PHYSIOLOGICAL REVIEWS

Vol. 79, Suppl., No. 1, January 1999

Printed in U.S.A.

Physiological Basis of Cystic Fibrosis: A Historical Perspective

PAUL M. QUINTON

Department of Pediatrics, University of California, San Diego, La Jolla; and Division of Biomedical Sciences,
University of California, Riverside, California

I.Introduction S3
II.From Witches to Science S4
III.Research in the ‘‘Wild West’’ S5
IV. The Mucus Story S5
A. Pancreas S6
B. Airways S6
C. Gastrointestinal tract S7
D. Reproductive tract S7
E. Salivary glands S7

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F. The cell S8
V. The Electrolyte Story S9
A. Sweat gland S9
B. Pancreas S11
C. Airways S12
D. Intestine S13
E. The gene and cell S13
VI. Which Story to Believe? S14

Quinton, Paul. M. Physiological Basis of Cystic Fibrosis: A Historical Perspective. Physiol. Rev. 79, Suppl.: S3–
S22, 1999.—Cystic fibrosis made a relatively late entry into medical physiology, although references to conditions
probably reflecting the disease can be traced back well into the Middle Ages. This review begins with the origins
of recognition of the symptoms of this genetic disease and proceeds to briefly review the early period of basic
research into its cause. It then presents the two apparently distinct faces of cystic fibrosis: 1) as that of a mucus
abnormality and 2) as that of defects in electrolyte transport. It considers principal findings of the organ and cell
pathophysiology as well as some of the apparent conflicts and enigmas still current in understanding the disease
process. It is written from the perspective of the author, whose career spans back to much of the initial endeavors
to explain this fatal mutation.

I. INTRODUCTION
During my career, cystic fibrosis (CF) has grown vig-
orously in science, medicine, and society. Scientifically,
CF has advanced from innumerable speculations about
its cause to a precise definition of causative mutations
accompanied by accurate, quantitative descriptions of
their physiological effects. Medically, the life expectancy
of CF patients has increased from death in early childhood
to an age over 30 years (98), with a great reduction in
pediatric morbidity.1 Socially, it has almost become a
household word, enlisting the support of millions of citi-
1
In the United States, the gene frequency is almost 4%, and CF
afflicts Ç1 in 3,200 live births (1 in 2,400 in the United Kingdom). Over
20,000 patients are under the care of 113 certified CF centers alone (76,
93, 111, 248).
zens in the struggle for its control (28). It is little wonder
in view of this wide range of effects and of the remarkable
progress made in our time in understanding the disease
that it is now considered by some to be a paradigm for
integrating scientific, medical, and social efforts in the
control of a disease. But still we have no cure and no
effective control of its relentless destruction of the lungs
and pancreas.
This review is constrained to the events and observa-
tions that, from my viewpoint, seem to bear directly on
the development of fundamentals in our understanding of
the disturbances in the physiological systems and pro-
cesses that result in the disease we call CF. I can in no
way deal with all of the observations, insights, and efforts
that have created our present understanding. An excellent
recent review (266) covers a number of contemporary and

