Regulation and Functional Significance

Raymond D Coakley, Richard C Boucher
The Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at
Chapel Hill. Chapel Hill, North Carolina, USA
Summary
In gastrointestinal tissues, cumulative evidence
from both in vivo and in vitro studies suggests a
role for the cystic fibrosis transmembrane
conductance regulator (CFTR) in apical
epithelial bicarbonate conductance. Abnormal
lumenal acidification is thus hypothesized to
play a role in the genesis of cystic fibrosis (CF)
pancreatic disease. However, consensus
regarding CFTR's participation in pH regulation
of airway surface liquid (ASL) and thus the
contribution of ASL pH to the etiology of CF
lung disease, is lacking. The absence of data
reflects difficulties in both sampling ASL in
vivo and modeling ASL biology in vitro. Here
we evaluate the evidence in support of a
lumenal acidification hypothesis in the CF lung,
summarize current knowledge of pH regulation
in the normal airway and illustrate how hyper-
acidified airway secretions could contribute to
the pathogenesis of CF lung disease.
Cystic fibrosis (CF) is a fatal hereditary disease
resulting from lack of functional expression of
the cystic fibrosis transmembrane conductance
regulator (CFTR) in the apical membrane of
epithelial cells [1, 2]. Lung disease in CF is
characterized by unremitting pulmonary
obstruction, infection and inflammation,
accounting for 90% of the mortality and
morbidity ascribed to the condition. Though it
has been known for almost a decade that CFTR
mediates an adenosine 3',5'-monophosphate
(cyclic AMP)-regulated apical chloride
conductance [3], a universally accepted
paradigm linking abnormal vectorial ion
transport to the complex manifestations of CF
lung disease is currently lacking. Though
current models of CF pathogenesis explain
many aspects of its etiology [4], additional
mechanisms of disease induction are also likely
to be important. In this regard, accumulating
evidence suggests that defective HCO3
-
transport may be pathophysiologically relevant.
A lumenal acidification hypothesis in CF has its
roots in in vivo studies that date back more than
30 years. They demonstrated that pancreatic
secretions from CF patients are acidic when
compared to those of their normal counterparts
[5, 6]. The more recent description of
abnormally acidic seminal fluid from male
patients with CFTR mutations lends further
weight to this postulate [7]. Indeed, these in
vivo studies have a resonance with the in vitro
literature, which suggests that a CF lumenal pH
defect may reflect abnormal HCO3
-
permeation
through CFTR into the epithelial lumen. The
relative bicarbonate:chloride conductance of
CFTR in vitro appears to range from 0.1-0.27
[8, 9, 10]. CFTR has also been proposed to
regulate lumenal bicarbonate secretion in the
gut by facilitating a molecularly distinct apical
anion exchanger (AE) [11]. The
pathophysiological relevance of CFTR-

Page 2
JOP. J. Pancreas (Online) 2001; 2(4 Suppl):294-300.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol.2, No.4 Suppl. – July 2001
295
dependent HCO3
-
secretion is further
emphasized by a recent report that a pancreatic
insufficient phenotype is associated with
properly processed, mutated CFTR that
normally conducts chloride but exhibits fully
defective HCO3
-
conductance, whereas mutants
with even partial HCO3
-
-transport result in a
normal clinical phenotype [12].
However, the pancreas and male urogenital
tract exhibit specialized HCO3
-
-transport
properties, and may differ in this regard from
airway tissues. Although there is an evolving
consensus that the defect of CFTR-dependent
bicarbonate secretion plays a role in the
etiology of CF pancreatic disease, consensus
regarding CFTR's participation in airway
surface liquid (ASL) pH (pHASL) regulation
(and thus its potential role in contributing to
lung disease) is lacking. Indeed, difficulties
sampling ASL in vivo and reproducing ASL
biology in vitro
have hindered our
understanding of many aspects of ASL pH
regulatory physiology and thus impeded
rigorous testing of the acidification hypothesis
in pulmonary epithelia.
