|
Inflammation & Allergy -
Drug Targets
(Formerly 'Current Drug Targets - Inflammation & Allergy')
ISSN: 1871-5281
Current Drug Targets - Inflammation
& Allergy
Volume 4, Number 6, December 2005
Contents
Chronic Obstructive Pulmonary Disease (COPD)
Guest Editor: Alexandre Trifilieff
Editorial: Chronic Obstructive
Pulmonary Disease (COPD) Pp.605
Alexandre Trifilieff
Inflammatory Cells and Chronic Obstructive Pulmonary
Disease Pp.607
Teresa D. Tetley
[Abstract]
Inflammatory Mediators in Chronic Obstructivex Pulmonary
Disease Pp. 619
Kian F. Chung
[Abstract]
Oxidants and COPD Pp.627
William MacNee
[Abstract]
Lung Structural Changes in Chronic Obstructive Pulmonary
Diseases Pp.643
Warren Davidson and Tony R. Bai
[Abstract]
Epithelial Mucus-Hyper-Secretion and Respiratory Disease
Pp.651
Henry. Danahay and Alan D. Jackson
[Abstract]
Animal Models of Pulmonary Emphysema Pp.665
Ravi Mahadeva and Steven D. Shapiro
[Abstract]
Emerging Targets for COPD Therapy Pp.675
Peter J. Barnes
[Abstract]
Abstracts
[Back to top]
Editorial: Chronic Obstructive Pulmonary Disease (COPD)
Alexandre Trifilieff
Chronic obstructive pulmonary disease (COPD) is a multi-component
disease (including emphysema and chronic bronchitis which
may or may not co-exist in the same individual) leading to
a disease state characterized by poorly reversible airflow
limitation that is usually progressive and associated with
an abnormal inflammatory response of the lung. This disease
constitute a major public health burden worldwide and the
World Health Organization estimates COPD to be the world’s
fifth most common disease and fourth leading cause of death
[1]. Both prevalence and mortality are expected to increase
in the coming decades. Cigarette smoking is the major risk
factor for development of COPD, and smoking cessation is the
only intervention that slows the disease progression. Very
few effective therapies are available and bronchodilatator
therapy, such as long acting inhaled β2 agonists or inhaled
anticholinergic agents, is the mainstay of the management
of this disease. For comprehensive reviews about the current
management of COPD the reader can refer to two recently published
reviews [2, 3].
The pathophysiology of COPD is multifactorial with an inflammatory
cells profile that includes macrophages, neutrophils and T
lymphocytes. However, the precise mechanism leading to this
lung inflammation is still unclear and currently no pharmacological
intervention has been shown to modify the progression of the
disease or the associated decline in health status. Although
this disease was neglected in the past, recently an increased
number of studies have been trying to define more precisely
the mechanism underlying this pathology. Consequently, our
understanding of this disease has recently improved and this
dedicated issue is aiming at cover the latest developments
in this topic.
The inflammatory process is covered by T. D. Tetley with
a focus on the inflammatory cell types involved in this disease
and K. F. Chung who recapitulated the various inflammatory
mediators that could be involved. W. MacNee has reviewed the
oxidant/anti-oxidant imbalance hypothesis in this disease.
W. Davidson and T. R. Bai, summarized the lung structural
changes associated with this pathology and H. Danahay and
A. D. Jackson put forward hypotheses that could help to determine
the mechanisms behind epithelial dysfunction in respiratory
diseases. R. Mahadeva and S. D. Shapiro have described the
pro and con of the animal models of pulmonary emphysema. Finally,
P. J. Barnes has put together a list of emerging targets that
could well be the future treatments for this disease. I would
like to express my gratitude to all the contributors and hope
the reader will benefit from reading this special issue on
COPD.
REFERENCES
[1] Murray, C.J.; Lopez, A.D. Science, 1996, 274, 740.
[2] Wouters, E.F. Lancet, 2004, 364, 883.
[3] Sutherland, E.R.; Cherniack, R.M. N. Engl. J. Med., 2004,
350, 2689.
Alexandre Trifilieff
Novartis Institute for BioMedical Research
Respiratory Disease Area
Wimblehurst Road
Horsham, RH12 5AB
UK
E-mail: alexandre.trifilieff@novartis.com
[Back to top]
Inflammatory Cells and Chronic Obstructive Pulmonary
Disease
Teresa D. Tetley
A major contributory factor to the development of chronic
obstructive pulmonary disease (COPD) is the inflammatory response
to cigarette smoke. However, when those with COPD stop smoking,
a continuous cycle of inflammation can lead to continued decline
in lung function. Understanding the role of inflammatory cells
in COPD is difficult because it is a mixture of diseases –
bronchitis, small airways disease and emphysema – that
exhibit different patterns of inflammation and different pathology.