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S4 PAUL M. QUINTON
more recent subjects that relate fundamental abnormali-
ties to clinical progress and gene therapy.
Over the past three decades, I have struggled, and
still struggle, to understand how CF can be seen both as
a disease simply caused by abnormally thick mucus and
as a disease of clearly fundamental defects in electrolyte
transport. This struggle admittedly shapes this review. In
so much as this approach may be controversial because
of the inevitable biases that I carry, I hope that it might
also provoke better resolution of the problem. Also, I have
taken the more personal, but less scientifically formal,
approach of citing the names in most instances of the
investigators of whom I have been privileged to know.
There are others that I have not named directly; I hope
that they will be forgiving. I am indebted to them all.
II. FROM WITCHES TO SCIENCE
Historical searches lead us to believe that at least
some of the characteristic symptoms of the disease may
have been recognized and been associated with its mor-
tality in the primitive societies of eastern Europe even
before the Middle Ages. Most of our information on the
earliest indications of CF come from the persistent dig-
gings of Busch (40 –46). A few references uncovered in
medieval folklore predict death for an infant that tastes
‘‘salty’’ when kissed. Such infants were thought to be
‘‘hexed’’ (46). In 1606, Alonso y de los Ruyzes de Fonteca,
professor of medicine at Henares in Spain, wrote that it
was known that the fingers taste salty after rubbing the
forehead of the bewitched child (3). The modern diagnos-
tic criterion of salty sweat seems to have been seen even
then as a premonition of sickness, emaciation, and early
death. Possibly the earliest accurate medical description
of the pancreatic lesion in a case of CF was given in an
autopsy report on a supposedly ‘‘bewitched’’ 11-yr-old girl
in 1595 by Pieter Pauw, professor of botany and anatomy
in Leiden, The Netherlands. He described the child as
being meager with a swollen, hardened, gleaming white
pancreas (46). Anecdotal records from the mid-1600s re-
port conditions that must have reflected steatorrhea, pre-
sumably arising from pancreatic insufficiency, another
diagnostic hallmark of the disease (40, 42, 44, 124). A few
records from the 19th century and early 20th century
associated steatorrhea, meconium complications, and
pancreatic lesions (103, 213). Landsteiner, who also de-
fined blood groups, published possibly the first modern
description of meconium ileus associated with a defec-
tive CF pancreas (156). Meconium ileus is now consid-
ered to be almost pathognomonic of the disease (216).
The turn of the 20th century brought the first obser-
vations that began to associate lung disease with diarrhea
and abnormal pancreatic function as well as reports of
congenital familial steatorrhea (103, 272). Although it was
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Volume 79
still nameless, the present day terminology for CF began
to evolve during the 1930s. These descriptions focused
on the pancreatic involvement and steatorrhea and often
related it to a form of celiac disease, although the concur-
rence of bronchopulmonary complications were noted as
well (4, 26, 95, 119). Fanconi et al. (95), in 1936, were
probably first to refer to the disease as ‘‘cystic fibro-
matosis with bronchiectasis’’ and recognized it as sepa-
rate from celiac disease. Andersen in 1938 (4) used the
term ‘‘cystic fibrosis of the pancreas.’’ Histochemical ex-
aminations of other organs revealed inspissations and
concretions in the ducts and lumens of intestine and lung.
By 1945 (before the abnormality in sweat was known),
Farber (96) had introduced the term mucoviscidosis to
challenge the fledgling nomenclature that Andersen had
focused on the pancreas. He firmly believed that the
cause of the disease was a generalized ‘‘state of thickened
mucus.’’ This name is still widely used and often preferred
outside the English speaking world. In retrospect, both
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names were misnomers reflecting the limited view of the
pathology at the time. In 1946, Andersen and Hodges (5)
refined the observations and presented the first compel-
ling evidence that the disease is genetic and results from
an autosomal recessive mutation. Two years later, an im-
pressive heat wave in New York resulted in a high inci-
dence of heat prostration among a number of her patients
at Columbia Hospital (136). Fascinated by this event, di
Sant’Agnese, also at Columbia, sought the source of the
salt loss that had precipitated the heat prostration (73).
His conclusion brought the empirical insights of primitive
folklore on salty tasting kisses into the medical literature
of the 20th century. di Sant’Agnese presented his findings
to the American Pediatrics Society in 1953 as the last
paper of the day which he noted ‘‘almost no one attended’’
(personal communication). General acceptance of the ab-
normality as a fundamental component of the disease
took several years. But within 5 yr, it was established that
the uniqueness of this particular abnormal physiological
function afforded a method for accurate, accessible diag-
nosis. The sweat test quickly became and remains the
most common and reliable single parameter, possibly ex-
cepting recently available genetic analysis, for differential
diagnosis of CF (158).
However, these apparently unrelated findings set the
stage for confusion. On the one hand, it was obvious to
the pathologist that the disease was caused by abnormal
mucus or proteinaceous inspissations in the lumens of
pancreas, lung, and intestine. Adjectives like ‘‘thick,’’
‘‘sticky,’’ ‘‘tenacious,’’ and ‘‘inspissated’’ were used liber-
ally in early reports (4, 26, 95, 96, 277) and continue to
be used (93, 94, 150, 184, 207, 255) to describe the micro-
scopic changes observed in affected tissues. On the other
hand, the sweat gland with its abnormally salty secretion,
which produced no mentionable amount of mucus and
showed no structural defects, became the clearest crite-
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January 1999 CYSTIC FIBROSIS: A HISTORICAL PERSPECTIVE
rion for diagnosis. Any unifying hypothesis needed to ex-
plain both.
III. RESEARCH IN THE ‘‘WILD WEST’’
In the ensuing 20 years, the search for a basic defect
that would unify the disparate symptoms of the disease
followed numerous paths mainly based primarily on em-
pirical observations, often completely unrelated to any
known pathology. Much of the literature from the late
1960s and 1970s came from what might be viewed as a
‘‘Wild West’’ era of research. Few things made sense, and
there seemed to be almost no guidelines. I well remember
Efraim Racker’s remark in 1985 as he began an overview
of CF as an address to a National Institutes of Health
sponsored symposium at the Heart House with the remark
that ‘‘Anyone who has read the literature in CF and says
he isn’t confused, is confused.’’
The first reported putative cellular defect was an off-
shoot of observations in glycogen storage disease in
which Danes and Bearn (63, 64) reported that fibroblasts
cultured from CF patients developed significantly more
metachromatically stained granules than those derived
from normal subjects. Later in the course of examining
the effect of tobacco smoke on ciliary beating, Spock
(242) reported that serum from patients with CF caused
increased mucus release and induced a marked dyskinesia
in the ciliary action of rabbit trachea when applied to
the luminal surface in vitro. The excitement gained much
momentum when Bowman et al. (34) reported that the
effect could be duplicated using oyster cilia and Dogett
and Harrison (83) reported that it could be reversed by
heparin and that a cationically charged protein was the
‘‘factor’’ responsible for the effect.
The idea that a circulating humoral factor was at the
heart of the pathology gained still greater attention when
Mangos and co-workers reported that sweat or saliva from
CF patients applied to the luminal surface of rat salivary
gland ducts (172) or human sweat gland ducts (173) inhib-
ited active Na/ absorption in these epithelia. Rao and
Nadler (202) suggested that a defect in arginine esterase
accounted for these effects by elevating the concentra-
tions of cationic amino acids. A large, heat stable macro-
molecule in CF tears and stool fluids was reported to
stimulate excessive mucin release from the urn cell of the
exotic marine invertebrate Sipunculus (10).
Then, Wilson and co-workers (270, 271) reported that
a unique protein band appeared in CF serum electropho-
resed through a pH gradient to its point of isoelectric
focus. Lieberman and co-workers thought that an elevated
protein with lectinlike binding properties that could be
detected via agglutination of red blood cells (163), but
which disappeared during menses (164), reflected the ba-
sic defect. Katz and co-workers (223) reported that intra-
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S5
cellular Ca2/ in mononucleocytes was abnormal. De-
creased protease activity (203, 261), arginine esterase
(202), g-glutamyl transpeptidase (19), galactosyl trans-
ferase (204), a-D-glucosidase (2) activities, and a2-macro-
globulin (234) were all reported to be altered as well.
Attention turned again to cultured cells when Breslow
and co-workers (35, 37) reported that CF fibroblasts were
much more resistant to dexamethasone in culture than
their normal counterparts. It was reported that Tamm-
Horsfall glycoprotein induced a multifold increase in alka-
line phosphatase activity in CF fibroblasts (49), that acid
phosphatase and a-mannosidase enzymes from CF cells
were more heat sensitive than normal (50), that intracellu-
lar Ca2/ was increased in CF fibroblasts (8, 51), and that
calmodulin regulation of Ca2/-ATPase was abnormal (132).
Sometimes many man years of labor were lost and careers
were changed in failed attempts to duplicate a result. For
example, several years and literally thousands of rats (D.
Dearborn, personal communication) were invested in try-
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ing to replicate the transport inhibitory factor effect re-
ported on rat parotid glands (171, 269). None of these re-
ports has been substantiated rigorously. Some have been
refuted or seriously challenged (22, 38, 209, 258, 268). A
very few have been courageously retracted (36).
Many of these reports most likely represent errone-
ous starts and premature conclusions that were supported
by the ease of publishing in a field without a reliable,
reproducible scientific point of reference. Often studies
of this period rested on an uncritical faith in published
results. The renowned CF physician Harry Shwachman
once remarked ‘‘There have been more Chairmen of pedi-
atrics made from CF than from any other disease because
anything can be published’’ (personal communication). As
a part of the CF story, these works may be most valuable
in emphasizing the importance of setting critical experi-
mental standards and in posting a warning of the pitfalls
that must accompany attempts to tie empirical pathologi-
cal observations to underlying physiological and biochem-
ical phenomena.
IV. THE MUCUS STORY
It is now clear that abnormalities extend well beyond
fibrotic cysts in the pancreas and that several target or-
gans such as the sweat, lacrimal, and parotid salivary
glands do not produce ‘‘viscid mucus’’ (194). Nonetheless,
no doubt because of the impressive histological findings
of accumulated mucus in the airways and to apparent
‘‘mucous plugs’’ in other organs (31, 96, 277), the idea that
CF was a disease primarily caused by thick sticky mucus
to this day commonly pervades the thinking of physicians,
scientists, and patients alike. This perspective of the dis-
ease was entrained by observations in several exocrine
organs that appeared to be based on some form of abnor-
mal mucus secretion or metabolism.
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S6 PAUL M. QUINTON
A. Pancreas
Abnormalities in the pancreas made it easy for early
investigators to conclude that the fundamental abnormal-
ity was altered and/or increased in mucus production.
Overt symptoms of pancreatic insufficiency did not ap-
pear until ú85–90% of the pancreas was lost (69, 99, 174).
Pancreatic insufficiency developed in utero in some pa-
tients and over a period of many years in others (259).
The progression has been qualitatively estimated as in-
volving four (subjective) degrees of involvement (65): 1)
eosiniphilic concretions in the lumen, 2) widening of the
ducts with intra- and interlobular fibrosis and microcysts
appearing to be due to ductal obstruction, 3) acinar and
ductal atrophy and disintegration accompanied by fatty
infiltration, and 4) scar tissue surrounding isolated islets
