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The role of cystic fibrosis transmembrane conductance regulator chloride channel in -receptor-mediated regulation of alveolar fluid clearance

Luton and Dunstable Hospital National Health Service Foundation Trust, Luton, Bedfordshire, United Kingdom

TO THE EDITOR: A recent study (6) reported on an association of genetically determined reduced -receptor function with increased pulmonary fluid accumulation after fluid challenge with rapid normal saline infusion in healthy human volunteers. The authors emphasized that key pathways by which -receptors can prevent excessive accumulation of fluid in the lungs increase the number and activity of epithelial sodium channels (ENaC) and Na-K-ATPase. A recent study on changes in epithelial ion transport in children with septicemia-induced pulmonary edema revealed that severity of respiratory compromise (ventilation index) and duration of ventilation were more closely related to parameters reflecting systemic epithelial chloride rather than sodium transport in airways, sweat, and salivary gland (1). The authors of the present study referred to a study demonstrating increased airway liquid in patients with congenital ENaC inactivation (pseudohypoaldosteronism). This study however did not demonstrate increased alveolar fluid in these patients. A previous study challenging mice homozygous for a mutation inactivating the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel with a fluid overload with normal saline found an increase in alveolar liquid (3). CFTR has recently been found to contribute independently to fluid transport in alveolar epithelial type II cells in vitro (4). CFTR is activated by protein kinase A in a cAMP- and, therefore, -receptor-dependent way (2). CFTR activation by cAMP in alveolar epithelial cells has been shown to be a condition for apical sodium influx into alveolar epithelial cells through ENaC by hyperpolarization (5). The role of CFTR in -receptor-dependent alveolar fluid clearance may be equally or more important than the role of ENaC or Na-K-ATPase. Future studies could compare the response of airway epithelial sodium and chloride channels to -agonists in vivo as demonstrated previously (1) as an explanatory outcome to assess the effectiveness of -agonists in stimulation of chloride transport in patients with different -receptor genotype groups not only affecting receptor density but also receptor function.

FOOTNOTES

Address for reprint requests and other correspondence: M. Eisenhut, Luton & Dunstable Hospital NHS Foundation Trust, Lewsey Road, Luton, Bedfordshire, UK (e-mail: michael_eisenhut{at}yahoo.com)

REFERENCES

1. Eisenhut M, Wallace H, Barton P, Gaillard E, Newland P, Diver M, Southern KW. Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport. Ped Crit Care Med 7: 119–124, 2006.[CrossRef]
2. Eisenhut M. Changes in ion transport in inflammatory disease. J Inflammation (Lond) 3: 1–15, 2006.[CrossRef]
3. Fang X, Fukuda N, Barbry P, Sartori C, Verkman AS, Matthay MA. Novel role of CFTR in fluid absorption from the distal airspaces of the lung. J Gen Physiol 119: 199–207, 2002.[Abstract/Free Full Text]
4. Fang X, Song Y, Hirsch J, Galietta LJ, Pedemonte N, Zemans RL, Dolganov G, Verkman AS, Matthay MA. Contribution of CFTR to apical-basolateral fluid transport in cultured human alveolar epithelial type II cells. Am J Physiol Lung Cell Mol Physiol 290: 242–249, 2006.
5. O'Grady SM, Jiang X, Ingbar DH. Cl-channel activation is necessary for stimulation of Na transport in adult alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 278: L239–L244, 2000.[Abstract/Free Full Text]
6. Snyder EM, Beck KC, Turner ST, Hoffman EA, Joyner MJ, Johnson BD. Genetic variation of the ₂-adrenergic receptor is associated with differences in lung fluid accumulation in humans. J Appl Physiol 102: 2172–2178, 2007.

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