Current Drug Targets - Inflammation & Allergy - Volume 4, Issue 6, 2005

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.

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 CD4+ 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 Tlymphocytes 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.

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.

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.

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.

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.

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.

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 chemokinedirected 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.