Opportunities for the Use of Aerosolized
α1-Antitrypsin for the Treatment of
Cystic Fibrosis
Elizabeth D. Allen
Chest 1996;110;256S-260S
DOI 10.1378/chest.110.6_Supplement.256S
The online version of this article, along with updated information
and services can be found online on the World Wide Web at:
http://chestjournal.chestpubs.org/content/110/6_Supplement/
256S
CHEST is the official journal of the American College of Chest
Physicians. It has been published monthly since 1935.
Copyright 1996 by the American College of Chest Physicians,
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No part of this article or PDF may be reproduced or distributed
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ISSN:0012-3692
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1996 by the American College of Chest Physicians
the Use of Aerosolized
Opportunities for
arAntitrypsin for the Treatment of
Cystic Fibrosis*
Elizabeth D. Allen, MD
Cystic fibrosis (CF), the most common lethal genetic disease affecting the white population, owes
its morbidity and mortality primarily to the devastating effects of chronic inflammation and infec¬
tion within the pulmonary airways. It has become increasingly recognized that the host's response
to Pseudomonas species and Staphylococcus aureus infection plays a paramount role in CF lung
destruction and eventual development of respiratory insufficiency. A massive pulmonary influx of
neutrophils, and fluid
accompanying excessive levels of neutrophil elastase (NE), can be detected in the
of even very young children with CF. The excess of NE adversely affects the
bronchoalveolar
CF airways by enhancing mucus secretion, directly injuring airway tissues, exacerbating the
inflammatory process by attracting more neutrophils, and derailing opsonization and elimination of
bacterial pathogens, particularly Pseudomonas aeruginosa. Neutralization of excess NE by deliver¬
ing supplemental cti-antitrypsin to the airways via aerosolization represents an exciting new poten¬
tial therapy for CF lung disease. (CHEST 1996; 110:256S-260S)
Key words: ai-antitrypsin; aerosolization; cystic fibrosis; neutrophil elastase
fibrosis (CF) is a complex, genetically based
/Cystic
^^ disease that is characterized the malfunction of
by
various exocrine glands. The CF gene codes for a cel¬
lular membrane
the CF transmembrane
protein,
reg¬
ulator, which forms a chloride channel and appears to
regulate other channel proteins.in Improper functioning
of this channel, which occurs individuals who have
2 ofthe more than 300 possible abnormal forms ofthe
gene, results in electrolyte abnormalities at the sur¬
faces of various secretary and resorptive cells.1,2 Mul¬
affected by the resulting glandular
tiple organs arechief
abnormalities;
among these are the lungs. Death
from respiratory failure is the major cause of mortal¬
ity for the CF population. Despite impressive advances
in the past several decades, the median survival for
individuals with CF is less than 30 years.3 With an in¬
cidence of 1 in 2,500x to 1 in 3,5003 live white births,
CF is the most common life-shortening autosomal
disease in the white population.
In the tracheobronchial tree, the inability of glan¬
dular cells to secrete normal amounts of chloride at
their apices results in excessive sodium absorption and
dehydration of surface mucus. For reasons that are not
entirely clear, this mucus readily supports secondary
bacterial infection, principally Staphylococcus aureus
and Pseudomonas aeruginosa. The host defense system
responds vigorously to this infection, and the resultant
*From Children's Hospital, Ohio State University, Columbus.
Dr. Allen, Pediatric Pulmonology, Children's
Reprint requests:
Hospital, 700 Childrens Drive, Columbus OH 4320d
256S
chronic, suppurative pulmonary disease obstructs the
airways and gradually causes widespread bronchiectatic dilation of the airways at the expense of normal
lung parenchyma.4,5 Clinically, the patient experiences
gradual loss of pulmonary function and increasingly
frequent productive coughing; the overall slow deteri¬
oration is punctuated by more severe exacerbations of
respiratory symptoms. Finally, for most patients, death
occurs as a result of frank respiratory insufficiency,
often accompanied by cor pulmonale.
