored serine protease that activates ENaC and is expressed on the surface epithelium lining the airway. In this report we present evidence that prostasin expression is regulated by the ASL volume, allowing for increased proteolytic activation of ENaC when the ASL volume is high. Prostasin activity is further regulated by the cognate serpin protease nexin-1 (PN-1), which is expressed in HAEC and inhibits Na+ absorption by forming an inactive complex with prostasin and preventing the proteolytic processing of prostasin. Whereas these mechanisms regulate prostasin expression in response to ASL volume in non-CF epithelia, HAEC cultured from CF patients express >50% more prostasin on the epithelial surface. These findings suggest that a proteolytic cascade involving prostasin, an upstream prostasin-activating protease, and PN-1 regulate Na+ absorption in the airway and that abnormal prostasin expression contributes to excessive proteolytic activation of ENaC in CF patients.

show abstract

Section: Prostasin Is Expressed In a Nonpolarized Distribution But Onsupporting

confidence: 89%

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

Myerburg

McKenna²,

Luke³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…EPI-hNE4 Does Not Inhibit Amiloride-sensitive Na ϩ Transport Induced by Co-injected Prostasin-Channel-activating proteases (CAPs) are membrane-bound serine proteases (12) known to be expressed and to regulate ENaC in the lung (13)(14)(15). To determine whether EPI-hNE4 was capable of inhibiting exogenously expressed membrane proteases, hENaC-injected oocytes were co-injected with human CAP-1 (prostasin) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of elastase by the specific inhibitor would have dual and synergistic effects on CF airways: blocking ENaC activity, thereby repleting PCL and improving mucociliary clearance, and blocking the effect of elastase on tissue inflammation and destruction. This inhibitor would have the advantage of not interfering with the physiological control of ENaC by endogenous lung serine proteases, such as prostasin or other membrane-bound serine proteases, expressed in airway epithelia (15).…”

Section: Elastase-induced Enac Activation and Cleavage At The Cell Sumentioning

confidence: 99%

See 1 more Smart Citation

A Novel Neutrophil Elastase Inhibitor Prevents Elastase Activation and Surface Cleavage of the Epithelial Sodium Channel Expressed in Xenopus laevis Oocytes

Harris

Firsov

Vuagniaux

et al. 2007

Journal of Biological Chemistry

Self Cite

116

View full text Add to dashboard Cite

The amiloride-sensitive epithelial sodium channel (ENaC) constitutes a limiting step in sodium reabsorption across distal airway epithelium and controlling mucociliary clearance. ENaC is activated by serine proteases secreted in the extracellular milieu. In cystic fibrosis lungs, high concentrations of secreted neutrophil elastase (NE) are observed. hNE could activate ENaC and contribute to further decreased mucociliary clearance. The aims of this study were (i) to test the ability of an engineered human neutrophil elastase inhibitor (EPI-hNE4) to specifically inhibit the elastase activation of ENaC-mediated amiloride-sensitive currents (I Na ) and (ii) to examine the effect of elastase on cell surface expression of ENaC and its cleavage pattern (exogenous proteolysis). Oocytes were exposed to hNE (10 -100 g/ml) and/or trypsin (10 g/ml) for 2-5 min in the presence or absence of EPI-hNE4 (0.7 M). hNE activated I Na 3.6-fold (p < 0.001) relative to non-treated hENaC-injected oocytes. EPI-hNE4 fully inhibited hNE-activated I Na but had no effect on trypsin-or prostasin-activated I Na . The co-activation of I Na by hNE and trypsin was not additive. Biotinylation experiments revealed that cell surface ␥ ENaC (but not ␣ or ␤ ENaC) exposed to hNE for 2 min was cleaved (as a 67-kDa fragment) and correlated with increased I Na . The elastase-induced exogenous proteolysis pattern is distinct from the endogenous proteolysis pattern induced upon preferential assembly, suggesting a causal relationship between ␥ ENaC cleavage and ENaC activation, taking place at the plasma membrane.

show abstract

“…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

View full text Add to dashboard Cite

-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.

show abstract

In vitro and in vivo regulation of transepithelial lung alveolar sodium transport by serine proteases

Abstract: . In vitro and in vivo regulation of transepithelial lung alveolar sodium transport by serine proteases.

Cited by 73 publications

References 40 publications

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

A Novel Neutrophil Elastase Inhibitor Prevents Elastase Activation and Surface Cleavage of the Epithelial Sodium Channel Expressed in Xenopus laevis Oocytes

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

Contact Info

Product

Resources

About