Neutrophils and macrophages have been implicated in this process;
they release proteolytic enzymes and generate oxidants, which
cause tissue damage, as well as cytokines and chemokines,
which can potentiate inflammation and trigger an immune response.
Analysis of sputum and bronchoalveolar lavage fluid shows
increases in both neutrophils and macrophages in respiratory
secretions in COPD subjects; neutrophils are the predominant
cell in the conducting airways, whereas macrophages are the
major cell in secretions from the small airways and parenchyma.
Airway tissue neutrophils are increased in the large and small
airways during infection and exacerbations, whilst parenchymal
neutrophil numbers are inversely related to alveolar wall
destruction, suggesting that they are not involved in the
progression of emphysema. Macrophages are increased throughout
the respiratory tract airway lumen and epithelium in COPD
and are positively related to severity of disease, airway
obstruction and degree of alveolar wall damage in emphysema.
Unactivated T-lymphocytes do not linger in lung tissue. Activated
(eg due to antigenic stimulus) memory T cells home in to the
lung and act as effector cells. CD-8+ T cell differentiation
into memory cells is facilitated by CD-4+ T cells. Binding
of CD-8+ T cells to collagen stimulates proliferation and
mediator production which may contribute to the inflammatory
response. CD8+ cytotoxic/suppressor T cells release cytotoxic
perforins and granzyme B which cause cell death and apoptosis,
a feature of emphysema. Lung secretions contain only a small
percentage of T cells; most T-lymphocytes reside in the subepithelial
and smooth muscle region of the tissue. During COPD, there
is either an increase in the CD8+/CD4+ ratio of T cells, or
an increase in the in total numbers of both CD8+ and CD4+
T cells, in the tissue. Smoking status, smoking history, degree
of airway obstruction and emphysema are all related to increased
CD8+ cells and/or CD8+/CD4+ ratio. During severe emphysema
requiring lung volume reduction surgery, there is a considerable
increase in macrophages, neutrophils, eosinophils, CD4+ and
CD8+ T cells which relates to the severity of the disease.
Interestingly, the marked increase in luminal CD8+ cells results
in an increased ratio of CD8+/CD4+ T cells that is not seen
in the parenchymal tissue. The florid inflammation observed
in severe emphysema is suggested to be related to latent viral
infection.
[Back to top]
Inflammatory Mediators in Chronic Obstructivex Pulmonary
Disease
Kian F. Chung
Chronic obstructive pulmonary disease (COPD) is characterised
by chronic obstruction of expiratory flow affecting peripheral
airways, associated with chronic bronchitis (mucus hypersecretion
with goblet cell and submucosal gland hyperplasia) and emphysema
(destruction of airway parenchyma), together with fibrosis
and tissue damage, and inflammation of the small airways.
Inflammatory mediators include lipid mediators, chemokines,
cytokines, growth factors, reactive oxygen species and proteinases.
Increased levels of interleukin (IL)-6, IL-1β, tumour
necrosis factor-α
(TNF-α)
and IL-8 have been measured in sputum, with further increases
during exacerbations, and the bronchiolar epithelium over-expresses
MCP-1 and IL-8. IL-8 and LTB4 can account for neutrophil
chemotactic activity of sputum. The expression of chemokines
such as RANTES and eotaxin may underlie the airway eosinophilia
observed in some COPD patients. Reactive oxygen species can
increase gene expression of many inflammatory mediators, such
as IL-1 and TNFα
from macrophages, alveolar and bronchial epithelial cells.
TNFα
and IL-1β stimulate macrophages to produced matrix metalloproteinase-9
(MMP-9), and bronchial epithelial cells to produce extracellular
matrix glycoproteins such as tenascin. Increased expression
of transforming growth factor-β (TGFβ) and of epidermal
growth factor (EGF) occurs in the epithelium and submucosal
cells of patients with chronic bronchitis. TGFβ and EGF
activate proliferation of fibroblasts, while activation of
the EGF receptor leads to mucin gene expression.
[Back to top]
Oxidants and COPD
William MacNee
Smoking is the main etiologic factor in chronic obstructive
pulmonary disease (COPD). Cigarette smoke produces an enormous
oxidant burden on the lungs, which is exacerbated by the release
of oxidants from inflammatory cells. There is considerable
evidence that an increased oxidative burden occurs in the
lungs of patients with COPD, and this may be involved in many
of the pathogenic processes, such as direct injury to lung
cells, mucus hypersecretion, inactivation of antiproteases,
and enhancing lung inflammation through activation of redox-sensitive
transcription factors. COPD is also recognized to have multiple
systemic consequences, such as weight loss and skeletal muscle
dysfunction. Moreover, it is appreciated that oxidative stress
extends beyond the lung and may, through similar oxidative
stress mechanisms as those in the lung, contribute to several
of the systemic manifestations in COPD such as skeletal muscle
dysfunction. Thus, there is a great need for an effective
antioxidant therapy to modulate the oxidative stress in COPD,
since this may be an important therapeutic target.