Historically, therapy for CF has focused on the
physical removal of tenacious airway mucus, efforts to
improve nutritional status, and attempts to reduce the
lungs' microbial burden. Daily therapy with broncho¬
dilating aerosols and chest physiotherapy is prescribed,
along with high-calorie diets and, for the 80 to 85% who
have pancreatic insufficiency, enzyme replacement.
Intermittent therapy with antibiotics, based on sensi¬
tivity results from sputum or deep throat swab cultures,
is also given. Unfortunately, once infection with P
aeruginosa has become established, it can rarely be
eradicated.
A relative explosion of novel therapies for CF has
developed during the past decade.6"8 A new mucolytic,
recombinant human deoxyribonuclease, or rDNase,
has recently become available in the clinical setting.9
Evaluations of agents (amiloride and uridine triphos¬
phate) aimed at correcting the surface electrolyte ab¬
normalities are in
Identification ofthe CF
gene has fueled
process.10"13research into means of
aggressive
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1996 by the American College of Chest Physicians
Alphai-Antitrypsin: A World View
transferring the normal gene into the abnormal CF
respiratory tract.114
Research into methods of reducing or stopping the
exuberant, and destructive, inflammatory process oc¬
curring within the CF airways has also come to the
forefront during the past decade. Recent reports have
deemphasized the importance of direct bacterial (spe¬
cifically P aeruginosa) tissue destruction, and instead
have suggested that the host response to infection is the
major cause of parenchymal damage.15"17 Attempts to
control the host inflammatory response with systemic
steroids initially appeared promising,18 but in larger
trials have proven to cause excessive side effects.19
Prolonged high-dose ibuprofen has been shown to
significantly slow the progression of lung disease in
patients with CF and mild lung disease.20,21
The inflammatory process in CF airways is charac¬
terized by a massive influx of neutrophils. Neutrophils
typically represent less than 5% ofthe cells recovered
by BAL in normal adults. In CF adults, neutrophils
may comprise greater than 95% ofthe cell population;
even in CF children 1 to 5 years of age, neutrophils
averaged 31.5% of epithelial lining fluid (ELF) cells.
Furthermore, the number of airway cells is markedly
increased, such that neutrophil density on the respi¬
ratory surface of even young CF children is typically
3xl03 or more neutrophils/microliter ELF.22 Neutro¬
elastase (NE), a highly destructive protease, has
phil
been found in large quantities in CF airway fluid. A
promising new therapeutic strategy for CF focuses on
blocking the effect ofa NE by supplementing the CF
pulmonary
supply of -antitrypsin (ai-AT). This arti¬
cle reviews the potential role of NE in the pathogen¬
esis of CF lung disease, outlines published experience
with the use of
for the treatment of this
i
disease,
ai-AT
and suggests future directions for further investigation.
Protease/Antiprotease Levels
in
CF
NE, released by neutrophils during periods of
inflammation or infection, is capable of hydrolyzing all
the major connective tissue proteins that make up the
lung matrix. In the normal host, pulmonary autodigestion by NE is prevented by the activity of antiproteases,
oq-AT.23 An imbalance in the levels of NE
primarily
and cq-AT, such as that caused by genetically based
ai-AT deficiency, allows active NE to attack the lung
parenchyma,
resulting in the development of emphy¬
sema early in adult life.
