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* From the Department of Medicine, Queen Elizabeth Hospital, Birmingham, UK.
Correspondence to: Robert A. Stockley, MD, DSc, Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, UK
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Abstract |
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 TOP Abstract IntroductionProteases/AntiproteasesOxidants/AntioxidantsReferences |
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Key Words: antiproteases • COPD • inflammation • neutrophil elastase • neutrophils
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Introduction |
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TOPAbstractIntroductionProteases/AntiproteasesOxidants/AntioxidantsReferences |
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In addition to these factors that lead to airflow obstruction, there are also structural changes in COPD resulting in peripheral airspace enlargement, probably because of long-term destruction of interstitial connective tissue and, in particular, lung elastin.
All these features lead to the development of a progressive disease traditionally characterized by a continuing reduction in FEV1 with time. In addition, in many patients there is an increase in the presence of peripheral airways disease and distal airspace enlargement. The loss of lung function is related to a decrease in exercise capacity associated with a long-term reduction in quality of life. The patients have a tendency to recurrent exacerbations of their disease characterized by short-term increases in symptomatology, and this is enhanced by the general reduction in respiratory reserve together with significant impairment of host defenses including, in particular, damage to the mucociliary escalator.1
Potentially, all these factors can be modified or stabilized, leading to better long-term prognosis with or without a gain in the quality of life. Whereas such an approach offers a real opportunity to understand the effect/role of many of the components of the syndrome, it remains necessary to design appropriate intervention trials in which the traditional monitoring of FEV1 becomes a secondary rather than a primary outcome measure. At present, some of the concepts of the pathogenesis of certain features of COPD are sufficiently well advanced to design appropriate intervention studies; others are currently in their infancies and require further extensive validation.
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Proteases/Antiproteases |
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TOPAbstractIntroductionProteases/AntiproteasesOxidants/AntioxidantsReferences |
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1-antitrypsin
(1-AT) deficiency and the development of
early-onset emphysema.2
This led to the subsequent
discovery that destruction of lung elastin was a central component to
the development of emphysematous changes in the peripheral airways.
Eventually, the human enzyme neutrophil elastase, which is normally
avidly inactivated by 1-AT, was shown to cause
structural changes in the lungs of experimental animals, which were
similar to changes observed in human emphysema.3
The
enzyme was also shown to induce bronchial disease and, in particular,
mucus gland hyperplasia, mucus secretion, and a decrease in ciliary
beat frequency, which are features of COPD.4
All these
features would lead to impairment of mucociliary clearance, which is
also a feature of patients with COPD.5
In addition,
neutrophil elastase has been shown to have a major effect
on epithelial cells, leading to damage as well as causing inactivation
of immunoglobulins and damage to opsonophagocytic receptors on
neutrophils. These changes would be expected to further impair host
defenses,5
leading to a general reduction in the ability
of the airway to remove bacteria and retain its sterility. The net
effect would be the facilitation of bacterial colonization, which in
its own right would lead to further neutrophil recruitment and release
of elastase into the airway.
The processes that result in these changes are generally poorly
understood. Initially, it was believed to be a simple process, since
1-AT deficiency was thought to reduce the
ability of the lung to inhibit any neutrophil elastase released within
it. This subsequently led to the suggestion that in subjects with
normal 1-AT, it was likely that functional
inactivation of the inhibitor would be the key to the development of
some of the features of COPD. Indeed, studies showed that oxidants from
cigarette smoke and activated neutrophils could inactivate the function
of 1-AT producing such a functional
deficiency. However, in vivo studies led to a major
controversy, since although oxidation of 1-AT
is widely quoted as a phenomenon, it remains poorly supported by
clinical studies (see below). Finally, the concepts are further
compromised by the existence of secretory leukoprotease inhibitor
(SLPI), which is a locally derived inhibitor of neutrophil elastase
released by airway cells and mucus glands. SLPI is thought to be the
most important inhibitor of neutrophil elastase in the airway, and
deficiency has yet to be described, thereby leading to uncertainty
concerning how the enzyme could evade inactivation in this anatomic
region of the lung.
