© Springer Science+Business Media Singapore 2017
Hiroyuki Nakamura and Kazutetsu Aoshiba (eds.)Chronic Obstructive Pulmonary DiseaseRespiratory Disease Series: Diagnostic Tools and Disease Managements10.1007/978-981-10-0839-9_1414. New Anti-inflammatory Drugs for COPD: Is There a Possibility of Developing Drugs That Can Fundamentally Suppress Inflammation?
(1)
Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation that is usually progressive and associated with chronic inflammation of the peripheral airways and lung parenchyma. The current therapeutic strategy for COPD consists mainly of the use of bronchodilators, such as long-acting muscarinic antagonists and long-acting beta stimulants. They reduce respiratory symptoms and exacerbations, but do not reduce airway inflammation or prevent disease progression. We have no effective treatments for suppressing airway inflammation in COPD. There are, however, several candidates as anti-inflammatory drugs that would fundamentally suppress airway inflammation in COPD and might prevent progression of COPD. This chapter discusses some of the most promising new therapeutic drugs that have been discovered and describes the status of development of anti-inflammatory drugs in the field of COPD.
Keywords
Airway inflammationPhosphodiesterase inhibitorsKinase inhibitorsCorticosteroid resistance14.1 Introduction
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation that is usually progressive and associated with chronic inflammation of the peripheral airways and lung parenchyma [1]. This chronic airway inflammation is caused mainly by inhaled noxious particles from smoke and other sources, including outdoor, occupational, and indoor pollution. It results in the narrowing of the small airways and parenchymal destruction and persists through unknown mechanisms, even after long-term smoking cessation. In addition, the persistent airway inflammation may move into systemic inflammation in patients with COPD. The systemic inflammatory response can cause systemic comorbidities such as cardiovascular and metabolic diseases, which are increasingly recognized as having major impacts on survival in patients with COPD [1].
Chronic inflammation is considered to be related to disease progression and mortality in COPD and should be regulated by treatment. However, current treatments recommended by the guidelines for COPD are mainly bronchodilators to reduce respiratory symptoms and exacerbations. Anti-inflammatory treatment with corticosteroids is not sufficient to suppress the inflammation and disease progression or improve survival [2]. As of this writing, there are no effective and safe drugs for suppressing chronic airway inflammation in COPD [3].
14.2 Inflammation in COPD
Chronic persistent inflammation exists throughout the airways and lung parenchyma in COPD. The airway inflammation consists mainly of increased numbers of T lymphocytes, including CD8 and CD4 cells, B lymphocytes, macrophages, and polymorphonuclear neutrophils [4–7]. These increased numbers of inflammatory cells are associated with the severity of COPD [5].
Many inflammatory mediators are involved in the persistent inflammatory process of COPD. Inhaled noxious particles and oxidative stress due to smoke and air pollution induce airway inflammation by causing release of various cytokines and chemokines, such as tumor necrosis factor-α (TNF-α), CXCL8/interleukin 8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-inducible protein 10 (CXCL10), from epithelial cells and macrophages [8]. Those mediators recruit inflammatory cells into the airway causing airway inflammation. These inflammatory responses are activated and maintained by autonomous mechanisms, even long after smoking cessation. Moreover, several intracellular signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway, phosphoinositide 3-kinase (PI3K) pathway, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and inflammatory transcriptional factors such as nuclear factor-kB (NF-kB) are activated in COPD by various stimuli. Thus, we need to find alternative anti-inflammatory therapies to regulate the persistent airway inflammation in COPD.