A number of investigators have measured strikingly
elevated levels of active NE in CF sputum24"26 and
respiratory ELF obtained at bronchoscopy.22,27"30 Nor¬
mal adult control subjects22,27"31 and patients with
nonsarcoid interstitial lung disease31 have no detect¬
able active NE in ELF. Subjects with chronic bron¬
chitis have detectable levels of free NE in their
sputum, but their values were less than 25% of CF
sputum-free NE. Based on measured sputum elastase
levels, and the volumes of sputum produced daily by
some patients, it has been estimated that NE may be
present in milligram amounts in CF lungs.24
By antigenic measurements, oq-AT is present in
normal to elevated amounts in both CF airway secre¬
tions22,24"26 and plasma.22,32,33 ai-AT from CF plasma
samples is functionally active.33 Further, elastase/antiprotease complexes have been demonstrated in both
and airway secretions. The presence of excess
plasma34
elastase
in the CF
activity
airway, therefore, does not
appear to be the result of a primary
abnormal function of CF ai-AT.
deficiency state or
Although cq-AT is present in normal to elevated
airway fluid, it appears to be inacti¬
as
evidenced
vated,
by the presence of high levels of
free NE and also the increased amounts of degraded
cq-AT found in CF sputum. This inactivation is most
likely the result of proteolytic destruction by NE, and
to a lesser extent, Pseudomonas elastase. Oxidative
destruction by neutrophil-released myeloperoxidase
may also play a role.24,35 In addition, or alternatively,
CF ai-AT may simply be overwhelmed by the massive
amounts of NE released by large numbers of chroni¬
cally present neutrophils in the CF airways. Molar
levels of total NE levels in CF sputum are 12 times
those of ai-AT, and the degradation of oq-AT may
occur after it has "completed its task" of inhibiting
NE.25
amounts in CF
Numerous observations suggest that the presence of
active NE in the CF airway has substantial clinical
relevance. Levels of active NE in CF respiratory flu¬
ids correlate with measures of overall clinical severi¬
ty25,26
and
pulmonary
function data (FEVi and
FEVi/FVC ratio)29 and fluctuate significantly during
episodes of disease exacerbation and following thera¬
Active NE has been found in ELF from very
py.2631 CF
children, although some young (<8 years)
young
CF children have undetectable NE
levels.22,36 NE
levels appear to increase with age and disease severity;
young children who have measurable ELF NE have
average levels of 3.5 ±1.2 pmol/L while older patients
with more advanced disease (average FEVi of 41±4%
predicted) have been reported to have NE levels as
high as 31 ±10 pmol/L. Plasma levels of elastase/antiprotease complexes are elevated at baseline, and rise
and fall during disease exacerbations and subsequent
therapy.37"39 Plasma elastase/antiprotease complexes
have also been noted to rise just prior to death,40 and
at the time of first isolation of P aeruginosa.41 Finally,
CF patients who also have ai-AT-deficient Pi-phenotypes have an earlier onset of Pseudomonas infection
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2, 2010 1996 SUPPLEMENT
1996 by the American College of Chest Physicians
257S
and higher IgG levels42 (which in turn are correlated
with poorer clinical outcome43,44).
Role of Active NE in CF Lung Disease
Active NE impacts negatively on the CF tracheo¬
bronchial tree in various ways. It contributes to the
physical distortion of the CF airways by enhancing
mucus secretion and directly injuring airway tissues. It
inflammatory process by attracting
neutrophils. Finally, it derails opsonization and
elimination of bacterial pathogens, particularly P aeru¬
ginosa.
Proteolytic destruction is a prominent feature ofthe
progressive pathophysiologic condition of CF. Desmosines are cross-linking amino acids that are degra¬
dation products of elastin and are produced as a result
of NE activity. They are present in significantly
elevated amounts in CF urine, suggesting increased
degradation of CF tissue elastin. Furthermore, abnor¬
mal elastin fibers can be seen by light microscopy in all
lung compartments at CF lung autopsy. Bronchial ab¬
scesses and ulcers are rimmed with fragmented and
exfoliated elastin.45 NE is an extremely potent secretagogue of airway submucosal glands.46,4' It also causes
detachment of ciliated cells from their neighbors,
this disruption, in turn,
leading to epithelial disruption;
clearance.48
likely delays mucociliarybronchial Distortion ofthein
elastin framework of
walls, resulting
bronchiectatic changes, combined with increased mu¬
cus secretion and interference with mucociliary clear¬
ance, may enhance the pooling of infected, NE-laden
secretions. This pooling further accelerates airway de¬
struction. Thus, NE plays a significant role in the in¬
disease.