of Langerhans with total loss of acinar and ductal struc-
tures with increased incidence of insulin and glucagon
insufficiency due to ‘‘strangulation’’ of the islets. The in-
spissated plugs or concretions in the ducts were reported
to contain high concentrations of Ca2/ (151). In general,
the caudal pancreas was found to deteriorate more rapidly
than the head, and although there is no bacterial infection,
mild leukocytic infiltration was seen even in early stages
of the destruction (71). The progressive loss of function
was highly variable, not an ‘‘all or none’’ phenomenon,
and in some cases seemed to occur almost ‘‘unit by unit’’
over extended periods as ducts were obstructed and acini
were lost to ‘‘mucus blockage’’.
B. Airways
Impressions from the pancreas that CF was a disease
of abnormal mucus were strongly reinforced by lung pa-
thology. In young infants, even before significant anatomic
changes occurred, the appearance of bronchial mucus
hypersecretion was the first notable evidence of a pulmo-
nary lesion (277). It remains an enigma that in contrast
to most other lung diseases, the upper lobes fell prey to
infection before the lower lobes, and like the pancreas,
the lungs deteriorated over months or years seemingly
almost unit by unit. Frequent involvement of the airways
was consistently noted at autopsy as dilated bronchi with
tubular bronchiectasis. Bronchial lumens were filled with
purulent exudates (4, 31, 93, 94). The tracheal bronchial
submucosal glands appeared normal in development but
frequently hypertrophied with dilated lumens that under
the microscope seemed to be filled with dense mucus
(207). Histochemical studies suggested that glands in
chronically infected patients produced more highly sul-
fated mucins, but probably not more so than non-CF, dis-
ease-related controls (154). Similarly, the airway epithe-
lium appeared to be excessively populated with globlet
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Volume 79
cells, but probably not more so than other chronically
inflamed airways (207).
Cystic fibrosis patients with infected airways gener-
ally produced sputum that was thick and viscid, but its
physical properties were largely determined by the pres-
ence of cellular and bacterial debris, especially DNA,
which made it impossible to define the nature of (or possi-
ble differences between) pure mucus secretions from na-
tive uninfected CF and control airways. Nonetheless, the
gross appearance of the expectorant as well as analyses
reporting abnormally low water content (96% for CF vs.
98% for bronchiectasis) supported the notion that airway
mucus secretions were abnormally thick and ‘‘dehy-
drated’’ (137a, 185–187). Even now, the question remains
as to which occurs first, increased (abnormal) mucus se-
cretion or infection and inflammation (17, 137, 139). Un-
doubtedly, it is noteworthy that infections begin in the
small bronchioles before detectable loss of lung function
takes place (66, 184, 251). Pertinent to the question, there
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is very recent evidence from studies of a specially bred
CF-gene knockout mouse that changes in mucus in the
airway may precede disease (133). It remains significant
that despite prodigious efforts to define a chemical aberra-
tion in mucins produced in CF, to date no unique composi-
tional differences have been defined (114, 159). However,
some progress may be being made (56, 220) in redefining
early reports of alterations in the sulfation (29, 53) and in
sialylation and fucosylation of CF mucus (79). The early
recognition that DNase had marked thinning properties
on crude CF sputum (52) and the recent application of this
knowledge through the therapeutic use of cloned human
DNase to reduce sputum viscosity in vivo (189, 201, 232,
233) underscored the fact that viscosity was not solely
due to abnormal mucus. Thus the disease in the lung was
frequently perceived as being caused by thick mucus, that
was clearly ‘‘abnormal’’ as compared with normal lung
secretions, but the more appropriate comparison is proba-
bly to mucus produced in other diseased lungs. Introduc-
tory sentences such as ‘‘Abnormally viscoelastic secre-
tions in CF cause impaired mucus clearance and persis-
tence of bacteria within the lung’’ were and are common
in the literature of CF. That is not to say that there is no
chemical abnormality in CF mucus, but it seems that it
was not widely recognized that such an abnormality was
still far from being established and that other diseases,
asthma and especially status asthmaticus (250), bronchi-
ectasis without CF (176), pseudohypoaldosteronism
(117), Kartagener’s (immotile cilia) syndrome (221), and
some cases of Sjogren’s (autoimmune destruction of exo-
crine tissue) syndrome (61), all produced sputum that is
‘‘thick and viscid’’ or ‘‘dry,’’ but did not result in CF lung
pathology (112). Cystic fibrosis sputum was found to be
almost uniquely characterized by bacterial flora con-
taining a mucoid form of Pseudomonas aeruginosa that
produced alginate. This protein, commonly used as a food
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January 1999 CYSTIC FIBROSIS: A HISTORICAL PERSPECTIVE
thickener, was once thought to be largely responsible for
the viscosity of CF sputum (84, 85). Why the CF lung is
predisposed to this form of a ubiquitous bacteria remains
as another mystery. Unfortunately, the complexity of spu-
tum, the nature of the infection, and the individual vari-
ability of the inflammatory responses (137a, 138, 196) have
prevented unassailable comparisons of the composition
of mucus in different diseases.
C. Gastrointestinal Tract
The biliary tree, the gallbladder, and the intestine
have all been reported to show similar signs of increased
mucus or ‘‘thickened’’ mucus production. Clearly, one of
the most dramatic and compelling demonstrations that
CF was a disease of ‘‘mucoviscidosis’’ derived from the
pathognomonic association between CF and meconium
ileus. During the 1960s, sufficient records were accumu-
lated to demonstrate that Ç10% of CF patients were born
with this condition (75, 216). In these infants, the small
bowel was blocked with a thick, dehydrated, rubbery,
tarry, tenacious mucoid plug. The loss of pancreatic en-
zymes in utero undoubtedly gave rise to accumulations
of undigested proteins (e.g., albumin) which when mixed
with intestinal mucus produced the impervious, hypervis-
cid meconium substance. Microscopic examination of the
surrounding intestinal epithelium showed dilated mucus
glands with prominent mucus cells along lumens that con-
tained a ‘‘stringy’’ secretion (31, 126, 255). It was taken
almost as a given that the mucus glands of the colon
similarly demonstrated an increased proportion of mucus
goblet cells (31), but a carefully executed morphometric
study of colonic biopsies showed no significant differ-
ences between goblet cell distribution in CF and normal
subjects. Differences in individual cell morphology be-
tween CF and normal cells were attributed to the high
lipid load associated with pancreatic insufficiency (179).
A more recent ultrastructure study of the small gut sug-
gested that cytological abnormalities were associated
with crypt cells where the highest concentration of cystic
fibrosis transmembrane conductance regulator (CFTR)
was expressed (219).
Liver cirrhosis was not usually encountered until
much later in life and then in only a few percent of pa-
tients, but a large fraction of patients at autopsy exhibited
‘‘focal biliary cirrhosis’’ in which focal zones of numerous
bile ducts and tubules contain distinctly eosiniphilic, gran-
ular secretions that appeared to form plugs that caused
ductal dilation (72).
In about one-third of autopsied cases, the gallblad-
der was found to be hypoplastic and to contain thick
or gelatinous mucus, viscid green bile, clear jelly, solid
green bile mucus sometimes along with obliteration of
the cystic duct. These bladders often exhibited submu-
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S7
cosal fluid-filled cysts, but these changes apparently
occurred without inflammation (92). As many as 20%
of CF patients were observed to suffer cholelithiasis
(gallstones), but it is most likely that this complication
was secondary to depletion of the bile acid pool be-
cause of decreased digestive enzymes and increased
stool (259).
D. Reproductive Tract
Observations in the female genital tract gave fur-
ther evidence of a disease of viscid mucus. Inspissated
mucus plugs were sometimes found obstructing the
cervical canal (183). At times, the endocervix and cer-
vix were found to exhibit polypoid masses presumed
to contain inspissated mucus (86, 183). The gross qual-
ity of the mucus was found to be thick, tenacious, and
of relatively low volume compared with controls (150).
Cystic fibrosis women showed a significantly lower fer-
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tility rate thought to be due to the impediment the
thick mucus imposed upon sperm entering the cervical
canal (59).
The tissue most sensitive to CF in terms of embryo-
logical development was the epididymal duct and vas def-
erens. In most cases of CF, these structures were found
to be incomplete (129, 181). It was speculated, but not
proven, that the atresia was due to blockage of the duct-
ules in utero (123, 155, 160). Most males with CF were
found to be aspermic or hypospermic (123).
E. Salivary Glands
A few other morphological aberrations mainly in the
submaxillary and minor labial salivary glands also seemed
consistent with abnormal mucus. These glands were re-
ported to contain mucous plugs and eosinophilic staining
mucus in their lumen (231), but it was not possible to
conclude that these observations were strictly unique to
the disease (161). Figures 1 and 2 offer an example of the
kinds of microscopic changes that have been observed in
mucus-producing exocrine glands in the form of minor
salivary glands from CF and control subjects. Even though
these glands were not known to become infected or in-
flamed or to autodestruct by autolysis, dilated ducts with
thinner walls were outstanding features of the CF speci-
mens, but what appeared to be more darkly stained mate-
rials, thickened, were present in the lumens of the ducts
of both glands.
Barbero and Sibinga (13) found that salivary glands
were significantly enlarged in CF, but this result was then
interpreted to be due to the chronic administration of b-
adrenergic agonists (222, 230). Saliva from CF patients
demonstrated an abnormal color and turbidity, presum-
ably due to higher concentrations of Ca2/ and phosphate
prsa APS-Phys Rev
S8 PAUL M. QUINTON
(30, 169) that appeared to reverse upon administration of
guanethidine (55). Pancreatic enzyme supplements were
thought to influence salivary composition as well (247).
F. The Cell
Even though CFTR, the gene affected in CF, was
cloned 10 years ago (134, 210, 215), the finding has little
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Volume 79
FIG. 1. Hematoxylin- and eosin-stained tis-
sues from cystic fibrosis (CF) minor labial sali-
vary glands. Note ducts are distended with rela-
tively thinner epithelial walls (right arrow).
Acini appear dilated also (middle arrow). Ironi-
cally, substance in lumen (left arrow) for most
part appears less ‘‘dense’’ and ‘‘thick’’ than in
normal tissue in Fig. 2. Magnification, 1200. (Mi-
crograph courtesy of Dr. Walter Finkbeiner, Uni-
versity of California, San Diego.)
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impact on understanding mucus abnormalities in CF.
However, once it became appreciated that CFTR was a
Cl0 channel, Al-Awqati and co-workers (1, 11) reported
that normal acidification of intracellular vesicles in CF
could not be achieved and that posttranscription sialyla-
tion and fucosylation of mucous molecules would be de-
creased and increased, respectively, due to the effect of
the altered pH on the optima of the glycosylating enzymes.
However, Verkman and co-workers (25, 229) found no
FIG. 2. Hematoxylin- and eosin-stained tis-
sues from normal minor labial salivary glands.
Walls of duct are clearly thicker (top right
arrow), and lumen diameters are significantly
smaller relative to comparable structures in CF
gland. Acini are not dilated, and their lumens
are hardly discernible at this level (left arrow);
however, substance in lumens (bottom right
arrow) could be interpreted as being ‘‘thick-
ened’’ compared with CF tissue submandibular
glands (Fig. 1). These examples are provided
to not only show tissue differences but also to
illustrate ambiguity in interpreting ‘‘appearance’’
of mucus in histological specimens as was com-
mon in early pathology studies. Magnification,
1200. (Micrograph courtesy of Dr. Walter Fink-
beiner, University of California, San Diego.)
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January 1999 CYSTIC FIBROSIS: A HISTORICAL PERSPECTIVE S9

