This seminar is based on a review of papers retrieved from PubMed Central between 1993 and November, 2003, on new treatments already known to us that are linked to the terms “COPD not asthma” and “emphysema”. We also used recent reviews found by this strategy to identify additional articles. Because of the large number of publications, we gave preference to recent articles and reviews in high-quality journals published in English.
SeminarProspects for new drugs for chronic obstructive pulmonary disease
Section snippets
Smoking cessation strategies
Cigarette smoking is the major cause of COPD in the world, and smoking cessation is the only therapeutic intervention so far shown to reduce disease progression. Nicotine addiction is the major problem, and treatment should be directed at dealing with this addictive state. An important advance has been the discovery that a short course of the antidepressant bupropion is an effective adjunct for smoking cessation in patients with COPD.10 However, the poor long-term quit rate (16% at 6 months)
New bronchodilators
Bronchodilators are the mainstay of current management,13 so a logical approach is to improve existing bronchodilators. Several β2 -agonists suitable for once-daily inhalation are now in clinical development, and the once-daily inhaled anticholinergic agent tiotropium has become available in several countries.14 Long-term studies with tiotropium bromide have shown significant improvement in symptoms and quality of life, as well as an unexpected reduction in exacerbations.15 Tiotropium is likely
Inflammation in COPD
Several cells and inflammatory mediators are likely to be involved in COPD (figure 1), because many inflammatory cells and structural cells are activated and there is a continuing inflammatory process, even in patients who have given up smoking.16 The profile of mediators in COPD differs from that in asthma, so different mediator antagonists are likely to be effective. Since COPD is characterised by inflammation with macrophages and neutrophils, attention has largely focused on inhibiting
Corticosteroid therapy in COPD
Four large controlled trials of inhaled corticosteroids of 3 years duration have shown little effect on the loss of lung function that occurs in COPD, although there is a reduction in the number of exacerbations.18, 19, 20, 21 Neither inhaled nor oral corticosteroids suppress the inflammation in the lungs, and alveolar macrophages seem to be steroid resistant.22 There could be active resistance to corticosteroids due to an inhibitory effect of cigarette smoke on histone deacetylation, which is
Anti-inflammatory strategies
Suppression of the inflammatory response with anti-inflammatory treatments is a logical approach to the treatment of COPD and should improve symptoms such as cough and mucus secretion, improve health status, and reduce exacerbations. In the long term, such treatments should reduce disease progression. However, no effective therapies of this type are currently available, so prediction of the clinical outcome is difficult.
Antioxidants
Oxidative stress is increased in patients with COPD,29, 30 particularly during exacerbations, and reactive oxygen species contribute to the pathophysiology.31 Thus, antioxidants might be useful in therapy. N-acetylcysteine provides cysteine for increased production of the antioxidant glutathione and has antioxidant effects in vitro and in vivo. A systematic review of studies with oral N-acetylcysteine in COPD suggested a small reduction in exacerbations,32 and a larger longer-term trial is now
Resveratrol
This phenolic component of red wine has anti-inflammatory and antioxidant properties. It has a strong inhibitory effect on cytokine release by alveolar macrophages from COPD patients that show little or no response to corticosteroids.34 The molecular mechanism for this action is currently unknown, but identification of the cellular target for resveratrol could lead to the development of a novel class of anti-inflammatory compounds. Resveratrol has very low oral bioavailability, so related drugs
Inhibitors of iNOS
Oxidative stress and increased release of nitric oxide from activity of iNOS can result in the formation of peroxynitrite, a potent radical that nitrates proteins and alters their function. 3-nitrotyrosine indicates peroxynitrite formation and is greatly increased in sputum macrophages of patients with COPD.35 Selective inhibitors of iNOS are now in development and one of these, a prodrug of L-N6-(1-imminoethyl)lysine, gives a profound and long-lasting reduction in the concentrations of nitric
Leukotriene inhibitors