14.3 Anti-inflammatory Therapies
14.3.1 Phosphodiesterase Inhibitors
Phosphodiesterase (PDE) regulates the concentrations of cyclic adenosine monophosphate (cAMP) in cells and modulates a broad range of cell functions, including airway smooth muscle contractions and release of inflammatory mediators. Theophylline, a well-known bronchodilator having many physiological activities, works as a phosphodiesterase inhibitor but is weak and nonselective. There are several distinct PDE isozymes, and different PDEs are responsible for cyclic nucleotide hydrolysis in different tissues. Among them, PDE type 4 (PDE4), which is called cAMP-specific phosphodiesterase, has been demonstrated to have broad functional roles in many inflammatory cells [9, 10]. PDE4 inhibitors are reported to effectively inhibit chemotaxis, leukocyte activation, and cytokine production [11] and to reduce the numbers of neutrophils and eosinophils in the sputum of patients with COPD [12]. Thus, PDE4 inhibitors are potentially effective therapies for COPD.
One PDE4 inhibitor, roflumilast, reduces airway inflammation in COPD and improves lung function [13, 14]. Further, orally administered roflumilast reduces the frequency of exacerbation in patients with severe airflow limitation, although adverse effects such as diarrhea, weight loss, nausea, and headache occur [15, 16].
In order to reduce the systemic adverse effects of PDE4 inhibitors, several PDE4 inhibitors have been developed as dry powders for inhalation. One inhaled PDE4 inhibitor, UK-500001, was administered to patients with moderate to severe COPD. Although UK-500001 had no adverse effects, it also showed no therapeutic effects on lung function or symptoms [17]. Another inhaled PDE4 inhibitor, GSK256066, showed anti-inflammatory efficacy in an animal model [18], but it did not show any anti-inflammatory effect and did not improve lung function in patients with COPD [19]. A third inhaled PDE inhibitor, CHF6001, was reported to be more potent in inhibiting PDE4 enzymatic activity than roflumilast, UK-500001, and GSK256066. To date, however, clinical efficacy of CHF6001 in COPD has not been demonstrated [20].
In addition to PDE4 inhibitors, a dual PDE3 and PDE4 inhibitor, RPL554, may provide bronchodilating and anti-inflammatory activities, since the PDE3 inhibitor relaxes airway smooth muscle [21]. Inhaled RPL554 showed anti-inflammatory and bronchoprotective activities and was well tolerated. In addition, combined administration of RPL554 and glycopyrronium interacted synergistically in relaxing both human medium and small isolated bronchi, showing strong relaxation and an extended duration of action, indicating that this combination may prove useful in the treatment of COPD [22].
Thus, several PDE4 inhibitors have been developed for treatment of COPD, but further studies will be needed to assess their efficacy and safety with long-term follow-up.
14.3.2 Specific Inflammatory Mediators
Many different inflammatory mediators, including cytokines, chemokines, growth factors, and lipid mediators, are involved in the pathogenesis of COPD. Theoretical therapeutic approaches for treatment of COPD include inhibition of the mediators by using antibodies specific for them, antagonists of their receptors, or inhibitors of signal transduction. Several specific inhibitors of inflammatory mediators are being developed. However, since many different mediators are closely involved in the pathogenesis of COPD, we do not yet know which mediators would be the best therapeutic targets. Clinical trials are needed to determine the efficacy of mediator inhibition.
14.3.2.1 Cytokines
Many cytokines are increased in patients with COPD and play important roles in airway inflammation [23]. Several therapeutic approaches could be taken to block the cytokines’ activities, including specific antibodies for the cytokines or their receptors, antagonists of their receptors, and inhibitors of intracellular signaling pathways.
TNF-α
TNF-α appears to play important roles in the pathogenesis of COPD as a primary mediator driving development of the inflammation and emphysema in COPD. TNF-α activates epithelial and smooth muscle cells in the airways to release inflammatory mediators and promote the fibrotic process in airway remodeling. TNF-α levels are increased in the blood and sputum of patients with COPD [24, 25]. However, administration of an anti-TNF-α antibody, infliximab, did not show any clinical efficacy in moderate–severe COPD. Moreover, in spite of the absence of beneficial effects, the risks of lung cancer and pneumonia were increased [26–28].
