Lesson 19, Volume 16—Inflammation and Treatment in Asthma and COPD

By James F. Donohue, MD, FCCP; and Jill A. Ohar, MD, FCCP

Objectives

1. Understand the similarities and differences in inflammatory cells in asthma and COPD.
2. Distinguish the Dutch hypothesis from the British hypothesis concerning the pathogenesis of COPD.
3. Describe the role of inhaled corticosteroids in asthma and COPD.
4. Identify appropriate therapeutic targets in asthma and COPD.
5. Choose appropriate anti-inflammatory agents and bronchodilators for asthma and COPD.

Key words

asthma; COPD; eosinophil; inflammatory cell; mast cell; Th1 lymphocytes; Th2 lymphocytes

Abbreviations

BDP = beclomethasone dipropionate; FP = fluticasone propionate; GOLD = Global Initiative for Chronic Obstructive Lung Disease; ICS = inhaled corticosteroid; IgE = immunoglobulin E; IL = interleukin; LAR = late-phase allergic response; LTB4 = leukotriene B4; MMP = matrix metalloprotease; PDE4 = phosphodiesterase-4; Th1 = subtype 1 helper T; Th2 = subtype 2 helper T; TNF-a = tumor necrosis factor

Asthma is a chronic respiratory disorder characterized by reversible airflow obstruction and bronchial hyperresponsiveness.¹ The primary pathologic components of asthma are inflammation and smooth-muscle dysfunction. In some patients, chronic inflammation of the airways may also result in structural changes, or remodeling, characterized by cellular proliferation of smooth muscle, basement-membrane thickening and to a lesser extent, increased deposition of matrix proteins and mucous gland hypertrophy.² The clinical consequences of inflammation are exacerbations and bronchial hyperresponsiveness. Similar consequences are seen in COPD, but the underlying profile of inflammatory cells differs.
Although the pathogenesis of asthma has not been fully determined, asthma in children and adults is frequently associated with atopy, an inherited propensity to produce abnormal amounts of immunoglobulin E (IgE) against common environmental antigens. IgE-induced activation of mast cells results in the release of proinflammatory mediators. Atopy is one of the strongest identifiable risk factors for developing asthma. For COPD, exposure to environmental irritants such as tobacco smoke is the strongest risk factor.
This review will examine the critical role of inflammation in the pathophysiology of asthma and COPD, including its impact on airway structure and function. In addition, effective management strategies that target the inflammatory process that underlies asthma and COPD will be discussed. The review will also comment on the Dutch hypothesis, which is a unifying explanation for both asthma and COPD.

Asthma

Significance

The prevalence of asthma has increased dramatically in the United States over the past 30 years. The mortality rates also increased until they reached a plateau recently. Mortality is especially high in African Americans (38.5 vs 15.1 per million in Caucasians) and it is also high in Hispanics of Puerto Rican heritage (40 per million). Asthma was estimated to affect more than 10.2 million adults during 1996. Direct and indirect costs associated with asthma during 1998 were $12.7 billion. A recent report from the 2000 Behavioral Risk Factors Surveillance System estimates that approximately 7.2% of adults residing in the United States have asthma. The prevalence of asthma decreases with increasing family income. The prevalence is 9.8% among people with family incomes of < than $15,000 and 5.9% among those with incomes > $75,000. Women had higher prevalence rates of asthma than men (9.1 vs 5.1%).³

For unclear reasons, more affluent Western countries have higher prevalence rates than impoverished nations, giving rise to the "health hygiene hypothesis." The basic tenet is that the immune system of the newborn infant is skewed toward subtype 2 helper T (Th²) cells and needs timely and appropriate environmental stimuli to create a balanced immune response with subtype 1 helper T (Th₁) cells. The presence of older siblings, early exposure to day care, tuberculosis, measles or hepatitis A infection, or living in a rural environment are factors that favor the Th₁ phenotype. The Th₂ allergic, asthmatic phenotype is favored by the widespread use of antibiotics, Western lifestyle, living in an urban environment, a diet high in sodium and fat, plus sensitization to house dust mites and cockroaches.

