The effects of cigarette smoke on airway inflammation in asthma and COPD: therapeutic implications

Asthma and COPD are two chronic inflammatory disorders of the airway characterized by airflow limitation. While many similarities exist between these two diseases, they are pathologically distinct due to the involvement of different inflammatory cells; predominantly neutrophils, CD8 lymphocytes in COPD and eosinophils and CD4 lymphocytes in asthma. Cigarette smoking is associated with accelerated decline of lung function, increased mortality, and worsening of symptoms in both asthma and COPD. Furthermore, exposure to cigarette smoke can alter the inflammatory mechanisms in asthma to become similar to that seen in COPD with increasing CD8 cells and neutrophils and may therefore alter the response to therapy. Cigarette smoke exposure has been associated with a poor response to inhaled corticosteroids which are recommended as first line anti-inflammatory medications in asthma and as an add-on therapy in patients with severe COPD with history of exacerbations. While the main proposed mechanism for this altered response is the reduction of the histone deacetylase 2 (HDAC2) enzyme system, other possible mechanisms include the overexpression of GR-β, activation of p38 MAPK pathway and increased production of inflammatory cytokines such as IL-2, 4, 8, TNF-α and NF-K?. Few clinical trials suggest that leukotriene modifiers may be an alternative to corticosteroids in smokers with asthma but there are currently no drugs which effectively reduce the progression of inflammation in smokers with COPD. However, several HDAC2 enhancers including low dose theophylline and other potential anti-inflammatory therapies including PDE4 inhibitors and p38 MAPK inhibitors are being evaluated.     

Pharmacology of airway inflammation in asthma and COPD

The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term treatment. Although inhaled glucocorticoids are highly effective in controlling airway inflammation in asthma, they are ineffective in the small group of patients with glucocorticoid-dependent and -resistant asthma. With very few exceptions, COPD is caused by tobacco smoking, and smoking cessation is the only truly effective treatment of COPD available. Current pharmacological treatment of COPD is unsatisfactory, as it does not significantly influence the severity of the disease or its natural course. Glucocorticoids are scarcely effective in COPD patients without concomitant asthma. Bronchodilators improves symptoms and quality of life, in COPD patients, but, with the exception of tiotropium, they do not significantly influence the natural course of the disease. Theophylline is the only drug which has been demonstrated to have a significant effect on airway inflammation in patients with COPD. Here we review the pharmacology of currently used antiinflammatory therapies for asthma and COPD and their proposed mechanisms of action. Recent understanding of disease mechanisms in severe steroid-dependent and -resistant asthma and in COPD, has lead to the development of novel compounds, which are in various stages of clinical development. We review the current status of some of these new potential drugs.     

Clinical implications of airway hyper-responsiveness in COPD

COPD represents one of the leading causes of mortality in the general population. This study aimed at evaluating the relationship between airway hyperresponsiveness (AHR) and COPD and its relevance for clinical practice. We performed a MEDLINE search that yielded a total of 1919 articles. Eligible studies were defined as articles that addressed specific aspects of AHR in COPD, such as prevalence, pathogenesis, or prognosis. AHR appears to be present in at least one out of two individuals with COPD. The occurrence of AHR in COPD is influenced by multiple mechanisms, among which impairment of factors that oppose airway narrowing plays an important role. The main determinants of AHR are reduction in lung function and smoking status. We envision a dual role of AHR: in suspected COPD, specific determinants of AHR, such as reactivity and the plateau response, may help the physician to discriminate COPD from asthma; in definite COPD, AHR may be relevant for the prognosis. Indeed, AHR is an independent predictor of mortality in COPD patients. Smoking cessation has been shown to reduce AHR. Further studies are needed to elucidate whether this functional change is associated with improvement in lung function and respiratory symptoms.     

The airway pathophysiology of COPD: implications for treatment

The pathophysiology of chronic obstructive pulmonary disease (COPD) is complex and can be attributed to multiple components: mucociliary dysfunction, airway inflammation and structural changes, all contributing to the development of airflow limitation, as well as an important systemic component. Current pharmacotherapies vary in their ability to address the underlying multi-component nature of COPD. Long-acting anticholinergics and long-acting beta2-agonists (LABAs) can both provide effective and convenient bronchodilation in moderate COPD (Stage II-GOLD) and are recommended as regular therapy in global treatment guidelines. However, there is evidence to suggest that LABAs can mediate additional benefits independent of their bronchodilatory effects and may help address the multi-component nature of COPD. Effects on mucociliary dysfunction and reduced bacterial-induced damage have been experimentally proven with LABAs, and anti-inflammatory activity and structural effects have also been suggested. The use of inhaled corticosteroids (ICSs) is now recommended for the treatment of COPD patients with frequent exacerbations. In addition, ICSs provide a range of anti-inflammatory effects in COPD and thus have effects that are complementary to those of LABAs. Recent data indicate that LABA/ICS combinations produce wide-ranging clinical benefits that are greater than with either agent alone. Other new strategies include selective phosphodiesterase 4 (PDE4) inhibitors, which in addition to anti-inflammatory activity, have been shown to provide bronchodilation in COPD. In summary, the potential to address the multicomponent nature of COPD with strategies such as LABA/ICS combination therapy, and the development of new treatments directed at novel targets means that the future for sufferers of COPD can be more optimistic.     