IL-1β
IL-1β is a pro-inflammatory cytokine and was demonstrated to be increased in COPD, suggesting that it plays a role in the pathogenesis of COPD by amplifying inflammation [29, 30]. However, an IL-1β-specific antibody, canakinumab, was ineffective in treatment of COPD in a recent unpublished clinical trial [31].
IL-6
IL-6 is also assumed to play an important role in the progression of COPD, and its levels are increased in patients with COPD [24]. An anti-IL-6 receptor antibody, tocilizumab, was effective in patients with rheumatoid arthritis refractory to TNF-α inhibitors [32], but no clinical studies have been conducted in patients with COPD.
IL-17
IL-17 promotes neutrophilic inflammation by inducing production of CXCL1 and CXCL8, which are chemoattractants for neutrophils, by airway epithelial cells [33]. IL-17 is increased in patients with COPD [34], implicating it in the pathogenesis of COPD. Antibodies specific for IL-17 and an IL-17 receptor are available for other indications [32, 35, 36], but no clinical trials have examined their efficacy in treating COPD.
GM-CSF
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory cytokine that promotes leukocyte survival and activation and regulates neutrophil function [37]. It has been implicated in the pathogenesis of COPD. A neutralizing GM-CSF antibody was effective in an animal model of cigarette smoke-induced airway inflammation [38], but no clinical studies have tested this for COPD.
In summary, inhibitors of cytokines, particularly those targeting single cytokines, have not yet shown clinical efficacy in treatment of COPD.
14.3.2.2 Chemokines
CXCL8 (IL-8), which is a chemoattractant for neutrophils and monocytes, is thought to be involved in the pathogenesis of COPD. Levels of IL-8 are elevated in the sputum of patients with COPD and correlate with disease severity [25]. IL-8-specific antibody improved dyspnea in patients with COPD but showed no beneficial effects on lung function, health status, or 6-min walking distance [39].
CXCR2 is a receptor for IL-8 and is expressed on neutrophils. Airway neutrophils are believed to be one of the key players in COPD. Treatment with CXCR2 antagonists reduced sputum neutrophils [40], improved lung function and health status, and reduced exacerbation in COPD [41]. However, they decreased blood neutrophil counts and resulted in an unacceptably high percentage of discontinuing patients. This clinical study suggested that an anti-inflammatory effect expressed via the CXCL8/CXCR2 axis might be clinically important.
14.3.3 Kinase Inhibitors
Many inflammatory genes encoding cytokines, chemokines, and proteinases show increased expression in patients with COPD and are regulated by inflammatory transcription factors via various activated pro-inflammatory kinase pathways. Those kinases are believed to play important roles in the airway inflammation in COPD. Selective kinase inhibitors are now being used to target those kinases as treatments for COPD.
14.3.3.1 p38 MAPK Inhibitors
The p38 MAPK pathway regulates the expression of many inflammatory genes such as CXCL8 and TNF-α that are involved in COPD. Phosphorylated p38 was reported to be increased in alveolar macrophages and alveolar walls from patients with COPD, so the p38 MAPK pathway seems to be involved in the pathogenesis of COPD [42].
Inhibitors of p38 MAPK inhibited TNF-α release from macrophages of patients with COPD [42]. Further, a p38α-selective MAPK inhibitor reduced pulmonary inflammation in mice exposed to cigarette smoke, whereas dexamethasone was ineffective [43], suggesting that p38 MAPK inhibitors may have potential as treatments for COPD.
An oral p38 MAPK inhibitor, losmapimod, was well tolerated and reduced plasma fibrinogen without significant reduction of IL-6, IL-8, or C-reactive protein [44]. Another oral p38 MAPK inhibitor, PH-797804, improved lung function and dyspnea in patients with moderate to severe COPD [45].
