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Communications to the Editor |

Manipulation of Volume vs Osmolality in Cystic Fibrosis Lung Disease Manipulation of Volume vs Osmolality in Cystic Fibrosis Lung Disease FREE TO VIEW

Shinji Teramoto, MD, FCCP; Takeshi Mastsue, MD; Yasuyoshi Ouchi, MD
Author and Funding Information

Affiliations: Tokyo University Hospital, Tokyo, Japan ,  Wake Forest University School of Medicine, Winston-Salem, NC

Correspondence to: Shinji Teramoto, MD, FCCP, Department of Geriatric Medicine, Tokyo University Hospital, 7-3-1 Hongo Bunkyo-ku Tokyo 113-8655, Japan; e-mail: shinjit-tky@umn.ac.jp



Chest. 1999;116(5):1494-1495. doi:10.1378/chest.116.5.1494-a
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Published online

To the Editor:

We appreciated the fine review article by Rubin et al (April 1999)1concerning a therapeutic strategy for cystic fibrosis (CF) lung disease. Defensins are broad-spectrum antimicrobial peptide products of neutrophils (α-defensins)2and epithelia (β-defensins).34 Because the chronic airway infection caused by Pseudomonas aeruginosa is the major source of pathogenesis of lung disease in CF, the killing of bacteria by human defensins produced by the airway epithelium in airway surface liquid (ASL) may be of clinical and pathologic importance in CF patients. It has been reported that healthy airway epithelia express two β-defensins, HBD-1 and HBD-2.,34 Both HBDs can be detected in BAL fluid.56 However, the antimicrobial activities of both HBDs were known to be inhibited by NaCl. The key issue concerning the antimicrobial action of HBDs may be the composition and osmolality of ASL.7Smith and coworkers8demonstrated that normal airways reabsorb excessive salt in the water from the ASL, thus producing a sufficiently low level of NaCl (≤ 50 mM) to activate defensins; but that salt is poorly absorbed in CF airways, resulting in excessively salty ASL that disrupts the bacterial killing activities of HBDs. However, this “hypertonic ASL in CF airways” hypothesis recently has been challenged by a “low, but isotonic volume of ASL in CF airways” hypothesis.9 Matsui et al9 have demonstrated that airways absorb salt and water isotonically, adjusting the volume and height of the ASL components to maintain efficient mucous clearance. Several investigators also have reported that the ASL is isotonic rather than hypotonic in both normal subjects and in pediatric and adult patients with CF.1012 The“ isotonic but low volume of ASL in CF airways” hypothesis may be in agreement with the earliest hypotheses to explain CF lung disease (the“ thick mucous” hypothesis1314; however, the major problem with it is that the layer of ASL is too thin to allow collection of a sufficient volume for reliable analysis of the composition.14 Further investigation of difference in regulation of the depth and composition of ASL between CF patients and healthy subjects may be important for the therapeutic strategy of CF lung disease.

Rubin, BK, Hiemstra, PS, van Wetering, S, et al (1999) Emerging therapies for cystic fibrosis lung disease.Chest115,1120-1126. [CrossRef]
 
Ashitani, J, Mukae, H, Nakazato, M, et al Elevated concentrations of defensins in bronchoalveolar lavage fluid in diffuse panbronchiolitis.Eur Respir J1998;11,104-111. [CrossRef]
 
Goldman, MJ, Anderson, GM, Stolzenberg, ED, et al Human β-defensin-1 is a salt sensitive antibiotic in lung that is inactivated in cystic fibrosis.Cell1997;88,553-560. [CrossRef]
 
Bals, R, Wang, BR, Wu, Z, et al Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung.J Clin Invest1998;102,874-880. [CrossRef]
 
Singh, PK, Jia, HP, Wiles, K, et al Production of beta-defensins by human airway epithelia.Proc Natl Acad Sci USA1998;95,14961-14966. [CrossRef]
 
Schnapp, D, Harris, A Antibacterial peptides in bronchoalveolar lavage fluid.Am J Respir Mol Cell Biol1998;19,352-356. [CrossRef]
 
Wine, JJ The genesis of cystic fibrosis lung disease.J Clin Invest1999;103,309-312. [CrossRef]
 
Smith, JJ, Travis, SM, Greenberg, EP, et al Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid.Cell1996;85,229-236. [CrossRef]
 
Matsui, H, Grubb, BR, Tarran, R, et al Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airway disease.Cell1998;95,1005-1015. [CrossRef]
 
Farinas, J, Kneen, M, Moore, M, et al Plasma membrane water permeability of cultured cells and epithelia measured by light microscopy with spacial filtering.J Gen Physiol1997;110,283-296. [CrossRef]
 
Hull, J, Skinner, W, Robertson, C, et al Elemental content of airway surface liquid from infants with cystic fibrosis.Am J Respir Crit Care Med1998;157,10-14. [CrossRef]
 
