Regulation of the epithelial Na+ channel and airway surface liquid volume by serine proteases

Abstract

Mammalian airways are protected from infection by a thin film of airway surface liquid (ASL) which covers airway epithelial surfaces and acts as a lubricant to keep mucus from adhering to the epithelial surface. Precise regulation of ASL volume is essential for efficient mucus clearance and too great a reduction in ASL volume causes mucus dehydration and mucus stasis which contributes to chronic airway infection. The epithelial Na + channel (ENaC) is the rate-limiting step that governs Na + absorption in the airways. Recent in vitro and in vivo data have demonstrated that ENaC is a critical determinant of ASL volume and hence mucus clearance. ENaC must be cleaved by either intracellular furin-type proteases or extracellular serine proteases to be active and conduct Na + , and this process can be inhibited by protease inhibitors. ENaC can be regulated by multiple pathways, and once proteolytically cleaved ENaC may then be inhibited by intracellular second messengers such as cAMP and PIP 2 . In the airways, however, regulation of ENaC by proteases seems to be the predominant mode of regulation since knockdown of either endogenous serine proteases such as prostasin, or inhibitors of ENaC proteolysis such as SPLUNC1, has large effects on ENaC activity in airway epithelia. In this review, we shall discuss how ENaC is proteolytically cleaved, how this © Springer-Verlag 2010Correspondence to: Robert Tarran, robert_tarran@med.unc.edu. NIH Public Access

CFTR: cystic fibrosis and beyond

“…At the same time, efforts are ongoing that focus on strategies for durable ENaC inhibition to improve efficacy in chronic CF airways disease. These efforts include: 1) the design of more potent and long-acting ENaC blockers [100,101]; 2) inhibition of ENaCactivating proteases [44,102]; 3) ENaC silencing with specific short interfering RNAs [103]; and 4) highcontent screens to identify novel ENaC regulators that may be druggable in CF lung disease [104]. Since ENaC is also expressed in the kidney, where it plays an important role in electrolyte balance, strategies are warranted that reduce systemic absorption of ENaC inhibitors effectively to prevent renal exposure and electrolyte imbalance including hyperkalaemia [105].…”

“…1) [47]. Therefore, an imbalance between NE and potentially other proteases released from inflammatory cells or bacteria on the one hand, and protective anti-proteases on the other hand [44], may inevitably aggravate airway surface dehydration and also impede therapeutic approaches targeting the basic ion transport defect in CF airways once chronic inflammation and infection are established.…”

“…For example, recent studies showed that neutrophil elastase (NE), a major product released from activated neutrophils that has recently been identified as a key risk factor for the development of bronchiectasis in young children with CF diagnosed by newborn screening [38], is also a potent regulator of CFTR and ENaC. Besides its previously described roles in the modulation of airway inflammation, mucus hypersecretion, bacterial killing, and proteolytic lung and immune cell damage [32,[39][40][41][42], NE can activate ENaC by proteolytic cleavage and removal of ''inhibitory'' segments, probably leading to a conformational change of the channel that improves its conductivity for Na + [43,44]. Interestingly, a recent study showed that wild-type CFTR, but not DF508, interacts with ENaC in the plasma membrane of airway epithelial cells and, thus, may impede the proteolytic stimulation of ENaC by NE and potentially other extracellular proteases released by inflammatory cells [45,46].…”

SPLUNC1 Is a Significant Marker in Pleural Effusion from Lung Cancer Compared to Tuberculosis

“…(17) SPLUNC1 has also been shown to have an anti-inflammatory function in exogenous microbe-induced respiratory infection, such as K. pneumoniae, (18) Mycoplasma pneumoniae, (19) P. aeruginosa, and Epstein-Barr virus. (20) Additionally, SPLUNC1 could also regulate ion/mucus transport and hydration levels in the lung, (21) lower surface tension by its surfactant-like properties, (22) and act as an inflammatory mediator. The earlier studies demonstrated that SPLUNC1 was associated with tumorigenesis.…”

Reduced Sodium Transport With Nasal Administration of the Prostasin Inhibitor Camostat in Subjects With Cystic Fibrosis

“…9 Prostasin, a trypsin-like serine protease, is a major channel-activating protease (CAP) of ENaC-mediated sodium currents in CF epithelia. [10][11][12][13][14] Attenuation of ENaC function by CAP inhibition is predicted to improve mucociliary clearance with potential downstream effects on pulmonary obstruction and clinical stability. Camostat is an inhibitor of prostasin that has been shown to inhibit ENaC function in vitro 15 and in vivo.…”