The Dutch Hypothesis

There are important pathophysiologic similarities between asthma and chronic airflow obstruction; a predisposition is required for the development of both obstructive lung diseases. These individuals are characterized by the presence of bronchial inflammation that includes (1) increased immune atopic responses, and (2) inflammatory mediator release and cellular responses and bronchial hyperresponsiveness. Potential interactions between asthma and COPD thus include genetic susceptibility and environmental factors (eg, allergy, infection, smoking, and air pollution) leading to bronchial inflammation and bronchial hyperresponsiveness, resulting in a phenotypic expression of asthma and COPD. The Dutch hypothesis holds that genetic susceptibility and allergens lead to both asthma and COPD. In contrast, the British hypothesis states that COPD is closely related to irritant exposure and to recurrent infections.

Disease Pathology in Asthma and COPD

While both diseases have components of variable airflow obstruction, asthmatics respond more frequently and to a greater extent to bronchodilators than do patients with COPD. COPD, as defined in the National Heart, Lung, and Blood Institute Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines⁴ as "progressive obstruction that is partially reversible." Both conditions are characterized by lung inflammation, although the magnitude of inflammation is greater in asthma (Table 1). COPD is associated with greater mucus hypersecretion and there are more epithelial changes, specifically more goblet cells, and squamous metaplasia. Asthma is more closely associated with airways epithelial shedding and thickening of the basement membrane. COPD has a greater component of alveolar destruction. Smooth muscle hypertrophy, while seen in both, is more often a feature of asthma, while submucosal gland proliferation is more typical of COPD. In chronic stable COPD, the cells active in the inflammatory process include macrophages, monocytes, CD8 lymphocytes, and neutrophils. In contrast, in asthma, the predominant cells are lymphocytes, mast cells, and eosinophils (Figure1). However, in acute exacerbations of COPD, eosinophils and lymphocytes take on a more prominent role.

Figure 1. Asthma and COPD. Reprinted from the GOLD guidelines (www.goldcopd.com).

The Inflammatory Process in Asthma

Evidence that inflammation is a key component of asthma initially came from autopsy findings in patients with fatal asthma. Histologic examination revealed infiltration of the airways by neutrophils, eosinophils, and degranulated mast cells. Structural changes were visible as well; these included subbasement-membrane thickening, loss of epithelial cell integrity, and occlusion of the bronchial lumen by mucus. Hypertrophy and hyperplasia of airway smooth muscle and hyperplasia of goblet cells were also present. Additional information on the inflammatory component of asthma has been noted from endobronchial biopsies and BAL samples. These show an increase in the numbers of eosinophils, mast cells, and epithelial cells in asthmatics compared with both atopic and nonatopic persons without asthma. These inflammatory changes have been seen even in patients with mild disease.

The airway response to inhaled allergens forms the basis of much of our current understanding of the inflammatory process in asthma. After inhalation of an allergen by a patient with atopic asthma, bronchial obstruction can be seen in a matter of minutes. This early-phase response results primarily from the release of preformed proinflammatory mediators such as histamine and synthesis of leukotrienes C₄, D₄, and E₄ from bronchial mast cells. Mast cells arise in the bone marrow and travel to the mucosal and submucosal sites in the airways. The cross-linking of mast cell-bound IgE with allergen induces the activation of membrane and cytosolic pathways, leading to the release of mediators such as histamine and the synthesis of arachidonic acid metabolites. Mast cells respond to IgE-mediated and non-IgE-mediated (eg, osmotic) changes with the release of mediators. These include prostaglandins; leukotrienes; cytokines such as interleukin (IL) 1, IL-2, IL-4, IL-10, and IL-13; growth factors; and potent proteases such as trypsin.⁵ A recent study found that the infiltration of airway smooth muscle by mast cells is associated with disordered airway function in asthma, such as variable airflow obstruction and airway hyperresponsiveness.⁶ These mediators induce smooth muscle contraction, mucus secretion, and vasodilatation. Inflammatory mediators also induce microvascular leakage of plasma proteins, causing edematous swelling of the airway walls and a narrowing of the airway lumen. The early-phase allergic response usually resolves within 1 h, either spontaneously or with therapeutic intervention.

