The Role of Inflammation in COPD and Asthma: Is This One Disease Entity?

The Role of Inflammation in COPD

The sixth most common cause of death worldwide, chronic obstructive pulmonary disease (COPD) is also a common cause of disability and source of healthcare cost. Despite this, COPD remains a disease for which no therapy has been shown to slow its progression effectively. While the early stage of disease is distinctly different from that of asthma, more severe COPD is characterized by structural changes and fibrotic lesions that resemble those of asthma, said Klaus F. Rabe, MD, PhD, Professor of Medicine, Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands. According to Professor Rabe, the inflammatory process of COPD, which continues throughout the course of this debilitat-ing disease, represents an important potential target for future treatment.

Pathophysiology of COPD
COPD, which is caused by long-term inhalation of toxic gases and particles, is characterized by airflow limitation that is not fully reversible, showing a progressive decline in FEV1, increasing shortness of breath, and ultimately respiratory failure. A driving factor in the pathophysiology of COPD is the inflammatory process, which contributes to the narrowing of the small airways and other underlying mechanisms of the disease process, Prof. Rabe explained (Table 1). Indeed, recent evidence suggests that the inflammatory response results in a number of effects, including an influx of inflammatory cells, such as macrophages, neutrophils, and lymphocytes; thickened airways; and structural changes such as increased smooth muscle and fibrosis (Barnes. N Engl J Med. 2000;343:269).

According to Prof. Rabe, a noxious agent, such as cigarette smoke, triggers an in-flammatory response in the lung. Importantly, this inflammatory response does not cease with removal of the stimulus. Once begun, the inflammatory response of COPD maintains itself and progresses for an unlimited period of time, he explained.

Prof. Rabe pointed out that the driving histology behind the inflammatory response in COPD may vary by individual. While the histology may vary, it appears that COPD involves an inflammatory response that results in the same clinical effects: narrowing of the airways and limitation of airflow of variable reversibility, Prof. Rabe said. Importantly, the relationship between COPD-associated inflammation and loss of FEV1 is multifactorial. In addition to restricted small airways, the inflammatory response involves loss of elasticity and destruction of the alveolar attachments of the airways within the lung. The research has shown a direct relationship between inflammation and loss of alveolar attachment: the higher the airway inflammation scores, the greater the loss of attachment, he said (Saetta et al. Am J Respir Crit Care Med. 2001;163:1304). People with severe asthma also show this detachment in the peripheral airways.

In addition, the loss of FEV1 appears to be co-determined by the presence of inflammatory cells, such as neutrophils and CD8 T lymphocytes in the lung. While Barnes and others have shown airway inflammation to be a neutrophil-centered process, recent evidence also demonstrates the presence of CD8 T cells as a hallmark of COPD, Prof. Rabe said. Importantly, CD8 T cells are also noted in severe asthma, and may be associated with FEV1 decline over time. Additionally, transforming growth factors, such as TGF beta-1, are present in moderate and severe asthma, and also in COPD. With chronic inflammation in persons with COPD, TGF beta-1 is released from the epithelium and acts on smooth muscle, leading not only to collagen deposition but also to interference with the receptor density of beta receptors on airway smooth muscle and loss of bronchodilation response. These effects show a direct link between airway inflammation and functional response, Prof. Rabe said. Importantly, Prof. Rabe added, this structure of cells closely resembles that of severe asthma (de Boer et al. AJCCM. 1998; Mak et al. Nauny-Schied Arch Pharmacol. 2000).

COPD Versus Asthma
The heterogeneity of inflammatory response within each disease—COPD and asthma—as well as the severity and exacerbation of disease are factors that make the comparison of these two diseases challenging. According to Prof. Rabe, the early phases of COPD and asthma are distinctly different. The factors that lead to the structural changes and loss of lung function in asthma clearly differ from those in COPD. However, even in early disease, there are overlapping factors, such as airway hyperresponsiveness, and common denominators, such as a thickened basement membrane, he noted. In chronic or more severe disease, Prof. Rabe explained that asthma and COPD are much less distinguishable. The inflammatory response, alveolar detachment, mucus hypersecretion and subepithelial fibrosis, for example, occur in the chronic phases of both diseases. In addition, it is important to consider the exacerbation or instability of disease. When asthma is exacerbated, an influx of neutrophils is observed; when COPD is exacerbated, an influx of eosinophils is noted (Barnes. N Engl J Med. 2000;343:269. Saetta et al. Am J Respir Crit Care Med. 2001; 163:1304).