Earlier studies of cultured human airway
epithelial cells (mounted in Ussing chambers),
support the presence of a CFTR-dependent
apical HCO3
-
conductance [13, 14]. However,
since these studies were necessarily carried out
under Cl
-
-free conditions, they cannot easily be
extrapolated
to
more
physiological
circumstances. More compelling are reports
suggesting that raising intracellular cAMP, in
cultured normal nasal respiratory epithelium
and Calu-3 cells, results in alkalinization of
culture surface liquid [15, 16]. However, since
similar experimental maneuvers were not
performed in CFTR-deficient tissues, this
alkalinization cannot confidently be ascribed to
CFTR activation. Thus, though provocative,
available studies in the literature fall short of
demonstrating that lack of CFTR causes
dysregulation of pHASL
on CF pulmonary
epithelium. This is a particularly important
distinction, since even if airway epithelial
CFTR indeed conducts HCO3
-
under
physiological conditions, it presumably acts in
concert with other pHASL modulatory processes,
whose activity may either overwhelm CFTR or,
alternatively, be altered in CF tissues, to
compensate for CFTR's absence. Recent in vivo
measurements of tracheal surface liquid failed
to reveal a significant pH difference in normal
and CFTR knockout mice [17]. Although these
findings are provocative, and underscore the
need for further clarification of CFTR's role in
pHASL regulation, they must be interpreted with
caution. The normal murine trachea exhibits
low levels of CFTR expression [18], and the CF
knockout mouse does not exhibit a pulmonary
phenotype, making extrapolation of these data
to the human situation problematic. Moreover,
since the activity of CFTR as a regulator of
ASL pH may vary under different physiological
and pathological situations, even human in vivo
measurements under basal conditions may not
illuminate CFTR's full role in this process.
To date, we have lacked a sufficiently
sophisticated understanding of normal pHASL
regulation to resolve these important issues. We
can claim a rudimentary knowledge of other pH
regulatory processes on the apical membrane of
airway epithelia. For example, we, and others
have not detected evidence of a Na
+
/H
+
exchanger in the apical membrane of
pulmonary epithelia [19, 20]. However, there
are suggestions that a K
+
H
+
ATPase, which
exchanges lumenal K
+
for cytosolic protons,
may acidify surface liquid. Though the
presence of this ATPase in nasal airway tissue
has been previously suggested [15], its
molecular identification and functional role in
regulation of pHASL by airway cells had not
been conclusively demonstrated. However, we
recently reported (in preliminary abstract form),
that cultured human bronchial epithelium (in
both normal and CF tissues) expresses
K
+
H
+
ATPase at a molecular and functional
level [21, 22]. In addition, the paracellular
shunt could contribute to pHASL regulation.
This poorly characterized pathway potentially

Page 3
JOP. J. Pancreas (Online) 2001; 2(4 Suppl):294-300.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol.2, No.4 Suppl. – July 2001
296
provides an alternative route for transepithelial
ion transport, including movement of H
+
and
HCO3
-
ions, though its conductivity for these
species has not been characterized. Indeed, if
CFTR is the sole path of bicarbonate
translocation across the apical membrane of
pulmonary epithelial cells, as might be
suspected, the paracellular pathway could be
the only mode of alkalinizing CF ASL if it
becomes acidified during inflammation,
infection or following aspiration of gastric
contents. However, it is also possible that a
'calcium-activated chloride conductance'
(CaCC) channel may also conduct bicarbonate
and provide another potential route by which
HCO3
-
could be transported into ASL. CaCC
had been reported to compensate for the
absence of CFTR in mediating HCO3
-
secretion
in CF pancreatic tissue [23] and murine
gallbladder [24]. CaCC has been identified in
human pulmonary epithelium, though its role in
pH regulation in ASL is uncertain. Its
prototypical agonists are short-lived
nucleotides, and its responses rapidly down-
regulated, arguing against a role in eliciting
sustained alterations in ASL pH. The capacity
of CaCC to regulate pHASL in CF airways thus
merits further attention. Anion exchangers are
also known to contribute to HCO3
-
secretion in
the gut. However, AEs have not, to date, been
identified at a functional or molecular level in
the apical membrane of airway cells. Similarly,
there are no reports documenting the presence
of proton translocating ATPases or ZnCl2-
sensitive passive proton conductance channels
at the same site. Further detailed in vitro studies
are necessary to resolve these issues. In
considering such experiments, it must be borne
in mind, however, that measurements of pH in
'bulk liquid' upon the culture surface may not
reflect the near-membrane pH. Appreciable pH
differences may be manifest across unstirred
layers as a result of concentration polarization
of unionized species either in liquid upon
cultured epithelia or conceivably even in the
thin ASL layer in vivo [25]. pHASL close to the
apical membrane may also be affected by the
presence therein of impermeant buffers, as is
likely to be the case due to the presence of the
glycocalyx, a feature of the apical surface of
airway epithelia [26]. Thus, differences in
pHASL
at the apical membrane could,
conceivably, be even greater, and studies
formally addressing gradients of pH in
individual compartments of ASL are necessary.