In many cases, a second phase of airflow obstruction, termed late-phase allergic response (LAR), occurs 6 to 10 h later. The LAR develops as a result of cytokines and chemokines generated by resident cells (mast cells, macrophages, and epithelial cells) and recruited inflammatory cells (T lymphocytes and eosinophils). The T lymphocytes involved in this process are Th₂, responsible for the immediate hypersensitivity reactions involved in allergic diseases, including asthma. The Th₂ subtype produces IL-4, IL-5, IL-6, IL-9, and IL-13; these cytokines have pronounced effects on inflammatory cells, particularly eosinophils. Eosinophils have an essential role in inflammation in asthma. IL-5 induces differentiation of immature eosinophils and stimulates their release from the bone marrow into the circulation and prolongs their survival. The eosinophil migrates from the circulation into the airway. On activation, the eosinophil releases inflammatory mediators such as leukotrienes and granule proteins such as major basic protein to injure airway tissues.

Features of the LAR include bronchospasm, further inflammation, and airway wall edema. Swelling of the airway wall also leads to a loss of elasticity, which further contributes to airflow limitation. An additional consequence of the LAR is an increase in airway hyperresponsiveness, which reinforces and perpetuates the asthmatic response.

Smooth Muscle Dysfunction

An exaggerated bronchoconstrictor response (airway hyperresponsiveness) to various stimuli plus an increase in bronchial smooth muscle mass are hallmarks of asthma. Airway hyperresponsiveness refers to the propensity of airways to "narrow too easily and too much." It leads to symptoms of wheezing and dyspnea after exposure to allergens. The increase in smooth muscle mass in asthma may result from several factors, including an increased release of inflammatory mediators, cytokines, and growth factors. The airway smooth muscle cell had been thought of primarily a resident structure cell that contracted in response to mediators. The smooth muscle cell, however, secretes a large number of inflammatory cytokines, proliferates in response to agents secreted by other cells, expresses adhesion molecules, and attracts other inflammatory cells to the site. Thus, the smooth muscle cell may have a central role in the inflammatory events of asthma.

Airway Wall Remodeling

Chronic inflammation of the airways may result in irreversible airflow limitation and altered airway structure, known as remodeling. It is characterized by airway smooth muscle hypertrophy secondary to prolonged smooth muscle dysfunction, new vessel formation, goblet cell hyperplasia, increased deposition of matrix protein, basement-membrane thickening, and occlusion of the bronchial lumen by mucus.

Chronic Inflammation

The physiologic and clinical features of asthma derive from interactions among resident and infiltrating inflammatory cells and from the increased airway smooth muscle responsiveness caused by both bronchoconstriction and inflammation. The severity of asthma correlates with the extent of inflammation, sputum eosinophilia, and neutrophilia. The site of inflammation is primarily in peripheral airways, but the central airways, alveoli, and bronchiolar tissues are also inflamed. Inflammatory cells have prolonged survival in asthma, a phenomenon reversed by inhaled corticosteroids (ICSs). Neutrophils play an important role in patients with more severe, long-standing asthma. Irreversible airflow obstruction, also known as remodeling, develops in some patients with asthma, even those with mild disease. Although the pathophysiology and pathogenesis of this airway remodeling are not completely understood, it is likely caused by chronic airway inflammation. Recent evidence suggests that treatment with ICSs may prevent remodeling or control its intensity in some patients. In a study of patients with mild asthma, Olivieri and colleagues⁷ found that treatment with fluticasone significantly reduced the number of inflammatory cells as well as the inflammatory process, thereby modulating collagen deposition beneath the basement membrane. Although long-acting b₂-agonists are potent inhibitors of mast cells and reduce neovascularity, there is no evidence that they have anti-inflammatory effects or affect airway wall remodeling.

Management

Because inflammation is considered an early and persistent component of asthma, current guidelines recommend that therapy be directed toward long-term asthma control with anti-inflammatory medications such as ICSs, cromones, leukotriene-receptor antagonists, and theophylline. The use of these medications reduces markers of airway inflammation and decreases airway hyperresponsiveness. Evidence suggests that possible early intervention with ICSs can improve asthma control, normalize lung function, and possibly prevent irreversible airway remodeling. Even mild persistent asthmatics should take controller medications. Asthma medications are categorized as either quick-relief medications or long-term, preventive or controller medications. Only anti-inflammatory agents will be discussed.

