Phosphodiesterase 4 inhibitors

Kerstjens, Huib A M

Antiinflammatory Therapy for Chronic Obstructive Pulmonary Disease at Last?

In the 1995 statement of the American Thoracic Society, COPD was still defined without reference to the underlying inflammation (1). Today, in the guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), a central role is attributed to chronic inflammation, present throughout the airways, parenchyma, and pulmonary vasculature (2). The intensity and cellular and molecular characteristics of the inflammation vary with disease exacerbations and progression. Over time, the inflammatory process damages the lungs and leads to the characteristic pathology of COPD (2). The inflammation is characterized by an increase in neutrophils, macrophages, and T lymphocytes (especially CD8^sup +^). Some patients also have increased eosinophil numbers, particularly during exacerbations (2). Hitherto, no therapeutic agent has been shown to reduce the numbers of important cells-macrophages, neutrophils and CD8+ lymphocytes-in COPD. Nevertheless, inhaled corticosteroids have yielded small improvements in other measures of inflammation, such as the density of mucosal mast cells (3).

In this issue of the Journal (pp. 976-982), Gamble and colleagues present the effects of a phosphodieslerase 4 inhibitor on inflammation in COPD (4). The phosphodiesterases are a large family of intracellular enzymes that degrade cyclic nucleotides. Theophylline is an example of a nonselective phosphodieslerase inhibitor. The phosphodiesterase 4 subtype specifically targets cyclic 3′, 5′-adenosine monophosphate, a second messenger that exerts inhibitory effects on many inflammatory cells (5, 6). Cyclic 3′, 5′-adenosine monophosphate also induces smooth muscle relaxation and modulates neural transmission in animal models (5). A different inhibitor of phosphodiesterase 4 than that used by Gamble and colleagues has been shown to improve exercise-induced bronchoconstriction patients with asthma (7). The first study of a phosphodiesterase 4 inhibitor in COPD was recently presented by Compton and colleagues, who noted an improvement in lung function after 6 weeks of therapy with cilomilast (8).

Gamble and colleagues administered cilomilast 15 mg (an oral agent) or placebo twice daily for 12 weeks (4). They obtained induced sputum and bronchial biopsies on two occasions. Repeating bronchoscopies in 57 patients in a randomized controlled trial is an achievement in itself for which the authors should be applauded. Significant reductions were seen in subepithelial neutrophil and CD8^sup +^ lymphocyte density. Additionally, in a post hoc analysis, decreases were found in subepithelial OPD4^sup +^ (CD45RO^sup +^) cells and neutrophils.

This is great news on the antiinflammatory front for a disease in desperate need of a novel treatment. But as so often, the results are complicated and confusing. The authors are exemplary in stating that their primary end-point was reduction of inflammation in sputum (not in bronchial biopsies), and that no change was demonstrated. Why are the results discordant between sputum and bronchial biopsies? Several authors have noted that cellular profiles are different when assessed by sputum, bronchial biopsies, and bronchoalveolar lavage in asthma, chronic bronchitis (9), and COPD (10). The percentage of neutrophils is generally higher in sputum than in lavage fluid, whereas the reverse is true for macrophages and lymphocytes. Lymphocytes and macrophages, but not neutrophils, are generally the predominant inflammatory cell in the submucosa (3, 9-11). The correlation between cell percentages in sputum, bronchoalveolar lavage, and biopsies is poor (9, 10). In other words, all three media for the analysis of inflammation originate in different compartments and convey different information.

In COPD, the most important site of the changes in inflammation, remodeling, and resultant airflow limitation is the small airways and surrounding parenchyma. These are not directly sampled by bronchial biopsies nor probably by induced sputum. It has been established that the inflammatory process differs markedly among compartments, yet it is possible that changes in inflammation induced by a therapeutic intervention, in this case the larger airways, may produce similar changes in the small airways and parenchyma. Whether changes with therapy in the larger airways indeed relate to changes in the small airways and parenchyma is difficult to evaluate directly. Use of transbronchial biopsy for assessing parcnchymal inflammation is probably too hazardous for research on COPD because of the risk of pneumothorax. Interesting insights, however, on parenchymal inflammation have been obtained by transbronchial biopsies in asthma (12). The development of methods for analyzing inflammation in small airways would be a quantum leap forward.