flammatory self-destruction seen in CF lung
NE also perpetuates its own presence in CF bron¬
chial fluid by its effects on the cytokines that regulate
influx. NE has been shown to stimulate the
neutrophil
release of interleukin-8 (IL-8), a potent neutrophil
chemoattractant, from a transformed airway epithelial
cell line homozygous for the most common CF allele
(AF508)49 and from a transformed normal human
bronchial cell line (BET-1A).30 In addition, NE stim¬
ulates the release of IL-6,49 which acts to downregulate local acute inflammation,50 but then subsequently
degrades it. As a result of these effects, IL-8, which is
not found in normal ELF fluid, is present in physio¬
in CF ELF fluid where it
significant amounts
logically
a continual influx of neutro¬
act to
exacerbates the
more
may
perpetuate
NE also stimulates the release of leukotriene
phils.30
B4, another potent neutrophil chemotactic factor, by
leukotriene B4 is present in
macrophages.51 Like IL-8,concentrations
in CF ELF.52
significantCF
physiologically
NE also
ing
potentiates airway disease by interfer¬
with host resistance to, and effective killing of,
258S
Pseudomonas species. The ability of P aeruginosa to
bind to respiratory tract epithelial cells is enhanced by
removal of fibronectin from cell surfaces^3
proteolytic
NE is capable of causing fibronectin removal and en¬
hanced P aeruginosa adhesion in an animal epithelial
model.54 Once attached, removal of P aeruginosa is
hampered by NE interference with opsonization. CF
IgG respiratory opsonins are fragmented, and as a re¬
sult, they function poorly and may actually inhibit
Treatment of isolated neutrophils with
phagocytosis.55
NE, or CF ELF, impairs their ability to kill opsonized
P aeruginosa; this appears to be due to cleavage of
specific complement receptor sites on the neutrophil's
surface.27,56
In summary, NE accelerates the invariable pulmo¬
nary deterioration seen in CF by directly damaging
mucociliary clearance, by
by interfering withcontinued
(via
neutrophil influx,
stimulating cytokines)
and by interfering with the host's ability to resist P
infection.
tissue,
aeruginosa
Pharmacologic Correction
of
CF NE Excess
The availability of supplemental forms of antiproteases, notably ai-AT and recombinant secretory leu¬
(rSLPI), provides an obvious and
koprotease inhibitor
of attempting to correct the
method
clinically
ready
severe protease/antiprotease imbalance in the CF air¬
ways. Thus far, studies have been limited to relatively
small numbers and short durations of therapy. Never¬
theless, they provide some interesting insights into the
to be obtained from
potential difficulties, inandthebenefits,
CF
antielastase therapy
population.
SLPI is a naturally occurring antiprotease found in
in
Like
SLPI is
the
cq-AT,
present
upper airways.