ICSs. These are the most potent and effective anti-inflammatory agents currently available. Studies have demonstrated their efficacy in improving lung function, decreasing airway hyperresponsiveness, reducing symptoms, reducing the frequency and severity of exacerbations, and improving quality of life. ICSs, if used regularly, are associated with a lower death rate due to asthma and reduced rates of hospitalization. Newer ICSs are fluticasone and mometasone; older agents include beclomethasone, budesonide, triamcinolone, and flunisolide.

ICSs are recommended for most patients with asthma; the dose is increased as required to obtain control or a second agent is added (eg, the long-acting b-agonist salmeterol or formoterol, or a leukotriene modifier). Published data are insufficient to determine with confidence the dose-response relation of ICSs. It appears that lower doses of the newer ICSs may be sufficient to control asthma in most patients. Holt et al⁸ recently reviewed data on the dose-response curve for inhaled fluticasone propionate (FP) in both adults and adolescents with moderate to severe asthma. All major clinical outcomes including exacerbations began to plateau at 100 to 200 mg/d and peaked at 500 mg/d.⁸ Furthermore, a study from the Asthma Clinical Research Network found that near-maximal FEV₁, FVC, and provocative concentration of substance causing 20% fall in FEV₁ occurred at low-medium doses of FP (88 mg) and medium doses of beclomethasone dipropionate (BDP) (627 mg). High-dose ICS therapy did not significantly increase the efficacy measures, but did increase the systemic effects such as overnight cortisol suppression.⁹

With evidence that inflammation occurs even in patients with mild asthma, therapy with ICSs is now recommended at a much earlier stage of the disease. The importance of intervention in mild asthma is underscored by the results of an Australian survey of deaths in children due to asthma^.22 A third of the deaths occurred in children who had been judged to have a history of trivial or mild asthma; 32% had no previous hospital admission for asthma. Many patients are misclassified as having intermittent asthma (> 40%), when in reality they have mild or moderate persistent asthma. Many have abnormalities seen in BAL and bronchial biopsy specimens and changes in small-airway mechanical function—which argues for more use of ICS therapy.

Cromolyn and nedocromil. These two compounds have similar anti-inflammatory actions, and their mechanism of action appears to involve the blockade of chloride channels; they also modulate mast-cell mediator release and, consequently, eosinophil recruitment. Cromolyn and nedocromil inhibit both the early and late asthmatic response to allergens and exercise-induced bronchospasm. Both compounds have an exceptionally good safety profile and are predominantly used as treatment for milder pediatric asthma. They are less effective in the setting of poorly controlled asthma, and are not useful in the treatment of acute asthma.

Leukotriene modifiers. The most recent National Asthma Education and Prevention Program guidelines¹ state that the leukotriene modifiers such as zafirlukast and montelukast may be considered as well as low-dose ICSs, cromolyn, and a nedocromil for patients with mild persistent asthma. Further clinical experience and study are needed to document the long-term usefulness of these agents in asthma therapy. Currently available leukotriene modifiers include leukotriene-receptor antagonists (eg, zafirlukast and montelukast) and an inhibitor of leukotriene synthesis (zileuton). Evidence suggests that these agents can improve lung function, lessen the need for short-acting inhaled b₂-agonists, and protect against exercise-induced bronchospasm.

However, leukotriene modifiers are not as effective as ICSs. In a recent study, patients with persistent asthma who were receiving BDP or triamcinolone acetonide were switched to a low dose of inhaled FP or to zafirlukast.²³ Significantly more patients in the zafirlukast group were more likely to be withdrawn from the study because of lack of efficacy. However, other recent reports suggest that leukotriene modifiers may play a role in combination with low-dose ICS regimens, although they appear to be less effective as add-on therapy than salmeterol. These agents can be used to reduce the dose of ICSs.

Uncontrolled asthma. Treatment guidelines recommend that patients with persistent asthma, whether mild or moderate, receive daily, long-term controller medications. The most effective long-term control medications are those with anti-inflammatory effects that reduce chronic airway inflammation and airway hyperresponsiveness. In some patients with moderate or severe persistent asthma, however, a combination of agents with complementary mechanisms of action may be needed to control the disease.