Gamble and colleagues showed that the phosphodiesterase 4 inhibitor reduced inflammation (neutrophil and CD8+ lymphocyte densities) in biopsies of the central airways (4). This is an important finding. We do not, however, know how this inflammation relates to features such as symptoms, quality of life, frequency of exacerbation, hospitalization rates, and exercise tolerance. Unfortunately, Gamble and colleagues do not provide data about symptoms or quality of life. Comparing the same dose of cilomilast in four times as many patients, Compton and colleagues (8) found no improvement in the St. George’s questionnaire after 6 weeks of treatment; symptoms were not mentioned. In the smaller study of Gamble and colleagues, no significant change in FEV^sub 1^ was found (4). Surprisingly, the observed mean difference in FEV^sub 1^ after 12 weeks was 70 ml compared with 160 ml in the study by Compton and colleagues in patients with a very similar level of pre-study obstruction (8). Reliable information on exacerbation and hospitalization rates requires much larger studies and these are undoubtedly underway.

The reason for emphasis on the treatment of inflammation is its relation to remodeling and therefore to relentless progression of the disease. Do we really understand the relationship? And again, do the changes in inflammation and/or remodeling in the large airways reflect the changes in small airways and parenchyma? These types of questions are vitally important, but are extremely difficult to address in human research. Basic mechanistic questions in this slowly progressive chronic disease can only be addressed in cell or animal models, but the results can only be interpreted correctly in conjunction with human and functional data. For small but important parts of the puzzle, and with the help of drugs provided by industry, we can design experiments in humans. Phosphodiesterase 4 inhibitors set ajar the window to better see the role of inflammation in the progression of COPD. The study of Gamble and colleagues provides an important step in evaluation of the role of inflammation in COPD.

References

1. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease: ATS statement. Am J Respir Crit Care Med 1995;152:S77-S120.

2. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256-1276.

3. Hattotuwa KL, Gizycki MJ, Ansari TW, Jeffery PK, Barnes NC. The effects of inhaled fluuticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Am J Respir Crit Care Med 2002;165:1592-1596.

4. Gamble E, Grootendorst DC, Brightling CE, Troy S, Qui Y, Zhu J, Parker D, Matin D, Majumdar S, Vignola AM, et al. Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;168:976-982.

5. Torphy TJ. Phosphodiestcrase isoxymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 1998;157:351-370.

6. Teixcira MM, Gristwood RW, Cooper N, Hellewell PG. Phosphodiesterasc (PDE)4 inhibitors: anti-inflammatory drugs of the future? Trends Pharmacol Sci 1997;18:164-171.

7. Timmer W, Leclerc V, Birraux G, Neuhauser M, Hatzelmann A, Bethke T, Wurst W. The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo. J Clin Pharmacol 2002;42:297-303.

8. Compton CH, Gubb J, Nieman R, Edelson J, Amit O, Bakst A, Ayres JG, Creemers JP, Schultze-Werninghaus G, Brambilla C, et al. Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study. Lancet 2001;358:265-270.

9. Maestrelli P, Saetta M, Di Stefano A, Calcagni PG, Turato G, Ruggieri MP, Roggeri A, Mapp CE, Fabbri LM. Comparison of leukocyte counts in sputum, bronchial biopsies, and bronchoalveolar lavage. Am J Respir Crit Care Med 1995;152:1926-1931.

10. Rutgers SR, Timens W, Kaufmann HF, van der Mark TW. Koeter GH, Postma DS. Comparison of induced sputum with bronchial wash, bronchoalveolar lavage and bronchial biopsies in COPD. Eur Respir J 2000;15:109-115.

11. Verhoeven GT, Hegmans JP, Mulder PG, Bogaard JM, Hoogsteden HC, Prins JB. Effects of nuticasone propionate in COPD patients with bronchial hyperresponsivcness. Thorax 2002;57:694-700.

12. Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 1996;154:1505-1510.

Conflict of Interest Statement: H.K. has been reimbursed by GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, and Altana Pharma for attending conferences. H.K. serves as a consultant to Altana Pharma and Boehringer Ingelheim. H.K.’s and W.T.’s institution receives unrestricted educational grants from GlaxoSmithKline and AstraZeneca. H.K.’s and W.T.’s institution receives research grants and/ or fees per patient from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, and Altana Pharma for performing trials.

Acknowledgment: The authors thank Dirkje Postma for helpful discussions.

HUIB A.M. KERSTJENS, M.D.

WIM TIMENS, M.D.

Departments of Pulmonary Medicine and of Pathology

University Hospital

Groningen The Netherlands

Copyright American Thoracic Society Oct 15, 2003

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