Leukotriene B4 is a potent chemoattractant of neutrophils and its concentrations in sputum and exhaled breath of patients with COPD are higher than normal.37, 38 It is probably derived from alveolar macrophages as well as neutrophils and may be synergistic with interleukin 8. Two subtypes of receptor for leukotriene B4 (BLT) have been described; BLT1 receptors are mainly expressed on granulocytes and monocytes, and BLT2 receptors are expressed on T lymphocytes.39 BLT1 antagonists, such as
Adhesion-molecule blockers
Recruitment of neutrophils, monocytes, and cytotoxic T cells into the lungs and respiratory tract depends on adhesion molecules expressed by these cells and on endothelial cells in the pulmonary and bronchial circulations (figure 2). Several adhesion molecules can now be inhibited pharmacologically. For example, E selectin on endothelial cells interacts with sialyl-LewisX on neutrophils. A mimic of sialyl-LewisX, TBC1269, blocks selectins and inhibits granulocyte adhesion, with preferential
Chemokine inhibitors
Several chemokines are involved in neutrophil chemotaxis, mostly those of of the CXC family, and chemokine antagonists are of potential therapeutic benefit in COPD.46 Concentrations of interleukin 8 are very high in the sputum of patients with COPD and are correlated with disease severity.47, 48 Blocking antibodies to interleukin 8 and related chemokines inhibit certain types of neutrophilic inflammation in animals49 and reduce the chemotactic response of neutrophils to sputum from COPD
TNFα inhibitors
Concentrations of TNFα and soluble TNFR are raised in the sputum of COPD patients.47, 54 TNFα augments inflammation and induces interleukin 8 and other chemokines in airway cells via activation of the transcription factor NFκB (figure 2). The severe wasting in some patients with advanced COPD could be due skeletal-muscle apoptosis, resulting from increased circulating TNFα. COPD patients with cachexia have increased release of TNFα from circulating leucocytes.55 Humanised monoclonal antibody to
Interleukin 10
This cytokine has a wide range of anti-inflammatory actions (figure 2). It inhibits the secretion of TNFα and interleukin 8 from macrophages, and tips the balance in favour of antiproteinases by decreasing the expression of MMP, while increasing the expression of endogenous TIMP. Concentrations of interleukin 10 are lower than normal in induced sputum from patients with COPD, so this may be a mechanism for increasing lung inflammation.59 Interleukin 10 is currently in clinical trials for other
PDE4 inhibitors
PDE4 is the predominant PDE expressed in neutrophils, CD8-positive cells, and macrophages (figure 3), so inhibitors of this enzyme should be effective in controlling inflammation in COPD.61 Selective PDE4 inhibitors, such as cilomilast and roflumilast, are active in animal models of neutrophil inflammation.62 Cilomilast had promising beneficial clinical effects in a 6-week study in patients with moderate to severe COPD63 and has some anti-inflammatory effects measurable in biopsy samples of
NFκB inhibitors
NFκB regulates the expression of interleukin 8 and other chemokines, TNFα and other inflammatory cytokines, and some MMP (figure 3). NFκB is activated in macrophages and epithelial cells of COPD patients, particularly during exacerbations.71, 72 There are several possible approaches to inhibition of NFκB, including gene transfer of IκB, inhibitors of IKK, NFκB-inducing kinase, and IκB ubiquitin ligase, which regulate the activity of NFkB, and the development of drugs that inhibit the
p38 MAPK inhibitors
MAPK have a key role in chronic inflammation, and several complex enzyme cascades have now been defined.76 One of these, the p38 MAPK pathway, is activated by cellular stress and regulates the expression of inflammatory cytokines, including interleukin 8, TNFα, and MMP.77 Small-molecule inhibitors of p38 MAPK, such as SB 203580, SB 239063, and RWJ 67657, have a broad range of anti-inflammatory effects.78 SB 239063 reduces neutrophil infiltration after inhaled endotoxin and lowers concentrations
PI3K inhibitors
The PI3K enzymes lead to the generation of lipid second messengers that regulate several cellular events. A particular isoform, PI3Kγ, is involved in neutrophil recruitment and activation. Knock-out of the gene for this isoform results in inhibition of neutrophil migration and activation, as well as impaired T lymphocyte and macrophage function.80 Thus, selective PI3Kγ inhibitors might have relevant anti-inflammatory activity in COPD. Small-molecule inhibitors of PI3Kγ and PI3Kγ are in
PPAR activators
PPARs are a family of ligand-activated nuclear hormone receptors in the steroid-receptor superfamily. The three recognised subtypes, α, γ, and δ are widely expressed. There is evidence that activation of PPARα and PPARδ has anti-inflammatory and immunomodulatory effects. For example, PPARγ agonists, such as troglitazone, inhibit the release of inflammatory cytokines from monocytes and induce apoptosis of T lymphocytes,82, 83, 84 suggesting that they might have anti-inflammatory effects in COPD.