normal amounts in CF ELF fluid (in the face of excess
NE levels). Relatively large (100 mg twice daily) doses
of aerosolized rSLPI given for 1 week have been shown
to significantly reduce (from 11.1 ±1.8 pmol/L to
6.1 ±1.2 pmol/L) NE ELF levels in a group of 16
moderately ill (average FEVi, 55% predicted) CF pa¬
tients.28 Furthermore, rSLPI caused a marked reduc¬
tion in ELF IL-8 levels and decreased the ability of CF
ELF to induce IL-8 production in a human respiratory
epithelial cell line in vitro.01 Unfortunately, radiolabeled aerosolized rSLPI appears to be unevenly dis¬
tributed to CF lungs with advanced disease; deposition
occurs only in well-ventilated areas.58
Addition of exogenous ai-AT to CF sputum in vitro
results in a dose-dependent inhibition of NE activity
and reduction of CF sputum's ability to induce secre¬
tion from porcine tracheal glands. Nearly complete
inhibition of NE occurred when concentrations of 10
pg/mL cq-AT were achieved.59 Initial work with IV
ai-AT indicated that 3 weekly infusions of 60 mg/kg of
ai-AT (twice the dose used for ai-AT deficiency) could
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1996 by the American College of Chest Physicians
AlpharAntitrypsin: A World View
pmol/L to
to 3.0
twice
1
for
able
to
was
week)
daily
mg/kg
completely
reduce CF ELF NE levels from 6.0±0.9
undetectable.60 Aerosolized cq-AT (dose, 1.5
inhibit ELF NE activity in CF patients with moderate
respiratory impairment when ELF eq-AT levels
reached 8 pmol/L. Additionally, while pretreatment
CF ELF impaired the ability of neutrophils to kill
Pseudomonas in vitro, posttreatment ELF did not
have this effect.61
Conclusion
The host inflammatory response and particularly the
neutrophil product NE appear to play a major role in
the pathogenesis of pulmonary disease in CF. NE is
capable of destroying important structural proteins of
the bronchial airways, and autopsy and urine collagendegradation product levels in CF patients confirm this
is occurring in the CF lung. Furthermore, NE activity
acts as a "positive feedback loop" by stimulating the
production of neutrophil chemoattractants. Interfer¬
ence with mucociliary clearance and encouragement of
P aeruginosa growth (by improving bacterial adhesion
and stifling opsonization and neutrophil killing) add
further to the accumulation of inflammatory, infected
secretions within the CF airways.
Treatment for CF to date has focused primarily on
the physical removal of secretions and (unsuccessful)
attempts to eradicate infection. To date and to our
no therapy specifically aimed at controlling
knowledge,
the exuberant inflammatory response occurring within
the airways has proved to be effective, yet free of sig¬
nificant side effects. (High-dose ibuprofen therapy
appears promising for those with mild lung diseases,
but safety issues have not been assessed in large pop¬
ulation trials.)
ai-AT therapy has been shown capable of com¬
pletely
eliminating NE activity in CF ELF. Antipro¬
tease therapy also corrects some of the "side effects"
of excess NE, including excessive IL-8 production and
interference with neutrophil killing of Pseudomonas. It
therefore may serve to break the cycle of accelerating
airway inflammation in CF.
Future lines of research regarding the pathophysi¬
ologic state of CF as it relates to NE should include
further studies into the onset of NE excess, which ap¬
pears to be quite early, and the relationship of NE ex¬
cess to acquisition of Pseudomonas infection. Tradi¬
tionally, bacterial infection has been assumed to be the
driving force behind the inflammatory uproar in the
CF airways. It is intriguing to consider the possibility
that NE excess occurs first (perhaps due to inadvert¬
ent stimulation of production of neutrophil chemoat¬
tractants by the electrolyte imbalances of abnormal
and that bacterial colonization oc¬
airway secretions),
curs only after an inflammatory milieu that allows
bacterial survival is established by excess NE.
Future research regarding the use of ai-AT to treat
patients with CF will require longer trials of therapy in
of patients. Initial studies have used
larger numbers
with
patients
moderately severe disease and very high
NE burdens. Targeting younger patients with less se¬
vere disease may prove to be a more successful
endeavor and may require lower drug dosages. In ad¬
dition to measuring ELF inflammatory markers, mea¬
surement of ELF bacterial burden (looking for a
reduction or elimination of Pseudomonas) and, with
studies, clinical measurements including
longer-term
FEVi and frequency of clinical exacerbations may be
pertinent. Finally, the potential interaction of NE with
other CF therapies, such as recombinant human
deoxyribonuclease, should be investigated.
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1996 by the American College of Chest Physicians
Alpha-i -Antitrypsin: A World View
Opportunities for the Use of Aerosolized α1-Antitrypsin for the
Treatment of Cystic Fibrosis
Elizabeth D. Allen
Chest 1996;110; 256S-260S
DOI 10.1378/chest.110.6_Supplement.256S
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