Recent studies, however, have clarified the mechanisms that may
be involved in the development of some of the features of
COPD caused by neutrophil elastase. Liou and Campbell6
described the processes whereby neutrophils could degrade connective
tissue following the release of neutrophil elastase. They proved
theoretically that the concentrations of enzymes being
released from the cell were so high that an area of obligate
proteolysis would always occur in the immediate vicinity of the
azurophil granule as it was released from the neutrophil. Once
released, the elastase would diffuse away from the azurophil granule
and its concentration would decrease until it becomes equal to that of
the surrounding inhibitors, whereupon its function would become
completely inactivated. This theoretical data was subsequently proven
in vitro, confirming that the concentration of the inhibitor
was the eventual limiting factor,7
and the experimental
data fit the theory indicating that no inactivation of
1-AT by oxidation was taking place in the
vicinity of the neutrophil. Furthermore, the data confirmed that the
relationship between tissue destruction and the concentration of the
surrounding inhibitors was exponential with a major increase, as the
inhibitor concentration was reduced to < 10 µmol/L, (ie,
to the concentrations found in subjects with
1-AT deficiency).
On the basis of these experiments, it now becomes quite clear that
neutrophil migration into the lung will always produce an area of
neutrophil elastase-induced changes in the immediate vicinity of the
cell. Thus, the greater the number of cells that migrate, the greater
the amount of tissue destruction or damage that will occur. This
process would be markedly enhanced in a subject with
1-AT deficiency, resulting in the earlier
development of clinical disease. Furthermore, in the airway, release of
the elastase from the neutrophil is likely to inhibit production of
SLPI by airway cells, further facilitating its function at this site.
This latter concept has been demonstrated in
vitro8
and would be consistent with studies of airway
secretions obtained from patients (Fig 1)
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The mechanisms involved are currently being worked out in more detail. Neutrophils from patients with established chronic bronchitis and emphysema show an increased chemotactic response, and, in addition, their destructive potential is greater than from age- and smoking-matched individuals.9 The implications of this observation are that the release of normal chemoattractants in the airways of subjects with these neutrophils would result in a greater neutrophil influx and, hence, even more tissue destruction than in a comparable healthy individual. In addition, studies have shown that increased adhesion molecule expression (necessary for neutrophil adhesion before migration) is also a feature of patients with COPD.10 Furthermore, the airways contain several chemoattractants that can influence neutrophil migration,11 including interleukin-8 and leukotriene B4, and, finally, the airway inhibitors can be decreased.
With this as a pathway (Fig 2) it is possible to develop strategies that would influence the whole process and hence should decrease the long-term progression of many of the neutrophil elastase (NE)-dependent features of COPD. For instance, studies have shown that nonsteroidal anti-inflammatory agents can alter the neutrophil population being produced by the bone marrow, resulting in cells that show decreased chemotactic response and destructive potential.12 The use of such therapy as in conditions like arthritis may lead to a reduction in lung inflammation and subsequent tissue damage. In addition, the chemotactic response can be blocked, and the development of specific receptor blockers for the chemoattractants will reduce cell response as has been shown for leukotriene B4.11 In addition, cell surface proteinases and, in particular, cathepsin G have been shown to be very important in modulating the cell response to a chemoattractant,13 and specific inhibitors may play a role in COPD. Blockage of adhesion molecules or their down-regulation would have a similar effect of reducing cell migration, and, finally, inactivating or switching off production of the chemoattractants within the airway would also lead to reduced neutrophil traffic. Clearly, this pathway is now reasonably well established and awaits the development of appropriate intervention studies to clarify the importance of individual components.