Such studies are mandated because the mucous
layer may also act as a diffusion barrier to acid
(as it does in the stomach) and thus modulate
pHASL [27]. Figure 1 models what we feel to be
the most likely scenario for movement of H
+
and HCO3
-
across the apical membrane of
normal and CF airway epithelium.
If absence of functional CFTR-dependent
epithelial HCO3
-
transport renders ASL
abnormally acidic, how might altered airway
surface liquid pH impinge on host defense
processes? Despite its shallow depth (about 5-
40 µM), ASL is a critical determinant of airway
epithelial defense. The efficient killing and
Figure 1. Schematic representation of hypothesized
pHASL
regulatory mechanisms in normal and CF
bronchial epithelium.
Regulation of pHASL
on normal cultured bronchial
epithelium may reflect the acidifying effects of a
K+H+ATPase opposed by bicarbonate/Hentry/exit into
ASL via the paracellular pathway and a cAMP activated
CFTR-dependent mechanism, in addition, potentially, to
calcium-activated chloride conductance channels. In CF,
however, only apically directed paracellular bicarbonate
(+/-CaCC) movement opposes K+H+ATPase function
and ASL (which is reduced in volume compared to
normals) becomes correspondingly more acidic.
K+
H+
Normal-(↑↑ pH)
CF-(↓↓ pH)
+
H+
HC03
-
CFTR
CFTR
HC03
-
HC03
-
K+H+
ATPase
Apical
Basolateral
HC03
-
K+H+
ATPase
ASL
+
+
CaCC
CaCC
HC03
-
?HC03
-

Page 4
JOP. J. Pancreas (Online) 2001; 2(4 Suppl):294-300.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol.2, No.4 Suppl. – July 2001
297
removal of microorganisms in ASL result from
the concerted action of a many independent
biological processes. Since so many of these
processes are pH dependent, the importance of
tightly regulated proton concentrations in ASL
is obvious. It was correctly noted recently that
this is a neglected area of epithelial biological
and, in particular, CF research [28].
Hyper-acidified ASL is predicted to negatively
impact upon the rheological properties of
mucus [29]. The polymeric gel (and thus
viscoelastic) properties of the mucus layer of
ASL are determined by hydration of mucin
molecules and their interactions [30]. pH not
only determines the degree to which the
hydrophobic regions of the protein component
of the mucin molecule are exposed, influencing
non-covalent mucin-mucin interactions [31],
but [H
+
] is a determinant of net charge of
sulphated and sialated carbohydrate sidechains
of the molecule ( which have a net neutral pKa)
and, consequently, its hydration state [32].
Reducing pH will diminish the electrostatic
repulsive forces between mucins and increase
ASL viscosity. In addition to promoting the gel
transition of mucins already integrated into the
mucus layer, more acidic ASL may also
adversely affect the initial hydration of freshly-
exocytosed mucins and, in this regard, the near
membrane pH is likely to be critical. The
effects of low ASL pH in CF may be even more
undesirable, since the prediction is that low pH
will also promote interactions between mobile
gel forming mucins and membrane surface
tethered mucins, likely attenuating cough-
clearance of mucous plaques [33]. This
situation may be compounded by low pHASL in
CF, since it has recently been suggested that
acidic lumenal pH increases ENaC activity
[34], which may exacerbate hyperabsorption of
apical liquid, already a putative hall mark of CF
epithelia, and diminish the solvent volume for
mucins therein.
Inability to normally regulate ASL pH may
compromise the function of airway immune
cells and thereby promote lung damage in CF.
An early and persistent inflammatory cell influx
into the airway lumen of CF patients is
characteristic of the condition [35].
Perplexingly, there is a failure to kill resident
bacteria therein. Instead, immune cell-derived
proteases and oxidants contribute to progressive
pulmonary parenchymal destruction typical of
CF [36, 37, 38]. An acidic extracellular pH has
been shown to suppress intracellular oxidant
generation, a key component of the
polymorphonuclear
leucocytes
(PMNs)
bacteriacidal armamentarium, while increasing
release of H2O2
into the extracellular
compartment, in a manner likely to accelerate
host damage [39]. Moreover, extracellular
acidification increases the release of neutrophil
azurophil granule contents [40] that include
myeloperoxidase, which generates long-lived
toxic oxidant species, and neutrophil elastase, a
broad spectrum and potent protease with the
propensity to permanently degrade pulmonary
connective tissues. Extracellular acidification is
not only chemotactic for neutrophils but also
inhibits their apoptotic involution and thereby
potentially prolongs the life span of ineffective
and thus potentially harmful cells on the airway
surface.