In closing, Prof. Rabe reiterated the great heterogeneity in pathogenesis, even within the individual diseases of asthma and COPD. He also emphasized the overlapping and common denominators between these diseases, particularly in severe asthma and COPD. Clearly, the inflammatory response plays a major contributing role in both COPD and asthma, with related structural and fibrotic changes making these two diseases much less distinguishable in their severe phases, he concluded.

Advances in Phosphodiesterase-4 Inhibition

No therapy exists to stop the progression of chronic obstructive pulmonary disease (COPD), or to target the underlying inflammatory process of this debilitating disease. However, phosphodiesterase (PDE)-4 inhibitors are currently under study for the treatment of both COPD and asthma. “PDE-4 inhibitors represent a promising class of drugs, exerting broad-spectrum anti-inflammatory effects that include the ability to target the eosinophils, mast cells, and Th2 cells predominant in asthma and the neutrophils, monocytes, macrophages, and CD8 cells more prevalent in COPD,” said Peter J. Barnes, DM, DSc, Professor, Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London (Barnes. Ann 1st Super Sanita. 2003;39(4):573).

Understanding the Pathophysiology
Both COPD and asthma involve an underlying inflammatory process. Importantly, this inflammatory process differs in the pathogenesis of COPD versus asthma. In COPD, chronic inflammation in small airways and lung parenchyma develops, with influx of neutrophils, macrophages, and CD8 T lymphocytes. This inflammatory process leads to fibrosis, small airway narrowing, and loss of FEV1 (Barnes. Ann 1st Super Sanita. 2003;39(4):573). “The cortico-steroid regimens used to treat asthma are ineffective in COPD, indicating the need for a different mechanism and different therapeutic approach for this disease,” Prof. Barnes said.

Targeting Inflammation in Asthma
Among the many selective PDE in-hibitors, it is believed that PDE-4 inhib-itors offer the greatest potential for treatment of airway disease. PDE-4 is the predominant enzyme serving to break down cyclic AMP in COPD and asthma inflammatory cells; thus PDE-4 inhibitors are able to target nearly all key inflammatory cells involved in these disease processes. In addition, PDE-4 inhibitors offer a lesser but significant effect on epithelial cells, which may be important in the treatment of asthma. “PDE-4 is widely distributed in inflammatory cells; therefore, inhibition of PDE-4 affords the potential for broad-spectrum anti-inflammatory action in COPD and asthma,” Prof. Barnes explained (Barnes. Ann 1st Super Sanita. 2003;39(4):573).

PDE-4 inhibitors currently under development include the second-generational cilomilast and roflumilast. In animal models of asthma, both agents offer anti-inflammatory effects, with roflumilast appearing to be the more potent. “Comparison animal studies of asthma have shown the anti-inflammatory effect of roflumilast to be similar to that of budesonide,” Prof. Barnes said (Bund-schuh et al. JPET. 2001). In addition, a first-generation PDE-4 inhibitor, rolipram, has been shown to suppress interleukin (IL)-5 in both animal and human asthma cells (Staples et al. BBRC. 2000). “It is believed the mechanism for this effect is suppression of Th2 gene expression, which is similar to the action of corticosteroids in controlling eosinophilic inflammation in asthma,” he noted.

In an in vitro study by Barnes and colleagues, a first-generation PDE-4 inhibitor exerted inhibitory effects on CD4 cells and IL-2 production. With addition of a PDE-3 inhibitor, a synergistic inhibitory effect was observed. A similar suppressive effect has been observed in CD8 cells, which are predominate in COPD. “Thus, PDE-4 inhibitors appear to be effective in the suppression of T cells key to both asthma and COPD pathogenesis,” Prof. Barnes said (Giembycz et al. Br J Pharmacol. 1996;118:1945).

In one clinical trial, patients with mild to moderate asthma who received once-daily oral roflumilast experienced a significant increase in FEV1, comparable to the effect observed with standard inhaled budesonide treatment (Albrecht et al. ERS. 2002).
“Emerging data suggest that
PDE-4 inhibitors suppress mast cells, eosinophils, T cells, macrophages, and neutrophils; relax airway smooth muscle [in animal models]; and inhibit epithelial cells and numerous neural bronchoconstrictor mechanisms,” Prof. Barnes noted.