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Oxidants/Antioxidants |
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TOPAbstractIntroductionProteases/AntiproteasesOxidants/AntioxidantsReferences |
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1-AT. Studies have undoubtedly confirmed that
there is an increased oxidant burden in cigarette smoking, and this may
lead to activation of airway cells and cytokine
production,14
as well as increasing neutrophil
sequestration within the pulmonary capillary
circulation.15
There is indirect evidence to support the
role of oxidants, since less antioxidants in the diet may be
associated with the development of airflow obstruction16
and oxidants can damage connective tissue and decrease elastin repair.
However, there is a strong antioxidant system within the lung; in
particular, free methionine is present in concentrations that reduce
the radius of activity of oxidants to approximately 1 nm, which should
protect the tissues.17
Finally, the limited studies that
have been carried out using antioxidants (N-acetylcysteine) have not
clarified the situation, as they have either shown no
effect18
or a decrease in the exacerbation
rate.19 More recently, studies have suggested that genetic polymorphisms of antioxidant genes are associated more commonly with the presence of COPD than would be predicted from the control population.20 This observation suggests that oxidants may play some role in the development of some of the features of COPD. Clearly, further studies are indicated and may lead to the development of appropriate intervention strategies.
Therapeutic Implications
The above concepts and their influence on ideas about the
pathogenesis of COPD have currently reached an impasse. Interventional
studies with appropriate and effective agents are awaited and will
require the design of relevant clinical studies to demonstrate efficacy
or the lack thereof. Nevertheless, disease modification, which would be
the long-term aim of such strategies, has both cost as well as safety
implications that will have to be carefully addressed. There are, of
course, other features of the condition, such as the regulation of
mucus production, ciliary beat frequency, and tissue and cell repair
mechanisms that may also be potential targets for appropriate therapy.
However, at present, these remain even more theoretical, and further
studies will be necessary to confirm their importance. In the meantime,
it is possible to develop newer strategies based on the conventional
complications of COPD, including airflow obstruction and recurrent
exacerbations. The development of new long-acting bronchodilators such
as the M3 receptor antagonists are nearing the
completion of clinical trials. In addition, there is renewed interest
in the nature of exacerbations and their modulation. There are
tantalizing data that inhaled corticosteroid therapy (although it may
have little effect on long-term decline in lung function) may have a
beneficial effect on exacerbation rate. The reasons for this at the
moment seem unclear, since exacerbations are poorly defined, some are
the result of increased airflow obstruction and air trapping, whereas
others will be caused by viral infections as well as bacterial
infections. The diverse nature of these episodes indicates the
difficulty in proving not only that antibiotics, but also
corticosteroids, have a role to play. Recent studies have indicated
that the development of purulent sputum alone is a feature that is
almost pathognomic of a bacterial infection (Fig 3)
.
Again, better stratification and clarification of the features of the
exacerbation may lead to the development of appropriate antibiotic and
other anti-inflammatory therapy during such episodes.
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Footnotes |
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1-AT = 1-antitrypsin;
SLPI = secretory leukoprotease inhibitor |
References |
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TOPAbstractIntroductionProteases/AntiproteasesOxidants/AntioxidantsReferences |
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1 globulin pattern of serum in 1-antitrypsin deficiency. Scand J Clin Lab Invest 15,132-140[CrossRef][ISI]
This article has been cited by other articles:
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  J. A Dougherty, B. L Didur, and L. S Aboussouan Long-Acting Inhaled {beta}2-Agonists for Stable COPD Ann. Pharmacother., September 1, 2003; 37(9): 1247 - 1255. [Abstract] [Full Text] [PDF]
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 P. J. Ancliff, R. E. Gale, R. Liesner, I. M. Hann, and D. C. Linch Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease Blood, November 1, 2001; 98(9): 2645 - 2650. [Abstract] [Full Text] [PDF]
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 P.J. Grant The Edinburgh Artery Study: is lytic activity bad for the heart? Eur. Heart J., October 1, 2000; 21(19): 1566 - 1567. [PDF]
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