differences in intraorganelle pH of CF cells and vigorously TABLE 1. Electrolyte concentrations in control and CF
refuted this observation and speculation. sweat
Electrolyte Concentration, mM
V. THE ELECTROLYTE STORY Cl0
Na/ K/ Ca2/

Except for the sweat gland, most clinical distur- Control 16 23 8 0.65
CF patients 99 101 15 0.83
bances have been related to abnormalities that appeared
to be directly related to abnormally viscid mucus secre- Measurements are averages from more than 500 cystic fibrosis
tion. The three to five times normal elevation of NaCl in (CF) and 1,000 control subjects and should not be taken as fixed or
the sweat of CF patients was long viewed as something absolute (see text). [Data from di Sant’Agnese and Powell (76).]
of an outlier in the etiology of the disease because the
sweat gland was without significant mucus. Even Ander-
tolerance among troops sent to North Africa was attrib-
sen was reluctant at first to believe that it could be im-
uted to adaptations in sweating, he pursued excessive loss
portant to the basic pathology of the disease (di
of salt in the sweat as the most likely origin of volume
Sant’Agnese, personal communication). A few investiga-
depletion during the high heat stress (personal communi-
tors tried to reveal similar electrolyte abnormalities in the
cation). He began collaborating with Darling, Perera, and
salivary glands (27, 74, 170, 263). In general, the Na/, Cl0,
Shea to prove it. Renal output and conservation of Na/
and K/ concentrations in CF salivary secretions, more so
was within normal range. Nothing in the stool could be
with submaxillary and labial than with parotid glands,

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implicated. However, when sweat was collected and ana-
appeared at somewhat higher concentrations than those
lyzed, the concentrations of both Na/ and Cl0 were greatly
from normal glands, but although Ca2/ was consistently
increased in sweat from CF patients (73). It was not possi-
found to be about twice normal, the results have not al-
ble to give strict concentration values for these ions in
ways been statistically significant (27, 194). If there are
either CF or normal subjects simply because the fractional
disturbances in tear glands, they are not large, probably
absorption of salt from the secreted sweat varied enor-
because these glands secrete a relatively unmodified iso-
mously with secretory rate, age, circulating aldosterone
tonic fluid (32, 74, 235). Throughout the history of CF, no
levels, acclimatization, drugs, and any number of less ob-
exocrine secretion or physiological function has provided
vious factors (167, 236). For example, in salt-depleted nor-
as clean a discriminator between normal and CF subjects
mal individuals, fractional absorption ranged from almost
as has sweat.
90% for sweating at low sweat rates to only a few percent
Undoubtedly, the overt lack of any clinically apparent
in some subjects surfeiting on sodium and sweating at
renal disturbance undermined early thinking of CF as a
very high rates (personal observations; Refs. 81, 90, 91,
disease of a generalized disturbance in electrolyte trans-
168). After analyzing samples from hundreds of patients
port (76). The CFTR was found recently to be expressed
(76, 236), however, it became evident that two relatively
in the human kidney (62, 178), but there was little evi-
distinct zones separated normal from CF pediatric sub-
dence of renal compromise. No morphological abnormali-
jects (Table 1). In normal subjects, sweat concentrations
ties have been observed (177). There is an increased unex-
of salt fell below Ç60 mM, and in CF, sweat concentra-
plained clearance of several drugs, especially aminoglyco-
tions rose above that value with almost no overlap (76,
sides (9, 97, 128, 157, 274). A few reports of other
236).3 In an extensive study, the average sweat electrolyte
functions such as reduced concentrating and diluting ca-
values for siblings and parents of CF patients were found
pacities (210) or altered glomerular filtration rate (121,
to be slightly, but significantly, increased over the normal
243) were either not followed up or remained controver-
population (76). A few years later, Shwachman and Mah-
sial (241).
moodian (236) refuted these results in putative heterozy-
gotes in another extensive report.
A. Sweat Gland Sweat had much value as a parameter in differential
diagnosis, but it was cumbersome to collect and difficult
As noted in section II, the first indication that CF to obtain without serious evaporative losses. Some early
extended beyond an apparently abnormal mucus ap- attempts to place the subject in a body bag to obtain
peared when di Sant’Agnese set out to determine the etiol- enough sweat for analysis proved that this approach pre-
ogy of volume (salt) loss in Andersen’s patients afflicted sented a high risk for fatal hyperthermia. In the late 1950s,
by the heat wave that hit the northeast United States in Gibson and Cooke (104) seized the idea of stimulating
the summer of 1948.2 Noting that the development of heat localized sweating by electrophoresing (iontophoresing)

2 3
One cannot help but wonder about the course of events had air The overlap is much greater with adults, presumably because of
conditioning been common then. the increased secretory capacity relative to its absorptive capacity.