Finally abnormally low pH of CF ASL may
facilitate bacterial survival in the airway lumen.
Phagocytic cells are less efficient at ingesting
and killing bacteria at lower extracellular pH
[41, 42]. In addition, pseudomonas aeruginosa,
the organism most typically associated with CF,
carries a net negative surface charge. In this
context, lowering the pH may eliminate
electrostatic repulsive charges between
organisms and facilitates "tighter" biofilm
formation, potentially hindering ease of access
of immune cells to the organism [43]. In
addition, electrorepulsive forces between
bacteria and negatively charged mucins and
glycocalyceal proteins may be similarly
reduced at low pH, altering bacterial interaction
with mucins and the cell surface. Clearance of
bacteria may also be sub-optimal at low pH
since ciliary beat frequency in bronchial

Page 5
JOP. J. Pancreas (Online) 2001; 2(4 Suppl):294-300.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol.2, No.4 Suppl. – July 2001
298
epithelium is reduced when external pH falls
[44]. These processes are modeled in Figure 2.
Therefore, ASL pH appears likely to play an
important role in the modulation of key
biological processes implicated in normal lung
host defense. Since, in addition, it may be
abnormal in CF patients, future investigations,
utilizing both in vitro and in vivo strategies, are
required to accurately define its mode of
regulation.
Key words Bicarbonates; Cystic Fibrosis
Transmembrane Conductance Regulator;
Epithelium; H(+)-K(+)-Exchanging ATPase;
Lung
Abbreviations AE: anion exchanger; AMP:
adenosine 3',5'-monophosphate; ASL: airway
surface liquid; CaCC: calcium activated
chloride conductance; CF: cystic fibrosis;
CFTR: cystic fibrosis transmembrane
conductance
regulator;
PMNs:
polymorphonuclear leucocytes
Correspondence
Richard C Boucher
Cystic Fibrosis/Pulmonary Research and
Treatment Center
Rm # 7011
Thurston-Bowles Building CB# 7248
University of North Carolina at Chapel Hill
Chapel Hill
North Carolina 27599-7248
USA
Phone: +1-919-966.1077
Fax: +1-919-966.7525
E-mail address: rboucher@med.unc.edu
Reference
1 Cheng SH, Gregory RJ, Marshall J, Paul S, Souza
DW, White GA, et al. Defective intracellular transport
and processing of CFTR is the molecular basis of most
cystic fibrosis. Cell 1990; 63:827-34.
2 Riordan JR, Rommens JM, Kerem B, Alon N,
Rozmahel R, Grzelczak Z, et al. Identification of the
cystic fibrosis gene: cloning and characterization of
complementary DNA Science 1989; 245:1066-73.
3 Kartner N, Hanrahan JW, Jensen TJ, Naismith AL,
Sun SZ, Ackerley CA, et al. Expression of the cystic
fibrosis gene in non-epithelial invertebrate cells produces
a regulated anion conductance. Cell 1991; 64:681-91.
4 Boucher RC. Molecular insights into the physiology
of the 'thin film' of airway surface liquid. J Physiol 1999;
516:631-38. [99218230]
5 Johansen PG, Anderson CM, Hadorn B. Cystic
fibrosis of the pancreas. A generalised disturbance of
water and electrolyte movement in exocrine tissues.
Lancet 1968; 1:455-60.
6 Kopelman H, Durie P, Gaskin K, Weizman Z,
Forstner G. Pancreatic fluid secretion and protein
hyperconcentration in cystic fibrosis. N Engl J Med
1985; 312:329-34. [85111006]
7 von Eckardstein S, Cooper TG, Rutscha K,
Meschede D, Horst J, Nieschlag E. Seminal plasma
characteristics as indicators of cystic fibrosis
transmembrane conductance regulator (CFTR) gene
mutations in men with obstructive azoospermia. Fertil
Steril 2000; 73:1226-31.
Dysregulation of pHASL - its potential consequences in
the CF lung
Normal ↑ pH
CF ↓ pH
HC03
-
HC03
-
CFTR
HC03
-
CFTR
HC03
-
Apical
Basolateral
Bacterium
Mucin
molecule
Immune Cell
Figure 2. Predicted adverse effects of reduced ASL pH
on CF airway epithelium.
On normal airway relatively higher pH results in a less
viscous surface layer, facilitating transport of retained
bacteria in the mucous layer in a cephalad directions.