Knowles, MR, Robinson, JM, Wood, RE, et al Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects.J Clin Invest1997;100,2588-2595. [CrossRef]
 
Jiang, C, Finkbeiner, WE, Widdicombe, JH, et al Altered fluid transport across airway epithelium in cystic fibrosis.Science1993;262,424-427. [CrossRef]
 
Boucher, RC Human airway ion transport: part 2.Am J Respir Crit Care Med1994;150,581-593. [CrossRef]
 

Manipulation of Volume vs Osmolality in Cystic Fibrosis Lung Disease

To the Editor:

Teramoto et al make some important points regarding my article (April 1999).1 It is tempting to hypothesize that chronic airway infection and inflammation and the abnormality in chloride transport resulting from mutations in the cystic fibrosis transmembrane (conductance) regulator protein are, in cystic fibrosis, related either through the inactivation of innate antimicrobial defense systems or by an alterion of the depth of the periciliary fluid layer, thus affecting the interaction between mucus and cilia. To date, there are few data to support either of these hypotheses.

It has been established that the sputum of patients with cystic fibrosis has neither abnormal viscoelasticity nor abnormal salt content when compared to sputum from patients with other chronic lung diseases. Because of the difficulty in directly sampling the periciliary fluid layer, the volume and composition of this layer remain controversial. Although it is theoretically possible that hyperosmolar airway surface fluid could inactivate tracheal antibacterial peptides (defensins), it is unlikely that inactivation of this one part of the airway defense system would lead to such catastrophic and ongoing airway infection as is seen in patients with cystic fibrosis.

Abnormalities in periciliary fluid depth would be expected to reduce mucociliary clearance. However, patients with primary ciliary dyskinesia who have congenitally dysfunctional mucociliary clearance do not develop the severe lung disease that is characteristic of those with cystic fibrosis.

Understanding the regulation of the composition of the periciliary fluid layer in health and disease is certain to provide us with important insights. Unfortunately, this understanding may not answer the vexing problem of the link between cystic fibrosis transmembrane (conductance) regulator dysfunction and lung disease in cystic fibrosis.

References
Rubin, BK, Hiemstra, PS, van Wetering, S, et al Emerging therapies for cystic fibrosis lung disease.Chest1999;115,1120-1126. [CrossRef]
 

Figures

Tables

References

Rubin, BK, Hiemstra, PS, van Wetering, S, et al (1999) Emerging therapies for cystic fibrosis lung disease.Chest115,1120-1126. [CrossRef]
 
Ashitani, J, Mukae, H, Nakazato, M, et al Elevated concentrations of defensins in bronchoalveolar lavage fluid in diffuse panbronchiolitis.Eur Respir J1998;11,104-111. [CrossRef]
 
Goldman, MJ, Anderson, GM, Stolzenberg, ED, et al Human β-defensin-1 is a salt sensitive antibiotic in lung that is inactivated in cystic fibrosis.Cell1997;88,553-560. [CrossRef]
 
Bals, R, Wang, BR, Wu, Z, et al Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung.J Clin Invest1998;102,874-880. [CrossRef]
 
Singh, PK, Jia, HP, Wiles, K, et al Production of beta-defensins by human airway epithelia.Proc Natl Acad Sci USA1998;95,14961-14966. [CrossRef]
 
Schnapp, D, Harris, A Antibacterial peptides in bronchoalveolar lavage fluid.Am J Respir Mol Cell Biol1998;19,352-356. [CrossRef]
 
Wine, JJ The genesis of cystic fibrosis lung disease.J Clin Invest1999;103,309-312. [CrossRef]
 
Smith, JJ, Travis, SM, Greenberg, EP, et al Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid.Cell1996;85,229-236. [CrossRef]
 
Matsui, H, Grubb, BR, Tarran, R, et al Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airway disease.Cell1998;95,1005-1015. [CrossRef]
 
Farinas, J, Kneen, M, Moore, M, et al Plasma membrane water permeability of cultured cells and epithelia measured by light microscopy with spacial filtering.J Gen Physiol1997;110,283-296. [CrossRef]
 
Hull, J, Skinner, W, Robertson, C, et al Elemental content of airway surface liquid from infants with cystic fibrosis.Am J Respir Crit Care Med1998;157,10-14. [CrossRef]
 
Knowles, MR, Robinson, JM, Wood, RE, et al Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects.J Clin Invest1997;100,2588-2595. [CrossRef]
 
Jiang, C, Finkbeiner, WE, Widdicombe, JH, et al Altered fluid transport across airway epithelium in cystic fibrosis.Science1993;262,424-427. [CrossRef]
 
Boucher, RC Human airway ion transport: part 2.Am J Respir Crit Care Med1994;150,581-593. [CrossRef]
 
Rubin, BK, Hiemstra, PS, van Wetering, S, et al Emerging therapies for cystic fibrosis lung disease.Chest1999;115,1120-1126. [CrossRef]
 
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