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S10 PAUL M. QUINTON
the positively charged secretagogue pilocarpine into an
area of skin of Ç20 cm2. The area was then hermetically
sealed under taped plastic, and after Ç30 min, the sweat
absorbed into the gauze was weighed, eluted, and ana-
lyzed for concentrations of Cl0.4 The protocol has become
internationally used and accepted as almost mandatory
for the diagnosis of CF (158). Only a few other very rare
conditions created false-positive results. Among them
were Addison’s disease (82), pseudohypoaldosteronism
(117), hypothyroidism (60), and malnutrition (48, 57, 175).
A few isolated cases diagnosed with CF have been re-
ported with sweat Cl0 concentrations in the normal range
(67, 244), but it is not clear whether these observations
are true exceptions with an unknown physiological com-
pensation or whether normal physiological parameters
that have not been accounted for are at play.
Numerous studies were conducted over the next de-
cade that firmly established the validity of the sweat test
(70, 76, 105, 158, 236), but in the course of these studies,
several observations were also noted that would form
the basis of, or provide helpful insights into, the future
understanding of the physiology of CF. First, almost con-
temporary with di Sant’Agnese’s observations, the ‘‘two-
step’’ theory of exocrine fluid formation was published
(227). The theory predicted that exocrine fluids were first
secreted as an iso-osmotic fluid in the secretory or acinar
structure of the gland and secondarily were modified in
composition as they passed through the ductal or tubular
network of the gland before being excreted.5 Direct ultra-
micro sampling from the gland (224–226), histological
cryo-osmometry (237, 239), and linear extrapolation (48,
80) were important approaches that verified the theory
and answered the initial question of whether CF sweat
was higher in concentration due to a primary secretory
defect that secreted fluid at hypertonic concentrations or
due to an absorptive defect in which ductal electrolyte
absorption failed in CF. It was also noted that sweat Na/,
but not Cl0, in CF dropped as expected in response to
increased levels of circulating aldosterone (78). Slegers
(238, 239) also observed that the ratio of Na/ concentra-
tion to Cl0 concentration in normal sweat was almost
invariably ú1.0, whereas in CF sweat, it was almost al-
ways õ1.0. Both of these observations hinted that Cl0
was less effectively absorbed than Na/. Schulz and
Fromter (225) noted in three patients with CF that the
electrical potential associated with sweat production on
the skin was more electronegative than normal and even
suggested that this could only occur if Cl0 were less per-
meable than Na/, but these results were neglected and
apparently were not mentioned again until pointed out by
a reviewer of my manuscript some 14 years later (193).
4
The differences from normal in Cl0 concentration are larger than
differences in Na/ concentration.
5
Some lower vertebrates, but not mammals, can secrete hyper-
tonic fluids (190).
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Volume 79
In 1981, Knowles et al. (140) reported that the electro-
negative potential across the nasal airway in CF was sig-
nificantly larger than normal. This report along with the
facts that NaCl absorption was inhibited in CF sweat ducts
and that Na/ was relatively more absorbed than Cl0 gave
me the idea that the basic defect in the CF duct had to
be due to anion impermeability (192) and not to defective
anion exchange (191) (as I had been thinking earlier based
on chemical measurements) or to increased Na/ absorp-
tion as was postulated for the airway (140).6 However,
the fluid volumes involved in microperfusion of single
ducts were far too small and the specific activity of Cl0
too low to accurately measure isotope fluxes to prove Cl0
impermeability. In microperfused isolated segments of ab-
sorptive ducts from CF and normal subjects, I found that
the average spontaneous transepithelial potential of nor-
mal sweat ducts was Ç7 mV, whereas in CF ducts it was
Ç75 mV (193). In the meantime, on the suggestion of
Maurice Burg, I found that we could demonstrate the
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anion impermeability electrophysiologically by ion substi-
tution and showed that replacing Cl0 with the relatively
impermeable SO20 4 anion in normal, microperfused ducts
raised the value of lumen negative potential to about equal
that of the CF duct, whereas the maneuver had much
less effect in CF ducts (193). Corroborating results were
obtained a little later in single glands in vivo (23, 198).
Because the defect was expressed in the morphologically
normal sweat gland, it appeared to be independent of any
secondary pathological or degenerative consequences due
to infection, inflammation, or mucus disturbances that
often occurred in other target tissues that secreted macro-
molecules. Thus this property not only provided a physio-
logical explanation for the high salt content in CF sweat,
but it also provided the first description of a basic, cellular
defect that has since proven to be uniformly inherent in
CF affected cells.
Abnormalities in adrenergic control in CF had been
suspected for several years (12, 246). Schwarz and Sut-
cliffe (228) suggested that the uptake of salt from the duct
might be influenced with adrenergic agonists. But not until
1984 did Sato and Sato (217) find a fundamental corollary
of the Cl0 impermeability defect in fluid secretion, also
in sweat glands. They found that the secretory activity of
CF sweat glands was almost completely insensitive to b-
adrenergic stimulation.7 The insensitivity was later shown
to be due to the fact that in the sweat gland b-adrener-
gically stimulated fluid secretion was coupled to the same
Cl0 channel that was altered in salt absorption (195). The
Cl0 conductance in absorption was also under b-adrener-
6
I felt some empathy with di Sant’Agnese because I presented this
idea in 1982 at a Cystic Fibrosis symposium where I too was the last
speaker of the evening, and although present, most of the audience was
asleep.
7
b-Adrenergic innervation serves no known physiological func-
tion; thermoregulatory sweating appears to be purely cholinergic and is
not abnormal in CF.
prsa APS-Phys Rev
January 1999 CYSTIC FIBROSIS: A HISTORICAL PERSPECTIVE S11

TABLE 2. Comparison of electrolyte composition and rate of pancreatic secretions collected from the duodenum of
control and pancreatic sufficient CF patients
Electrolyte Composition, mM
Volume, Trypsin, Protein,
0
Cl HCO30 Na/ K/ mlrkg01rh01 mg/ml mg/ml

Hadorn’s study
Control subjects (n Å 10–30) 60 (258) 75 (258) 107 (73) 11 (73) 4.7 (115) 220 (115)
CF patients (n Å 10) 86 (115) 19 (115) 119 (73) 9 (73) 0.8 (115) 515 (115)

Kopelman’s study
Control subjects (n Å 9) 81 45 142 8 9.7 2.75
CF patients (n Å 9) 77 39 151 8 4.9 5.6

Reference numbers are given in parentheses. Data for Kopelman’s study are from Kopelman et al. (149).

gic, cAMP-dependent control (199, 200, 206, 267). Chloride of Vater and collect relatively pure pancreatic secretions
impermeability and insensitivity to activation by protein also during in vivo pharmacological stimulation with intra-
kinase A has now become the signature of expression venous pancreozymin/secretin. Although Kopelman et al.
of CF in the single cell, whether native, transfected, or (148) did not find significant differences in electrolyte con-