Putatively, in CF, lower pH results in an increasingly
viscous "low-volume" gel, adherence of soluble and
tethered mucins, resulting in mucous plaques, persistence
of dysfunctional immune cells and bacteria.

Page 6
JOP. J. Pancreas (Online) 2001; 2(4 Suppl):294-300.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol.2, No.4 Suppl. – July 2001
299
8 Linsdell P, Tabcharani JA, Rommens JM, Hou YX,
Chang XB, Tsui LC, et al. Permeability of wild-type and
mutant cystic fibrosis transmembrane conductance
regulator chloride channels to polyatomic anions. J Gen
Physiol 1997; 110:355-64. [98021949]
9 Poulsen JH, Fischer H, Illek B, Machen TE.
Bicarbonate conductance and pH regulatory capability of
cystic fibrosis transmembrane conductance regulator.
Proc Natl Acad Sci USA 1994; 91:5340-4. [94261581]
10 Tabcharani JA, Rommens JM, Hou YX, Chang XB,
Tsui LC, Riordan JR, et al. Multi-ion pore behaviour in
the CFTR chloride channel. Nature 1993; 366:79-82.
11 Clarke LL, Harline MC. Dual role of CFTR in
cAMP-stimulated HCO3
-
secretion across murine
duodenum. Am J Physiol 1998; 274:G718-26.
[98236768]
12 Choi JY, Muallem D, Kiselyov K, Lee MG, Thomas
PJ, Muallem S. Aberrant CFTR-dependent HCO3
-
transport in mutations associated with cystic fibrosis.
Nature 2001; 410:94-7. [11242048]
13 Smith JJ, Welsh MJ. cAMP stimulates bicarbonate
secretion across normal, but not cystic fibrosis airway
epithelia. J Clin Invest 1992; 89:1148-53. [92210710]
14 Devor DC, Bridges RJ, Pilewski JM.
Pharmacological modulation of ion transport across wild-
type and DeltaF508 CFTR-expressing human bronchial
epithelia. Am J Physiol Cell Physiol 2000; 279:C461-79.
[20372872]
15 Smith JJ, Welsh MJ. Fluid and electrolyte transport
by cultured human airway epithelia. J Clin Invest 1993;
91:1590-7. [93232283]
16 Devor DC, Singh AK, Lambert LC, DeLuca A,
Frizzell RA, Bridges RJ. Bicarbonate and chloride
secretion in Calu-3 human airway epithelial cells. J Gen
Physiol 1999; 113:743-60. [99246328]
17 Jayarayaman S, Song Y, Vetrivel L, Shanker L,
Verkman AS. Noninvasive in vivo fluorescence
measurement of airway-surface liquid depth, salt
concentration, and pH. J Clin Invest 2001; 107:317-24.
[R017-002-04-72]
18 Rochelle LG, Li DC, Ye H, Lee E, Talbot CR,
Boucher RC. Distribution of ion transport mRNAs
throughout murine nose and lung. Am J Physiol Lung
Cell Mol Physiol 2000; 279:L14-24. [20351805]
19 Paradiso AM. ATP-activated basolateral Na+/H+
exchange in human normal and cystic fibrosis airway
epithelium. Am J Physiol 1997; 273:L148-58.
[97396361]
20 Dudeja PK, Hafez N, Tyagi S, Gailey CA,
Toofanfard M, Alrefai WA, et al. Expression of the
Na+/Hand Cl-/HCO3
exchanger isoforms in proximal
and distal human airways. Am J Physiol 1999; 276:L971-
8. [99292444]
21 Coakley RD, Grubb BR, Gatzy JT, Chadburn JL,
Boucher RC. Differential airway surface liquid (ASL)
pH, HCO3
and Khomeostasis in cultured human and
dog bronchial epithleium. Pediatr Pulmonol 2000;
20:194.
22 Paradiso AM, Burch LH, Rochelle LG, Kreda SM,
Ribiero SM, Winders A, et al. Functional identification
and tissue distribution of two forms of H+, K+-ATPase in
proximal human airway. Pediatr Pulmonol 2000; 20:206.
23 Zsembery A, Strazzabosco M, Graf J. Ca2+-activated
Clchannels can substitute for CFTR in stimulation of
pancreatic duct bicarbonate secretion. FASEB J 2000;
14:2345-56. [20507653]
24 Clarke LL, Harline MC, Gawenis LR, Walker NM,
Turner JT, Weisman GA. Extracellular UTP stimulates
electrogenic bicarbonate secretion across CFTR knockout
gallbladder epithelium. Am J Physiol Gastrointest Liver
Physiol 2000; 279:G132-8. [20357578]
25 Barry PH, Diamond JM. Effects of unstirred layers
on membrane phenomena. Physiol Rev 1984; 64:763-
872.
