Affiliations: Tokyo University Hospital, Tokyo, Japan ,
Wake Forest University School of Medicine,
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: email@example.com
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).3–4 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.,3–4 Both HBDs can be
detected in BAL fluid.5–6 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.10–12 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” hypothesis13–14; 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
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
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
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