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cultured.8 Although overlap was too great to permit detec-
tion of heterozygotes on an individual basis, the average
sweat rate of the heterozygote population in response
to a b-adrenergic challenge still remains one of the few,
perhaps the only, physiological parameter that showed
intermediate expression of the gene in vivo (18, 218).
B. Pancreas
Untreated, the large majority of CF patients suffered
from severe malnutrition that was attributed to the loss
of pancreatic parenchyma and the concomitant loss of
digestive enzymes. Some questioned whether the defect
in sweat NaCl might be due to poor nutrition. About 10% of
diagnosed patients escaped pancreatic insufficiency (71),
which we now know is due to different genotypes (135,
152). Although the gross and microanatomy of pathologi-
cal changes in the pancreas were obvious from the outset,
it was not until the late 1960s that Beat Hadorn recognized
that fluid and electrolyte secretion, like electrolyte ab-
sorption in sweat, was also abnormal in CF. In 10 patients
who did not exhibit overt pancreatic insufficiency, se-
creted volumes and HCO30 content were markedly de-
creased in CF while Cl0 and digestive enzyme concentra-
tions were increased (115, 116, 125) (Table 2). Most CF
patients were relatively refractory to secretin stimulation
but responded to pancreozymin. These early observations
were the first evidence that like the sweat gland, only one
of at least two mechanisms of fluid secretion involved in
pancreas was seriously impaired.
About 15 years later, Kopelman et al. (149) used an
enteric double-ballooned catheter to isolate the ampula
8
Protein kinase A is the most established intracellular mediator
of CFTR Cl0 conductance, although other pathways may be involved.
centrations (Table 2), both studies concluded that macro-
molecules were abnormally concentrated and that
HCO30 and volume outputs were abnormally low in CF
patients. The fact that secretin-stimulated HCO30 secretion
was mediated by cAMP-dependent protein kinase and that
the pancreas was so adversely affected in CF revealed
that Cl0 impermeability has a pronounced negative effect
on exocrine HCO30 transport. This effect still remains as
one of the most important but neglected and poorly under-
stood aspects of pathophysiology in CF. With the recogni-
tion that fluid secretion was inhibited, the explanation for
pancreatic deterioration no longer required ductal
blockage by abnormally viscid mucus. Without sufficient
fluid and HCO30, digestive proenzymes stagnated and acti-
vated prematurely in the pancreatic ducts. The results,
nonetheless, were the same: microautolysis, focal injury,
inflammation, infiltration, calcification, plugged ducts, fi-
brosis, and scarring until the entire parenchyma of the
pancreas, like the lung, but from a seemingly different
cause, was destroyed.
The first fundamental work on the molecular proper-
ties of the Cl0 conductance affected in the disease also
arose from the pancreas. The earliest attempts (101, 264)
to use patch-clamp techniques to show the molecular de-
fect through Cl0 single-channel activity encountered se-
vere controversy. Several investigators, most of whom did
not publish (J. Hanrahan, J. Wine, J. Bijman, and R.
Greger), were unable to repeat the published results that
a nonlinear rectifying Cl0 channel could be activated by
b-adrenergic agonists, as required for the affected channel
in CF (153). After 2 years of controversy, using an organ
culture system of human pancreatic ducts developed by
Ann Harris, Argent et al. (109) found two types of Cl0
channel activity: one with outwardly rectifying chord con-
ductances ranging from Ç19 to 53 pS was seen rarely and