26 Dzekunov SM, Spring KR. Maintenance of acidic
lateral intercellular spaces by endogenous fixed buffers in
MDCK cell epithelium. J Membr Biol 1998; 166:9-14.
[99003335]
27 Bhaskar KR, Garik P, Turner BS, Bradley JD, Bansil
R, Stanley HE, et al. Viscous fingering of HCl through
gastric mucin. Nature 1992; 360:458-61.
28 Quinton PM. The neglected ion: HCO3
-. Nat Med
2001; 7:292-3. [11231624]
29 Holma B. Influence of buffer capacity and pH-
dependent rheological properties of respiratory mucus on
health effects due to acidic pollution. Sci Total Environ
1985; 41:101-23. [85168253]
30 Bansil R, Stanley E, LaMont JT. Mucin biophysics.
Annu Rev Physiol 1995; 57:635-57. [95297805]
31 Bhaskar KR, Gong DH, Bansil R, Pajevic S,
Hamilton JA, Turner BS, et al. Profound increase in
viscosity and aggregation of pig gastric mucin at low pH.
Am J Physiol 1991; 261:G827-32. [92059468]
32 Tam PY, Verdugo P. Control of mucus hydration as
a Donnan equilibrium process. Nature 1981; 292:340-2.
33 Matsui H, Grubb BR, Tarran R, Randell SH, Gatzy
JT, Davis CW, et al. Evidence for periciliary liquid layer

Page 7
JOP. J. Pancreas (Online) 2001; 2(4 Suppl):294-300.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol.2, No.4 Suppl. – July 2001
300
depletion, not abnormal ion composition, in the
pathogenesis of cystic fibrosis airways disease. Cell
1998; 95:1005-15. [99091058]
34 Awayda MS, Boudreaux MJ, Reger RL, Hamm LL.
Regulation of the epithelial Nachannel by extracellular
acidification. Am J Physiol Cell Physiol 2000;
279:C1896-905. [20533185]
35 Danel C, Erzurum SC, McElvaney NG, Crystal RG.
Quantitative assessment of the epithelial and
inflammatory cell populations in large airways of
normals and individuals with cystic fibrosis. Am J Respir
Crit Care Med 1996; 153:362-8.
36 Brown RK, Kelly FJ. Evidence for increased
oxidative damage in patients with cystic fibrosis. Pediatr
Res 1994; 36:487-93.
37 Bruce MC, Poncz L, Klinger JD, Stern RC,
Tomashefski JF Jr, Dearborn DG. Biochemical and
pathologic evidence for proteolytic destruction of lung
connective tissue in cystic fibrosis. Am Rev Respir Dis
1985; 132:529-35.
38 Nakamura H, Yoshimura K, McElvaney NG, Crystal
RG. Neutrophil elastase in respiratory epithelial lining
fluid of individuals with cystic fibrosis induces
interleukin-8 gene expression in a human bronchial
epithelial cell line. J Clin Invest 1992; 89:1478-84.
[92235262]
39 Simchowitz L. Intracellular pH modulates the
generation of superoxide radicals by human neutrophils.
J Clin Invest 1985; 76:1079-89.
40 Trevani AS, Andonegui G, Giordano M, Lopez DH,
Gamberale R, Minucci F, et al. Extracellular acidification
induces human neutrophil activation. J Immunol 1999;
162:4849-57.
41 Allen DB, Maguire JJ, Mahdavian M, Wicke C,
Marcocci L, Scheuenstuhl H, et al. Wound hypoxia and
acidosis limit neutrophil bacterial killing mechanisms.
Arch Surg 1997; 132:991-6.
42 Bidani A, Heming TA. Effects of bafilomycin A1 on
functional capabilities of LPS-activated alveolar
macrophages. J Leukoc Biol 1995; 57:275-81.
[95155896]
43 Stoodley P, deBeer D, Lappin-Scott HM. Influence
of electric fields and pH on biofilm structure as related to
the bioelectric effect. Antimicrob Agents Chemother
1997; 41:1876-9.
44 Clary-Meinesz C, Mouroux J, Cosson J, Huitorel P,
Blaive B. Influence of external pH on ciliary beat
frequency in human bronchi and bronchioles. Eur Respir
J 1998; 11:330-3

There are no products listed under this category.