Targeting Inflammation in COPD
Importantly, PDE-4 inhibitors act not only to mimic the effects of cortico-steroids on eosinophilic inflammation, but also to exert actions not exerted by corticosteroids, such as neural bronchoconstrictor mechanisms. “Corti-costeroids are not effective against neutrophilic inflammation, found in
diseases such as COPD and cystic fibrosis,” Prof. Barnes explained.

In COPD, neutrophils produce large amounts of oxidants, with oxidative stress being strikingly increased in COPD compared with asthma. In addition,
neutrophils release chemoattractants, recruiting more neutrophils to the airway and perpetuating the inflammatory process. “Importantly, PDE-4 inhibitors are effective both in inhibiting the neutrophilic oxidative burst and chemo-attractant production,” Prof. Barnes said (Hatzelmann & Schudt. JPET. 2001).

In one study by Au and colleagues, cilomilast was shown to inhibit IL-8 release from human neutrophils. In addition, marked inhibition was observed in the presence of prostaglandin E2, which has been shown to be significantly increased in COPD. (Au et al. Br J Pharmacol. 1998). Inhibitory effects of PDE-4 inhibitors have also been demonstrated on monocytes, TNF-alpha, and GM-CSF—all key factors in the COPD inflammatory process. “In particular, the inhibition of TNF is a critical aspect of any anti-inflammatory therapy for COPD,” Prof. Barnes explained.

In a clinical trial of patients with COPD, cilomilast was associated with a significant improvement in lung function. Much like the effect of cortico-steroids in asthma, this effect occurred over time. Importantly, said Prof. Barnes, no change in bronchodilation was observed (Compton et al. Lancet. 2001).

Tolerance and Safety of PDE-4 Inhibitors
According to Prof. Barnes, PDE-4 inhibitors can be associated with side effects, such as nausea and vomiting; headache; hypotension; tachycardia; and increased acid secretion and diarrhea. “The dosage of PDE-4 inhibitors is limited by its potential side effects, preventing a maximal anti-inflammatory effect,” Prof. Barnes explained. Study is currently underway to identify an iso-enzyme subtype selective inhibitor (targeting anti-inflammatory PDE-4B subtype) to allow for reduction of side effects and higher dosing in the future. Importantly, roflumilast appears to avoid inhibition of potentially nausea-mediating PDE-4D, and therefore is better tolerated than cilomilast, allowing comparatively higher dosing and greater anti-inflammatory effects.

“In closing, emerging evidence suggests that PDE-4 inhibitors used alone, or synergistically with cyclic AMP-elevating drugs, offer enormous potential for improving the current treatment of COPD, severe asthma, and other serious inflammatory lung disease,” Prof. Barnes concluded.

Reducing Inflammation in Asthma and COPD: PDE-4 Inhibitors and Steroid-Based Combinations

Inflammation plays a significant role in the pathogenesis of both asthma and chronic obstructive pulmonary disease (COPD), with this process in asthma being predominately eosinophil driven and in COPD mainly neutrophil driven. “While corticosteroids are effective in inhibiting the inflammatory symptoms in persons with asthma, they are not effective in the stopping the progression of COPD,” said Sidney S. Braman, MD, Professor of Medicine and Division Director of Pulmonary and Critical Care Medicine, Brown Medical School, Brown University, Providence, Rhode Island. According to Dr. Braman, “Phosphodiesterase [PDE]-4 inhibitors represent a promising new area of potential anti-inflammatory therapy for COPD and severe asthma.”

Corticosteroid Use in Asthma and COPD
“In persons with asthma and COPD, inflammation is believed to be responsible for the symptoms and remodeling that occur with these diseases,” said Dr. Braman. In severe or persistent asthma, inhaled corticosteroids represent the standard anti-inflammatory therapy of choice. In addition, corticosteroid combination therapies—such as budesonide plus long-acting beta agonist formoterol or fluticasone plus salmeterol—have been shown to confer an advantage on severe exacerbations and other indices of asthma control. Despite multiple studies showing reduced exacerbations and reduced short-acting beta agonist use with a corticosteroid-long-acting beta agonist combination (rather than higher-dose corticosteroid alone), neither short-acting beta agonist use nor exacerbations have been eliminated (Pauwels et al. N Engl J Med. 1997; 337:1405. Shrewsbury et al. BMJ 2000;320:1368. Condemi et al. Ann Allergy Asthma Immunol. 1999;82:383). “The data show that more than 90% of persons with asthma have persistent asthma. Despite improvements in the management of symptomatology, asthma remains a disease that is significantly undertreated,” Dr. Braman said (Mannino et al. MMWR. 2002;51:1-13).