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S12 PAUL M. QUINTON
was activated by strong depolarization and another with
Ç4–7 pS linear conductance was abundant and activated
by cAMP/protein kinase A. These results were rapidly con-
firmed (21, 58, 120, 273), and the rectifying channel was
shown not to be correlated with CF (262).
C. Airways
While searching for evidence that electrolyte trans-
port in the airways was important for host defense,
Knowles et al. (140) included a few CF patients in his
cohort of asthmatic and heart disease subjects. He discov-
ered that the electrical potential associated with the nasal
mucosa of CF patients was significantly more electronega-
tive with respect to blood than with all other subjects.
This finding in 1981 provided the first physiological link
between the lung, the pancreas, and the sweat gland (140).
The common link was not mucus, but electrolytes. Al-
though it was not rapidly appreciated, the finding allowed
the possibility that problems with mucus were due not to
abnormalities with its synthesis or composition, but to
the fluid environment into which mucus was secreted
(195, 196). In CF subjects, the spontaneous electrical po-
tentials measured across respiratory mucosa were about
twice normal (53 mV in CF vs. 25 mV in healthy control
subjects) with no overlap in values. The difference in elec-
trical potential between CF patients and normal subjects
persisted down the airways as far as the airway lumen
could be accessed, although the absolute values became
smaller so that in CF segmental bronchi the average po-
tential difference was 32 mV (CF) vs. 15 mV (normal) in
bronchi (145), lumen negative relative to blood. In the
presence of amiloride, a diuretic known to block epithelial
Na/ conductance, the transepithelial electrical potential
fell in both groups to about the same level (Ç5 mV).
Knowles et al. (140) postulated that in the airways, the
increased potential found in CF was due to significantly
accelerated active Na/ absorption from the airway surface
fluids in the lumen. This hypothesis was appealing be-
cause it presented a mechanism (dehydration by exces-
sive fluid absorption) by which abnormally thick mucus
could be formed in the airways (33). The same Cl0 imper-
meability defect previously described in the sweat duct
(192, 193) was then found in the airways (142, 144). So-
dium absorption was not enhanced but clearly decreased
in the sweat duct, and it is not clear that Na/ transport
is affected in the pancreas or intestine. Neither the mecha-
nism of enhanced Na/ absorption in CF airways nor its
link to the genetic defect has yet been explained.
From these initial observations, a new clinical proce-
dure using the potential differences measured across the
nasal mucosa was developed to assist in the diagnosis of
CF (141). The potential was measured while the nasal
mucosa was perfused with different solutions. After the
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Volume 79
TABLE 3. Concentrations of electrolytes in airway
surface fluids from two studies
Electrolyte Concentration, mM
0
Cl Na/ K/
Joris’ study
CF patients 121 129 23
Control subjects 82 84 29
Knowles’ study
CF patients 76 86 24
Control subjects 80 88 22
spontaneous potential was read, Na/ conductance was
blocked with amiloride, the mucosa was challenged with
isoproterenol, a b-sympathomimetic agonist, and Cl0 was
removed from the perfusate. The response of the electri-
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cal potential to amiloride was two- to threefold larger, but
the response to b-adrenergic challenge and Cl0 substitu-
tion was significantly smaller or nonexistent in CF sub-
jects; all effects were consistent with inherent Cl0 imper-
meability in CF.
With the recognition that CF was a disease of electro-
lyte transport came a renewed concern regarding abnor-
malities in the composition of the airway surface fluids
(ASF). Earlier attempts to gain insights from sputum and
laryngeal secretions collected from CF patients and con-
trol bronchiectatic subjects indicated that the solid con-
tent of these fluids were increased (Ç10 vs. Ç5%) and
that Na/ and Cl0 concentrations were lower, respectively
(176, 186, 187). However, these results probably did not
reflect the actual physiological values of the ASF in vivo
because these secretions were badly contaminated with
debris from infection and inflammation. Unfortunately, it
has proven to be extremely difficult to collect and analyze
‘‘pure’’ ASF from the airways because it normally exists
in an extremely thin layer estimated to be from 10 to 50
mm in depth. More recent studies reporting the composi-
tion of salt in the fluid in the large airways are inconsistent
for CF. During bronchoscopy, samples were collected on
filter paper placed in the ASF on the airway wall. In addi-
tion to the difficulty of analyzing such small samples free
of evaporative and gravimetric errors, even these direct
sampling techniques suffer serious potential artifacts aris-
ing from the invasiveness of the method and the respon-
siveness of the epithelium to disturbances (Table 3).
As of this writing, the airway continues to build CF
history. Recently, Smith et al. (240) reported that primary
cultures of CF airway epithelial cells grown at an air inter-
face were compromised in their ability to resist bacterial
infections with respect to their normal counterparts. They
further showed that reducing the salt concentration of
fluid collected from the CF epithelium restored bacteri-
prsa APS-Phys Rev
January 1999 CYSTIC FIBROSIS: A HISTORICAL PERSPECTIVE
cidal activity and raising the salt concentration of the fluid
collected from control epithelia removed its bactericidal
activity. Similar results were reported for CF and control
cells grown on tracheal xenografts in immunodeficient
mice (107). Analysis of the salt concentrations in the ASF
over primary cultures supported the conclusion that, like
the sweat gland, the NaCl concentration in CF ASF was
significantly elevated (276). These results may strengthen
the possibility that abnormalities in the composition of
the airway fluid as opposed to inherent abnormalities in
the composition of airway mucus was the component that
predisposes the CF lung to airway disease.
D. Intestine
Work on the electrolyte abnormality in the gut was
slow to evolve probably because of an early prevalence
of the idea that malabsorption in CF was essentially due
to pancreatic dysfunction. In 1985, the first transport ab-
normality in the CF intestine was reported as an enhanced
rate of glucose uptake in vivo (100), which was proposed
to be due to smaller diffusional barriers. The finding was
later confirmed in vitro and shown to be associated with
significantly higher nutrient-stimulated short-circuit cur-
rents in CF (15, 118, 254). Additional electrolyte transport
disturbances in the CF intestine arose from observations
that jejunal biopsies from CF patients in contrast to nor-
mal subjects failed to respond with a significant increase
in lumen to serosal positive current when stimulated with
PGE2, dibutryl cAMP, acetylcholine (252, 253), or the Ca2/
ionophore A-23187 (180). Consistent results were ob-
tained in the ileum, colon, and rectum (20, 24). The in
vivo intraluminal potential in the jejunum when perfused
with Cl0-free solution was significantly more positive in
CF than in control subjects, whereas theophylline stimu-
lated net fluid secretion in control, but not CF, subjects
(254). Both the increased Na/-dependent nutrient uptake
and the depressed secretory responses of the CF gut were
compatible with an inherent loss of Cl0 conductance. The
absence of a normal anion shunt in the apical membrane
should increase the apical membrane Na/ gradient of the
enterocyte in CF, thereby producing larger currents when
nutrients were present. As for diminished secretion, any
agonist that required the CFTR Cl0 channel in the apical
membrane would necessarily fail to elicit a response if
the channel were missing or nonfunctional.
There was accompanying evidence of pH aberrations
in the CF intestine. Postprandial contents in the early gut
remained at a lower pH (õ6.0) for significantly longer
periods of time than in that of control subjects (106, 211,
275). These effects may be simply the result of diminished
pancreatic HCO30 secretion but could also, like the pan-
creas, reflect a compromised ability of the intestine to
secrete HCO30 as a function of lost Cl0 permeability in the
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S13
enterocyte cells. Several other alterations in the gastroin-
testinal tract have been reported, but clear abnormalities
have been difficult to establish (110).
Ironically, it now seems that these abnormalities in
the gut may be the most likely cause for the high incidence
of some CF mutations, notably DF508. Earlier, the selec-
tive pressures thought to be responsible for the high gene
frequency of CF were numerous and almost completely
speculative (147, 188, 245). When it became clear that all
three target organs, the sweat gland, the pancreas, and
the lung, were products of electrolyte transport distur-
bances, I suggested altogether too narrowly that the selec-
tive advantage of the CF heterozygote might be in the
intestine and related it to surviving cholera infections
(192). I did not realize that cholera did not strike Europe
until the 19th century, obviating this plague as a selective
pressure. However, I later learned that that diarrheal dis-
eases caused by ubiquitous organisms such as enterotoxic
Escherichia coli (197) have affected humans for long
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enough period to conceivably constitute the selective
pressure. Proof of the notion has not been forthcoming,
but CF patients have been found to be refractory to acute
exposure to Sta (heat-stable E. coli enterotoxin) in vivo
(108). The survival of transgenic CF mice exposed to chol-
era toxin perhaps provided the strongest support of the
hypothesis (102).
E. The Gene and Cell
In addition to being a dramatic achievement in sci-
ence, the search for the CF gene was one of the greatest
successes in CF research. Because there was no known
gene product and only Cl0 impermeability, a membrane
function property, was known to be characteristically al-
tered, the gene had to be found without a chemical
marker. The alternative approach was positional cloning,
but only the assumption that the mutated gene had to be
expressed in the sweat gland, where Cl0 impermeability
had been demonstrated, linked the patient phenotype to
the positional cloning effort. Before 1985, the location
of the CF gene in the human genome was completely
unknown. Eiberg et al. (89) observed that a polymorphic
serum paroxonase was inherited with high frequency
(linked) with the CF gene. In the same year, Tsui and
co-workers (146, 257) used another restriction fragment
linked polymorphism (RFLP) marker to localize the gene
to the long arm of chromosome 7. Thereafter, the race
was on to find the gene. Its localization was narrowed to
within 1–2 1 106 base pairs using RFLP. The most vigor-
ous competition was between Williamson’s group in Lon-
don and Tsui’s group in Toronto. It was rumored that Bob
Williamson had the gene, but the lead did not hold. In
1985, in a stunning trilogy of papers published simultane-
ously (134, 210, 215), the Toronto group including Jack
prsa APS-Phys Rev
S14 PAUL M. QUINTON
Riordan’s laboratory supported by Francis Collins’ group
at Michigan reported the cloning of the gene for CF. The
gene was conserved throughout numerous species, indi-
cating its evolutionary importance; it was predominantly
expressed in the target organs affected by the disease
including cells from the sweat gland. The cDNA hybridiz-