Reduced histone deacetylase in COPD: clinical implications

COPD is characterized by progressive inflammation in the small airways and lung parenchyma, and this is mediated by the increased expression of multiple inflammatory genes. The increased expression of inflammatory genes is regulated by acetylation of core histones around which DNA is wound, and conversely these activated genes are switched off by deacetylation of these histones. Histone deacetylases (HDACs) suppress inflammatory gene expression, but their activity and expression (particularly of HDAC-2) is reduced in the peripheral lung and in alveolar macrophages of patients with COPD. This results in amplification of the inflammatory response as COPD progresses but also accounts for corticosteroid resistance in COPD, since HDAC-2 is required by corticosteroids to switch off activated inflammatory genes. The reduction in HDAC-2 appears to be secondary to the increased oxidative and nitrative stress in COPD lungs. Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in COPD, but this can also be achieved by low doses of theophylline, which is an HDAC activator. This mechanism is also relevant to asthmatic patients who smoke, patients with severe asthma and cystic fibrosis, in whom oxidative stress is also increased.     

Eosinophil progenitors in airway diseases: clinical implications

Asthma, allergic rhinitis, nasal polyposis, chronic rhinosinusitis, and related forms of upper and lower airway diseases are often characterized by eosinophilic and basophilic inflammation, involving systemic processes. Eosinophil/basophil (Eo/B) lineage-committed progenitor cells in cord blood, peripheral blood, bone marrow, lung tissue, and sputum are up-regulated in the above conditions, and respond to allergen and other stimuli with increased differentiative and migratory capacity. A considerable body of evidence now exists showing that activation of such Eo/B-selective hemopoietic processes is not only associated with the onset and maintenance of allergic inflammation in atopic adults, but also with the development of the allergic diathesis. Moreover, eosinophilopoietic processes within hemopoietic compartments and, importantly, at mucosal tissue sites during an allergic inflammatory response provide novel targets for the treatment of allergy as a systemic process and disease.     

Small airways disease in asthma

A mounting body of physiologic and pathologic evidence indicates that asthma involves the central and the more distal airways. In patients with asthma, the peripheral lung accounts for a significant portion of airway resistance and, similar to the large airways, the small airways have been shown to be hyperresponsive to nonspecific stimuli, such as methacholine. Cellular inflammation, consisting of an infiltrate rich with lymphocytes and eosinophils, is present in the small airways of patients with asthma and may be more intense than that observed in the large airways. Clinical assessment of the peripheral airways continues to be a challenge, and new techniques, such as quantitative analysis of chest CT images, have proven to be useful research tools. The recognition of small airways involvement in asthma has clinical relevance, as new formulations of inhaled corticosteroids with smaller particle aerosols may be more effective in addressing this component of asthma.     

Acute and chronic airway responses to viral infection: implications for asthma and chronic obstructive pulmonary disease

Despite the high clinical impact of established and emerging respiratory viruses, some critical aspects of the host response to these pathogens still need to be defined. In that context, we aimed at two major issues: first, what are the innate immune mechanisms that control common respiratory viral infections; and second, whether these mechanisms also cause long-term airway disease. Using a mouse model of viral bronchiolitis, we found that antiviral defense depends at least in part on a network of mucosal epithelial cells and macrophages specially programmed for immune-response gene expression. When this network is compromised, the host is highly susceptible to infection, but network components can be engineered to provide increased resistance to infection. Similar alterations appear in asthma and chronic bronchitis/chronic obstructive pulmonary disease, suggesting that evolving attempts to improve antiviral defense may also lead to inflammatory airway disease. Indeed, in genetically susceptible mice, respiratory paramyxoviruses cause a "hit and run" phenomenon that is manifested by the development of a permanent airway disease phenotype long after the infection has cleared. The phenotype can be segregated into individual traits to achieve more precise definition of just how viruses reprogram host behavior. Identifying specific components of the mucosal immune system that manifest an aberrant antiviral response may thereby allow for adjusting this response to improve acute and chronic outcomes after viral infection.