[Back to top]
Lung Structural Changes in Chronic Obstructive Pulmonary
Diseases
Warren Davidson and Tony R. Bai
Structural changes in COPD are found in the central airways,
peripheral airways, lung parenchyma, and pulmonary vasculature.
Broadly there are two different pathways leading to the same
physiologic phenotype: one centered on the small airways and
involving mucosal inflammation and structural change, and
the other centered on the parenchyma involving excessive proteolysis
and /or disordered repair processes. A highly variable combination
of these changes exists in different patients, in part due
to genetic factors. The composite picture seen on pulmonary
function tests is evidence of over-inflation of the lung,
decreased airflow and abnormalities in gas exchange. Earlier
stages of the airway disease are associated with more potentially
reversible changes, whereas later stages show more collagen
deposition and hence irreversibility. Thus a careful assessment
of the structural phenotype of subpopulations of COPD patients
is likely to lead to optimal categorization for therapeutic
trials, and earlier disease is more likely to response to
interventions.
[Back to top]
Epithelial Mucus-Hyper-Secretion and Respiratory Disease
Henry Danahay and Alan D. Jackson
Mucus production, secretion and clearance are considered
to play a critical role in maintenance of airway health, however
in diseases such as COPD, epidemiological and pathological
studies suggest that excess mucus contributes to airway plugging
and decline in lung health. The airway surface epithelium
is composed of a heterogeneous mix of cell types one of which,
the goblet cell, is dedicated to the production of secretory
gel-forming mucins. Changes in epithelial cellular composition
and function in response to irritants and microbes generally
leads to enhanced co-ordinated functioning of the major facets
of the mucociliary clearance (MCC) system i.e. mucus secretion,
ion/fluid transport and ciliary function. The presence of
mucus plugs in the airways of COPD patients demonstrates that
facets of the MCC system have become compromised i.e. normally
co-ordinated epithelial functions have become uncoupled. Almost
nothing is known about the processes leading to such uncoupling.
Understanding these processes may provide insights into mechanisms
involved in regulation of epithelial integrity and the genesis
of respiratory diseases such as COPD. In this review we will
discuss regulation of airway epithelial cellular composition
and function primarily with respect to goblet cell formation,
mucus secretion, airway surface liquid (ASL) homeostasis,
hydration of secreted mucus and ciliary clearance. We will
discuss the functional overlap between cell populations, the
potential impact of derivation from different progenitors
and the implications of generating high goblet cell densities
in the surface epithelium. The aim of this review is to stimulate
discussion and develop hypotheses that could help to determine
the mechanisms behind epithelial dysfunction in respiratory
disease.
[Back to top]
Animal Models of Pulmonary Emphysema
Ravi Mahadeva and Steven D. Shapiro
Chronic obstructive pulmonary disease is a major cause of
morbidity and mortality worldwide. The mechanisms by which
cigarette smoke leads to the irreversible dilatation and destruction
of terminal airspaces of the lung are being unravelled largely
as a result of the explosion of studies in animals. At the
forefront of this has been the use of genetically manipulated
mice, and the evolution and understanding of different models
of emphysema. This review will summarise the current models
of emphysema.
[Back to top]
Emerging Targets for COPD Therapy
Peter J. Barnes
No currently available treatments reduce the progression
of COPD or suppress the inflammation in small airways and
lung parenchyma. However, several new treatments that target
the inflammatory process are in clinical development. A group
of specific therapies are directed against the influx of inflammatory
cells into the airways and lung parenchyma that occurs in
COPD; these include adhesion molecule and chemokine-directed
therapy, as well as therapies to combat tumour necrosis factor-α
and augment interleukin-10. Broad spectrum anti-inflammatory
drugs are now in phase III development for COPD, and include
phosphodiesterase-4 inhibitors. Other drugs that inhibit cell
signalling include inhibitors of p38 mitogen-activated protein
kinase, nuclear factor-κB
and phosphoinositide-3 kinase-γ.
More specific approaches are to give antioxidants, inhibitors
of inducible nitric oxide synthase, and leukotriene B4
receptor antagonists. Epidermal growth factor receptor kinase
inhibitors and calcium-activated chloride channel inhibitors
have potential to combat mucus overproduction. Therapy to
inhibit fibrosis is being developed against transforming growth
factor-β1 and protease activated receptor-2. There is
also a search for serine proteinase and matrix metalloproteinase
inhibitors to prevent lung destruction and the development
of emphysema, as well as drugs such as retinoids that may
even reverse this process. Effective delivery of drugs to
the sites of disease in the peripheral lung is an important
consideration, and there is the need for validated biomarkers
and monitoring techniques in early clinical studies with new
therapies for COPD.
|