ing to the candidate gene sequences from the CF locus
were isolated from libraries constructed from sweat gland
mRNA from CF patients and unaffected subjects. Se-
quence comparisons between initial partial cDNA from
the two sources revealed the absence of three nucleotides
in the patients even before the full-length sequence was
obtained, which was ultimately necessary to predict the
protein product structure. The subsequent finding that
this DF508 deletion was present in almost 70% of the
chromosomes from patients diagnosed with the disease
provided assurance that the correct gene had been found.
They named its protein product CFTR, suggesting that it
might not be a Cl0 channel itself, but that it might regulate
Cl0 channel activity (210).
The next important step was to express the gene in
living cells. At first, great difficulty was encountered in
creating a full-length cDNA that could be propagated in
bacteria and expressed in cells. Gregory et al. (111) clev-
erly surmised and validated that a cryptic region in exon
6 of the CFTR cDNA induced a transcript that was toxic
to the host bacteria. When they inactivated the promoter,
the bacteria were able to carry plasmids containing CFTR
cDNA. This important conclusion was fundamental to de-
veloping cell lines expressing the gene and its mutants.
Using a low copy number plasmid, Welsh and co-workers
(208) first corrected CF in cells ex vivo by transfecting a
CF cell line with normal cDNA. The approach was quickly
improved upon by using mutated E. coli in which produc-
tion of the toxic component was suppressed (54, 87). With
the advent of cell lines capable of expressing CFTR and
its mutants came Seng Cheng’s startling discovery that
mutations in the putative nucleotide binding folds pro-
duced proteins that were incompletely processed or de-
graded before reaching the membrane. The hallmark of
this event was failure to glycosylate asparagine residues
at positions 894 and 900 of the CFTR protein, which was
readily monitored from the electrophoretic mobility shift
associated with the extension of the N-linked oligosaccha-
ride chains elaborated in the Golgi (54). Kartner et al.
(130) then showed that DF508 CFTR did not reach the
membrane in native CF epithelia. However, equally sur-
prisingly when mutant CFTR such as DF508 did reach the
membrane, it exhibited reasonably good function as a Cl0
channel (88, 162). Shortly later, Welsh and co-workers
(68) also discovered that these mutants were thermosensi-
tive, and growing cells at reduced temperature enhanced
processing and allowed expression of CFTR Cl0 channels.
These findings generated new thinking about therapeutic
approaches. They suggested that correcting the defect
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Volume 79
would require enhancing expression and delivery of the
mutant protein to the membrane. Still, direct proof that
CFTR was a Cl0 channel was lacking. It remained possible
that it was a regulator, not a channel itself. The first evi-
dence that CFTR was a channel was presented by mutat-
ing lysine at position 95 and 335 to glutamate and showing
that this change reversed the anion selectivity sequence
of the channel (7). Although Greger and co-workers (122)
refuted these results, it is difficult to imagine how such
alterations would cause changes in permselectivity if they
were not directly involved with conducting the anion.
Bear et al. (16) provided the first direct proof that CFTR
was a Cl0 channel by reconstituting CFTR protein into
artificial membranes and demonstrating cAMP/ATP-de-
pendent channels with the same properties as those pre-
viously described for CFTR wild type expressed ex vivo
in patch clamping.
We pass over an avalanche of data provided subse-
quently by patch-clamp and whole cell electrical re-
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cording techniques. The principal results of which de-
scribed an ion channel with an anion selectivity of NO3
ú Br ¢ Cl ú I ú gluconate and a nonrectifying conduc-
tance of Ç6 – 8 pS (58, 109, 131, 273). The channel was
primarily activated by cAMP-dependent protein kinase
(58, 214, 248, 265). Activity was ATP dependent (6, 200),
and ATP hydrolysis was required for channel opening
and for channel closing as well as a nonhydrolyzed li-
gand (14, 113, 205, 256).
VI. WHICH STORY TO BELIEVE?
What does CF history show us in the past half cen-
tury? It is clear that CF involves electrolyte transport ab-
normalities in all affected epithelial tissues and that mu-
cus secretion is or becomes enhanced in some tissues but
not in others. It is clear that mutations in CFTR directly
affect Cl0 permeability and likely have other effects either
directly or indirectly on Na/, HCO30, and probably other
ion distributions. However, the effect on mucus remains
unclear. Admittedly, I have been biased for many years
that the basic defect probably does not directly involve
both electrolytes and mucus, largely because it seemed
superficially, at least, incompatible with my obsolete edu-
cation in the ‘‘one gene, one protein’’ concept. The sweat
gland offers no support for a defect in mucus production
or synthesis. The luminal blocks and concretions of the
pancreas can probably be explained as the result of focal
stagnation of autolytic enzymes as discussed in section
IVB. It has been tempting to say that the ‘‘abnormality’’ of
mucus in the airways is simply the result of infection and
that the apparently abnormal increase in viscosity is due
to the presence of DNA or to relative dehydration. Cer-
tainly, a number of related anecdotal observations made
on very young infants as well as on adults dying of nonres-
prsa APS-Phys Rev
January 1999 CYSTIC FIBROSIS: A HISTORICAL PERSPECTIVE
piratory causes report the presence of multiple casts and
plugs in very small airways that conceivably could pre-
cede infection. The lack of normal, cyclical changes in
the viscosity of vaginal fluids during the menstrual cycle
and the occasional mucus plugs encountered in the female
CF cannot be easily explained by infection either. In addi-
tion, the submucosal glands of the large airways and the
intestine have been described repetitively as containing
thick, stringy, or viscous mucus. It also seems unlikely
that these results are directly due to infection. Still, the
evidence that the mucus per se in these glands is abnormal
in CF is weak. We may surmise that the ‘‘apparently’’
abnormal mucus might well be a normal response to an
underlying challenge, but it is not possible to dismiss the
mucus condition in CF as simply due to chronic infection.
There are fundamental tissue phenomena that may
help in integrating these events, at least from my armchair.
First, one of the most primitive defenses that epithelia
offer to challenges from the outside world is mucus re-
lease. Irritation of an epithelium results in hypersecretion
of mucus. If mucus secretion is increased in CF and not
inherently constituitively increased or a function of infec-
tion, some form of ‘‘irritation’’ of the epithelium seems
likely to be present. Changes in the composition (and/or
volume) of the epithelial surface or luminal milieu should
inherently accompany the physiological defect in electro-
lyte transport in CF. Because epithelia are skilled in de-
tecting surface or luminal changes, I ask if the defective
changes in themselves could constitute a chronic irrita-
tion to target epithelia. The defect would be even more
aggravating if CFTR has functions that extend beyond
creating a Cl0 conductance, especially if it either directly
or indirectly impedes the movement of other ions such
as HCO30, where the pancreas has tried so emphatically
to teach us for years that the transport of the two ions
must be coupled. In addition to potentially constituting a
chronic irritation and provoking increased mucus secre-
tion, alterations in composition also present an abnormal
environment into which mucus secretions are released,
leading to a second, related phenomenon: physical prop-
erties of mucus are intrinsically dependent on their envi-
ronment. The viscoelastic properties of macromolecular
polyelectrolytes such as mucus are critically sensitive to
ionic strength and pH (165, 166, 249). Alterations in the
ionic strength, divalent ion concentration, or pH are cer-
tain to affect the physical status of the mucus, which
again, in itself, may contribute to irritation to create a
vicious cycle. The facts that in nature mucus and HCO30
secretion are often coupled and that there is clearly a
defect in HCO30 movements in CF suggest that this aspect
of the basic pathophysiology may be as important, if not
more important, to the clinical disease than Cl0 imperme-
ability, if indeed the two can be separated.
The possibility that this inherent weakness in the epi-
thelial system can be provoked or at least exacerbated by
/ 9j0e$$ja06 P28-8 12-31-98 07:13:50
S15
sporadic events seems to fit well with the disease process;
that is, neither of the two organs that completely fail in
CF, the lungs and the pancreas, do so suddenly. Rather,
there is progressive destruction (sometimes enduring de-
cades) of the organ unit by unit as it were. In the airways,
the sporadic insults that continually occur with debris
that is deposited from inhaled air push isolated units be-
yond the threshold of homeostasis to produce a localized,
destructive spiral of mucus release, accumulation of de-
bris, and inspissation of ineffective mucus with subse-
quent loss of function. We know too little about variations
in acinar and lobular functions in the pancreas to be able
to suggest what precipitating factors initiate focal stagna-
tion in ductules, but it seems likely that such variations
exist and that beyond a point, localized flow and probably
pH, becomes too low to provide proper clearance of the
unit before proteolytic enzyme activation and autolysis
occurs. Because a few percent of CF males are fertile, the
vas deferens may follow the same pattern, possibly again
Downloaded from physrev.physiology.org on April 7, 2011
due to problems in HCO30 and pH. Without further knowl-
edge of the processes incumbent with its development,
we cannot know which potentially destructive elements
might be present, but stagnant lytic enzymes in the semi-
nal fluid seem likely to lead to the same course seen in
the pancreas. The intestine and other organs largely es-
cape this tirade of deterioration because there seems to
be few, if any, destructive elements such as highly concen-
trated digestive enzymes in the pancreas or intensely in-
flammatory agents in the airway to damage the epithelia.
The sweat gland escapes structural alterations for at least
two reasons: 1) physiological sweating is driven by a se-
cretory mechanism that is not affected in CF so that there
is no reduction in flow, and 2) the composition of its
product, sweat, normally varies over a wide range that
includes the composition of sweat produced in CF so that
the composition in the CF gland lumen is still within a
well-tolerated physiological range.
Which story is correct? Neither a consideration of
mucus nor of electrolytes alone is likely to present the
whole truth. Both must be interdependent and interre-
lated. History has not yet resolved where and why they
overlap to produce the complex path that witches dubbed
as a curse and that we in science still struggle to find.
Until we chart that path, we may wander the Wild West
with the stark possibility that even now we have not yet
considered the true reason that CF is a disease.
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Physiological Basis of Cystic Fibrosis: A Historical
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PAUL M. QUINTON
Physiol Rev 79:S3-S22, 1999.

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