Topical administration of p38 MAPK inhibitors may yield stronger anti-inflammatory effects in the airway. An inhaled p38α MAPK antisense oligonucleotide attenuated airway inflammation in a murine asthma model [46], indicating that p38 MAPK inhibitor inhalation may be an effective treatment for inflammatory airway diseases. Several selective inhaled p38 MAPK inhibitors (GSK-610677, AZD-7624, PF-03715455, and RV-568) are undergoing clinical development for COPD [47, 48].
14.3.3.2 PI3K Inhibitors
PI3Ks generate lipid second messengers that regulate various intracellular signaling pathways involved in inflammatory responses in the small airways in COPD [49–51]. Among the PI3K isoforms, PI3Kγ and PI3Kδ are involved in the pathogenesis of inflammation in respiratory disease [50–52].
An aerosolized PI3Kγ/P13Kδ inhibitor, TG100-115, reduced airway inflammation and airway hyperresponsiveness in a murine asthma model and inhibited airway neutrophilic inflammation in smoke-exposed mice [53].
14.3.3.3 JAK/STAT Inhibitors
Several cytokines implicated in COPD signal via the JAK/STAT pathway, and the activated pathway is associated with COPD [56, 57]. Therefore, inhibition of JAK/STAT signaling may have therapeutic potential for inhibiting airway inflammation in COPD. An oral selective inhibitor of JAK, tofacitinib, was reported to be effective in treatment of rheumatoid arthritis [58] and ulcerative colitis [59]. Its clinical efficacy in COPD should be investigated.
14.3.3.4 NF-kB Inhibitors
NF-kB induces expression of many pro-inflammatory mediators, including cytokines and chemokines, in response to inflammation and smoke exposure [60, 61]. NF-kB is activated in macrophages and epithelial cells of patients with COPD [30], and expression of NF-kB in the epithelium is associated with disease severity [62]. Since IkB kinases (IKKs), especially IKK-β, are essential for NF-kB signaling, their inhibition is a promising approach for intervention in COPD. IKK-β inhibitors are now undergoing development for treatment of airway inflammation in COPD.
14.3.4 Restoration of Corticosteroid Function
Corticosteroid resistance in patients with COPD is reported to be associated with reduced activity of HDAC2, which is caused by oxidative stress. Reduced HDAC2 activity leads to enhanced expression of inflammatory genes and increased acetylation of glucocorticoid receptors, which blocks the anti-inflammatory effects of corticosteroids [63]. Conversely, increasing HDAC2 activity would result in restoration of corticosteroid function and lead to anti-inflammatory effects, thus representing a therapeutic strategy for COPD.
Theophylline was reported to increase HDAC2 activity in alveolar macrophages from patients with COPD [55, 64]. In patients with COPD, combination therapy with an inhaled corticosteroid and low-dose theophylline was more effective than corticosteroid alone in reducing airway inflammation and improving lung function, and low-dose theophylline increased HDAC2 activity in peripheral blood monocytes [65].
14.3.5 Pro-resolving Lipid Mediators
It is unknown why the airway inflammation in COPD persists even after smoking cessation. The conventional wisdom has been that resolution of inflammation is a passive process until inflammatory stimuli are removed. In recent years, however, it has been postulated that resolution of inflammation is a bioactive process mediated by several lipid mediators and that balance between pro-inflammatory and pro-resolving pathways maintains normal immune homeostasis [68, 69]. Those lipid mediators include resolvins, protectins, and maresins, which are bioactive products derived from dietary ω-3 and ω-6 polyunsaturated fatty acids and act on distinct receptors. Among those mediators, resolvin D1, which is a derivative of docosahexaenoic acid, has potent anti-inflammatory effects that suppressed pro-inflammatory mediators [70] and reduced emphysema and chronic inflammation in cigarette smoke-exposed mice [69]. In patients with COPD, pro-resolving and metabolic pathways are disrupted in the lung tissue, presumably due to cigarette smoking. Supplementation with specialized pro-resolving lipid mediators is a potentially important therapeutic strategy for COPD [69].
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