Osmolytes and ion transport modulators: new strategies for airway surface rehydration

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Mucociliary clearance (MCC) in CF lung disease is limited by airway dehydration, leading to persistent bacterial infection and inflammation in the airways. Agents designed to rehydrate the airway mucosa lead to improved MCC. Hyperosmolar agents, such as hypertonic saline and mannitol, create a luminal osmotic gradient, drawing water into the dehydrated ASL. Ion transport modulators function to activate alternative chloride channels and/or to block sodium hyperabsorption that occurs through a dysregulated ENaC channel. Combinations of these therapies may result in a synergistic improvement in airway hydration, and thus, restore MCC. Active ongoing phase II and III trials of new pharmacotherapeutics are covered in this review.

Introduction

The clearance of mucus from the airways of cystic fibrosis (CF) patients is reduced as a result of airway surface liquid (ASL) dehydration. Airway epithelial cells secrete or absorb liquid to maintain an appropriate ASL hydration (i.e. volume) and ensure efficient mucociliary clearance (MCC). The ability to regulate ASL volume depends on coordination of Na+ absorption and Cl secretion (Figure 1) [1•, 2]. In the CF airway epithelium, which lacks functional cystic fibrosis transmembrane regulator (CFTR), failure of Cl secretion and unchecked Na+ absorption produces dehydration of the ASL. As a result, airway dehydration leads to mucus adhesion, promoting persistent bacterial infection and inflammation in the CF airways.

From a therapeutic perspective, the goal of rehydrating agents is to re-establish the hydration state of the ASL and improve MCC rates. Rehydration should restore MCC by improving the periciliary layer lubricant function and mucus rheology [3]. Rehydration can be achieved via active or passive mechanisms. Inhaled hyperosmolar agents, such as hypertonic saline (HS) and mannitol, trigger diffusion of water down imposed osmotic gradients, increasing the water content in the ASL. Other agents, such as ion channel modulators, produce net fluid secretion by modulating apical membrane ion channels. These different rehydrating agents are the focus of this review.

Section snippets

Osmotic agents

Hyperosmolar agents achieve their effect of rehydrating ASL by drawing water from the interstitium into the ASL via imposed transepithelial osmotic gradients (Figure 2). Osmotic agents also may stimulate mucus clearance by increasing ciliary beat frequency and cough clearance [4] and stimulating mucin and lysozyme secretion (reviewed in Wills 2007) [3].

Ion transport regulators

The second approach to rehydrate airway surfaces is to re-direct the pattern of ion transport from an absorptive to a secretory direction. Several examples of this approach are in the clinical trial stage.

Purinergic (P2Y2) receptors are abundant on luminal surface of human bronchial epithelium (HBE) and are known to stimulate Cl secretion and inhibit Na+ absorption (Figure 3) [24••]. Studies have shown that agents that activate P2Y2 receptors increase ASL hydration. Early studies using

ENaC (epithelial sodium channel) inhibitors

Unrestrained ENaC-mediated hyperabsorption of sodium in the CF airways results from the lack of CFTR-dependent regulation of ENaC activity (Figure 3). Note, the biology of ENaC activation is complex as it has been demonstrated that channel activating proteases (CAPs) regulate ENaC activity in vivo and in vitro. Consequently, it is possible to inhibit ENaC activity directly with open channel blockers or indirectly by inhibiting CAP activities.

Even though no clinical benefit in CF patients with

Conclusions

Multiple drugs with different mechanisms of action exist to rehydrate the ASL, a central feature of the pathophysiology of CF lung disease. Importantly, the observation that multiple ‘rehydrating’ agents of different classes appear to be effective in the clinical setting suggests rehydration is a validated target in therapy of CF lung disease. Further studies are needed to investigate the combination of these therapies in the treatment of CF lung disease.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors would like to thank Lisa Brown for her assistance in the preparation of the figures. This work was supported by the NIH and Cystic Fibrosis Foundation.

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