A meta-analysis²⁴ found that salmeterol added to low-to-moderate doses of ICSs improved lung function and increased the number of symptom-free days and nights, with no increase in exacerbations. Salmeterol or formoterol as an adjunct to ICS is more effective than monotherapy with an ICS dose 2 to 4 times higher, regardless of the type of ICS used. The addition of a long-acting inhaled b₂-agonist is particularly useful in patients with nocturnal symptoms.

Recent studies also suggest that adding a long-acting inhaled b₂-agonist, with its minimal effects on airway inflammation, to a therapeutic regimen of ICS does not eliminate the need for the ICS. There are recent conflicting reports as to whether adding a long-acting inhaled b₂-agonist can even safely permit the dosage of the ICS to be reduced without risking clinical deterioration. In a 24-week study,^25,26 patients whose asthma was poorly controlled with triamcinolone were randomized to receive add-on therapy with salmeterol or placebo. A reduction in corticosteroid dose with salmeterol was attainable, but treatment failure occurred in 46% of patients who discontinued corticosteroid therapy while continuing with salmeterol.

Studies have evaluated combining ICSs with leuoktriene modifiers. Montelukast provided additional asthma control in patients whose asthma was incompletely controlled by inhaled BDP, although withdrawing corticosteroids while continuing montelukast led to deterioration. In patients with chronic asthma receiving high doses of ICSs, the addition of montelukast (10 mg once a day at bedtime) allowed a reduction in the ICS dose while still maintaining clinical control of asthma symptoms.^31,27

ICSs also appear to be superior to leukotriene modifiers as monotherapy. Patients receiving ICSs had a significantly larger increase in FEV1 and a larger decline in daytime symptom scores. While montelukast did have a favorable effect on peak expiratory flow rates, quality of life, nocturnal awakenings, and asthma attacks, outcomes for these variables were better in the BDP group. The combination of FP and salmeterol provided more effective asthma control, including significantly lower exacerbation rates, than did FP and montelukast.^28,29

In some cases, patients whose asthma is not controlled by high doses of ICSs or the addition of long-acting bronchodilators also need oral corticosteroids on a regularly scheduled, long-term basis. When control of asthma is achieved, however, persistent attempts should be made to reduce systemic corticosteroids and replace them with ICSs, since these agents have fewer systemic effects.

COPD

Significance

COPD represents a disease state characterized by poorly reversible airflow limitation that is usually both progressive and associated with an abnormal inflammatory response of the lung.⁴ It is a disorder largely caused by the inhalation of tobacco smoke. Other risk factors include environmental exposures such as coal, asbestos, or indoor air pollution. Genetic predisposition, childhood respiratory tract infections, and low birth weight are also factors that influence the development of COPD. COPD is by definition a progressive disorder. Healthy nonsmokers > 30 years of age lose FEV₁ at a rate of 20 mL/yr, but the age-related loss of FEV₁ in smokers with COPD is accelerated.¹⁰ No currently available COPD therapy except oxygen and smoking cessation changes the rate of FEV₁ loss. While 80 to 90% of the burden of COPD is caused by cigarette smoking, only 15 to 20% of smokers develop COPD. COPD is currently the fourth leading cause of death in the United States and the only disease among the top 10 causes of death that is increasing in prevalence. The World Health Organization predicts that COPD will be the third leading cause of death worldwide within the next two decades.⁴ Despite these startling statistics, tobacco consumption rates are on the rise worldwide, which will result in new cases of COPD for decades to come.

Pathophysiology

COPD primarily affects the distal airways.¹¹ Generally, inflammation affects bronchioles at the level of the respiratory bronchiole extending to the alveolar wall.^11,12Airway walls are infiltrated with macrophages and lymphocytes. In contrast to asthma, the airway lymphocytes tend to be CD8+ rather than CD4+ cells. The CD4+ cells that are present in COPD tend to be Th₁ rather than the Th₂ cells found in asthma. Neutrophils are found in greater numbers in the airway lumen, and peribronchiolar fibrosis is seen in mid- to late-stage disease. Affected airways tend to be < 2 mm in diameter; airway obstruction results from structural narrowing caused by the inflammatory process, loss of elastic recoil due to breakdown of intra-alveolar elastic fibers, and loss of alveolar attachments from emphysema-induced alveolar septal destruction.¹¹ Neutrophils are increased in and around bronchial glands, where the elastase they produce promotes mucus hypersecretion. Although neutrophils, macrophages, and lymphocytes predominate in stable COPD, eosinophils may be increased in the airway walls and lumens in COPD exacerbations.