In persons with COPD, a combination regimen of inhaled corticosteroids and long-acting beta agonists has resulted in sustained improvement in FEV1 of approximately 15%, demonstrating a clear advantage over either therapy alone. Other studies of this combination approach have shown a modest effectiveness in improving FEV1, and a positive effect on quality of life, number of hospitalizations, distance walked, and exacerbation rates in COPD (Mahler et al. Am J Respir Crit Care Med. 2002;166:1084. Szafranski et al. Eur Respir J. 2003;21:74. Jones et al. Am J Respir Crit Care Med. 2002). The Lung Health study, however, showed no effect on FEV1 in persons with COPD with inhaled corticosteroid use over time (Lung Health Study. JAMA. 1994).

According to Dr. Braman, “It is hoped that the future of anti-inflammatory therapy in persons with asthma and COPD will contribute to the modification of the disease process as well as reduction of symptomatology.” Several clinical trials have shown promise for the use of PDE-4 inhibitors against these diseases.

Future Directions: PDE-4 Inhibition Therapy in Asthma
“The chief function of PDE-4 is to cata-bolize cyclic AMP, a second regulatory messenger that plays a pivotal role in the inflammatory process of asthma and COPD,” Dr. Braman explained. Thus, PDE-4 inhibitors act upon multiple disease pathways to inhibit the inflammatory processes of asthma and COPD.

Two PDE-4 inhibitors currently under development include cilomilast and roflumilast, both of which are in clinical trials. The target indications are COPD for cilomilast and both COPD and asthma for roflumilast.

In asthma, young persons with mild disease underwent allergen challenge while receiving either placebo or roflumilast (250 mcg or 500 mcg once per day).

The patients experienced an immediate acute reaction to the allergen, and within minutes began to recover from the allergic response. A late-phase response to the allergen also occurred; however, both roflumilast dosages were shown to blunt this delayed asthmatic response. “In addition, in comparison with inhaled corticosteroids, once daily roflumilast 500 mcg has shown similar effects over a 12-week treatment period in persons with mild to moderate asthma,” Dr. Braman noted. With similar baseline symptomatology, roflumilast demonstrated outcomes comparable to budesonide in terms of symptom scores and albuterol use (van Schalkwyk et al. European Respiratory Society Annual Meeting, Stockhom, 2002, Poster P751. Bousquet et al. American Thoracic Society Annual Meeting, Seattle, 2003, Poster 607. Albrecht et al. Eur Respir J. 2002).

Future Directions: PDE-4 Inhibition Therapy in COPD
According to Dr. Braman, both cilomilast and roflumilast are under study in persons with COPD. Cilomilast has shown promise in improving lung function and quality of life in persons with COPD. “The research with cilomilast is ongoing, and further evidence is expected in the near future,” Dr. Braman noted.

In the 24-week, double-blind, placebo-controlled RECORD trial, 1400 patients with moderate to severe COPD underwent treatment with either roflumilast (250 mcg or 500 mcg) or placebo. In those receiving either dose of roflumilast, FEV1 was significantly improved from baseline over placebo. In fact, those who received placebo experienced a significant decline in FEV1 from baseline. FEV6 also improved in those receiving roflumilast 500 mcg, but declined in the placebo group. In addition, patients receiving roflumilast 500 mcg had 34% fewer exacerbations compared with those receiving placebo. Side effects were generally mild to moderate in severity, and included diarrhea, headache, and abdominal pain. “Importantly, earlier dose-finding studies suggest that these side effects may dissipate with continued use of roflumilast,” Dr. Braman pointed out.

“By targeting a broad array of inflammatory cells and pathways in both COPD and asthma, PDE-4 inhibitors hold promise for the future as a novel and much needed anti-inflammatory treatment option for patients with these debilitating diseases,” Dr. Braman concluded.