Inflammation

The inflammatory process in COPD appears to be fueled by the interaction of several chemokines and proteolytic enzymes. Interleukin (IL-8), tumor necrosis factor (TNF-a), and leukotriene B₄ (LTB₄) are all found in increased concentration in the sputum of patients with COPD.¹¹ Macrophages produce LTB₄, IL-8, and the proteolytic enzymes matrix metalloprotease (MMP) 12, MMP-1 (collagenase), and MMP-9 (gelatinase B). Macrophage-derived TNF-a amplifies neutrophil recruitment and accumulation in lung tissue by activation of neutrophil surface adhesion molecules. TNF-a upregulates cytokine production and is associated with COPD cachexia. Expression of TNF-a, IL-8, and the MMPs is regulated by the transcription factor, nuclear factor kappa B, which is activated by oxidants. Oxidants such as superoxide anion, nitric oxide, hydroxyl radical, peroxide (H₂O₂), and peroxynitrite are abundant in cigarette smoke. The concentration of oxidants may be as high as 10¹⁷/puffs activated. Macrophages and neutrophils also serve as an endogenous source for oxidants such as H₂O₂ and O₂. Oxidants may cause direct tissue damage or augment the inflammatory process indirectly through oxidative inactivation of the inhibitors of neutrophil elastase such as a-antitrypsin. LTB₄ and IL-8 are chemotactic for neutrophils and interact synergistically. IL-8 promotes neutrophil chemotaxis and activation through binding to chemokine CXC receptors, CXCR1 and CXCR2, on their cell surface. Neutrophils produce LTB₄ and the proteolytic enzymes elastase, proteinase 3, cathepsin G, MMP-1, and MMP-9. Both TNF-a and neutrophil elastase promote IL-8 secretion from airway epithelial cells. The role of T lymphocytes in COPD is thought to be through the induction of apoptosis of airway epithelial cells, mediated by CD8 cell release of TNF-a and perforins. The number of both CD8 cells and neutrophils present in lung tissue is proportional to the degree of airways limitation present in COPD.

Therapy

Bronchodilators. The effect of therapy for COPD is difficult to assess because it is a progressive disorder with a long preclinical stage. Patients rarely present for medical therapy until their FEV₁ is < 50% predicted. COPD is characterized by irreversible destruction of the alveolar wall, loss of elasticity, and peribronchial fibrosis, leaving little reserve for clinical improvement. Therefore, much of the treatment for COPD is symptomatic in nature. Only two known interventions have been shown to change the natural history of COPD: smoking cessation and supplemental oxygen for hypoxemic patients. Smoking cessation is best achieved with a multimodal approach including bupropion, a nicotine replacement product such as the patch, and multidisciplinary behavior modification.

Bronchodilators are the mainstay of COPD management. These include long-and short-acting b-adrenergics and anticholinergics. Although available in Europe, long-acting anticholinergics are not yet on the market in the United States. The short-acting anticholinergic ipratropium has been shown to be superior to short-acting b-adrenergics such as albuterol; the efficacy of long-acting b-adrenergics such as salmeterol and formoterol appears equivalent to that of ipratropium, but they have a longer duration of action.¹³ Salmeterol has been shown to have several in vivo and in vitro nonbronchodilator anti-inflammatory effects. These include enhancement of mucociliary clearance, inhibition of allergen-induced airway edema, and bronchoprotection from the adherence and epithelial destruction of Haemophilus influenzae and Pseudomonas. The nonbronchodilator anti-inflammatory effects of salmeterol may be the mechanism involved in its ability to reduce the frequency of COPD exacerbations.

Tiotropium is a long-acting anticholinergic, with a duration of action of 24 h. In a recent head-to-head comparison with salmeterol, tiotropium produced superior bronchodilatation in COPD patients.^14,15 In a very preliminary report, tiotropium was shown to decrease the rate of FEV₁ decline in COPD patients from 58.8 mL/yr to 19.9 mL/yr.¹⁵ If replicated, tiotropium would be the only known bronchodilator that would affect the natural history of COPD. Combivent (Boehringer Ingelheim Corp; Ridgefield, CT) is a combination inhaler of albuterol and ipratropium that takes advantage of two concepts to provide enhanced efficacy. Both albuterol and ipratropium are marketed in submaximal strength; when combined, they have an additive effect on FEV₁. Furthermore, a greater percent of patients experience a bronchodilating response from the combination product than from either product alone.

Phosphodiesterase inhibitors. The methylxanthines (eg, theophylline) are bronchodilators thought to exert their effect by phosphodiesterase inhibition. Although a weak bronchodilator, theophylline has many salutary effects helpful to COPD patients. These include pulmonary arterial vasodilatation, enhancement of diaphragmatic contractility, and increased CNS respiratory drive. Theophylline is a cardiac ionotrope and chromotrope. It is a weak diuretic and increases mucociliary sweep. Theophylline is difficult to use because of its narrow therapeutic index and plethora of drug interactions. Theophylline has anti-inflammatory effects in COPD, reducing neutrophil counts, IL-8, and total inflammatory cells in the sputum.

New phosphodiesterase 4 (PDE4) inhibitors are in development. PDE4 inhibitors have been shown to increase intracellular cyclic adenosine monophosphate in neutrophils, leading to a decreased state of activation. They inhibit neutrophil chemotaxis, adhesion, degranulation, and release of proteases. PDE4 inhibitors decrease macrophage elaboration of LTB₄ and IL-8. They may also upregulate the anti-inflammatory cytokine IL-10 that increases secretion of tissue inhibitor of metalloproteases and inhibits macrophage secretion of IL-8, TNF-a, and MMPs.¹⁷ Cilomilast is a PDE4 inhibitor currently in clinical trials. In recent preliminary reports, use of cilomilast decreased hyperinflation, the frequency of COPD exacerbations, and the rate of FEV₁ decline.18,19 Roflumilast is another once-a-day oral PDE4 inhibitor being developed for both asthma and COPD.

Corticosteroids. The inflammation of COPD is not suppressed by corticosteroids.11 This is not totally unexpected because it is the neutrophil rather than the eosinophil that is prominent in the pathogenesis of COPD. Corticosteroids prolong neutrophil survival by suppressing apoptosis. Furthermore, they fail to inhibit the increased concentrations of neutrophil chemoattractants IL-8 and TNF-a seen in induced sputum from COPD patients. Despite this, two of five recent long-term clinical trials revealed that the use of ICSs was associated with a decrease in the frequency of COPD exacerbations but no change in the rate of FEV₁ decline.²⁰ Patients enrolled in these two trials tended to have a lower baseline FEV₁ than in the other three trials. A recent report shows that ICSs may also decrease mortality and repeat hospitalization after an exacerbation.²¹

Leukotriene modifiers. Inhibition of 5-lipoxygenase prevents LTB₄ synthesis. Zileuton is a 5-lipoxygenase inhibitor, and others are in development. No large-scale clinical trials have yet reported on the efficacy of 5-lipoxygenase inhibitors in COPD. LTB₄ antagonists are in also development.

Drugs in development. A plethora of drugs are in development that inhibit mediator and cytokine activity and/or synthesis. These include the following: (1) protease inhibitors such as inhibitors of neutrophil elastase, cathepsin G, proteinase 3, and the MMPs; (2) TNF-a inhibitors such as TNF-a-converting enzyme inhibitor, monoclonal antibodies to TNF-a, and TNF-a-soluble receptors; (3) IL-8 and CXCR1 and CXCR2 antagonists; and (4) antioxidants such as N-acetylcysteine, stable glutathione analogues, and nitrones. Drugs that are already available for other indications, such as tetracycline and marimastat, are nonselective MMP inhibitors. Macrolide antibiotics inhibit mucus secretion. Finally, retinoic acid has been shown in a rat model of elastase-induced emphysema to increase alveolar number by an apparent regrowth of new septae.

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