Mucoregulation
Mucus hypersecretion is common in cigarette smokers but is not necessarily associated with airflow limitation. In individuals with COPD, mucus hypersecretion is associated with more rapid decline in forced expiratory volume and might increase the frequency of exacerbations.85 A reduction in mucus hypersecretion might therefore have therapeutic benefit, although suppression of the normal airway mucus secretion could be detrimental. Mucolytic drugs have been used for many years to reduce mucus
Fibrosis inhibition
TGFβ1 is highly expressed in airway epithelium and macrophages of small airways in patients with COPD.91, 92 It is a potent inducer of fibrosis, partly via the release of the potent fibrogenic mediator connective-tissue growth factor, and it may be important in inducing the fibrosis and narrowing of peripheral airways (obstructive bronchiolitis) in COPD. TGFβ1 also activates MMP9, which then further activates TGFβ1, thus providing a link between small-airway fibrosis and emphysema in COPD. MMP9
Antiproteinases
There is compelling evidence for an imbalance between proteinases that digest elastin (and other structural proteins) and antiproteinases that protect against such digestion.102, 103 Inhibition of these proteolytic enzymes or an increase in endogenous antiproteinases should therefore be beneficial and theoretically should prevent the progression of airflow obstruction in COPD (figure 4). Much progress has been made in identifying the enzymes involved in elastolytic activity in emphysema and in
Lung regeneration
A major mechanism of airway obstruction in COPD is loss of elastic recoil due to proteolytic destruction of lung parenchyma; reversal of this process by drug therapy seems unlikely, although reduction of the rate of progression might be possible by preventing the inflammatory and enzymatic disease process. Retinoic acid increases the number of alveoli in developing rats and even reverses the histological and physiological changes induced by elastase treatment of adult rats.111, 112 However,
Drug delivery
Bronchodilators are currently given by means of metered-dose inhalers or dry-powder inhalers that have been optimised to deliver drugs to the respiratory tract in asthma. But in emphysema the inflammatory and destructive process is localised to the lung parenchyma, and in chronic obstructive bronchitis the predominant irreversible changes are in small airways. Thus, if a drug is to be delivered by inhalation, it should have a lower mass median diameter, so that there is preferential deposition
Future directions
New drugs for the treatment of COPD are greatly needed. Although prevention of or quitting smoking is the obvious preferred approach, it has proved to be very difficult in the majority of patients. Identification of the genetic factors that determine why only a minority of heavy smokers develop COPD is important,116, 117 and identification of genes that predispose to the development of COPD could lead to discovery of novel therapeutic targets. However, demonstration that novel treatments are
Search strategy and selection criteria
Glossary
- NE
- Neutrophil elastase
- MMP
- Matrix metalloproteinases
- iNOS
- Inducible nitric oxide synthase
- BLT
- Leukotriene B4 receptor
- CC
- Cysteine-cysteine
- TNFα
- Tumour necrosis factor α
- TNFR
- TNF receptors
- NFκβ
- Nuclear factor κβ
- CXC
- Cysteine-X-cysteine
- TACE
- TNFα converting enzyme
- MAPK
- Mitogen-activated protein kinases
- PDE4
- Phosphodiesterase type 4
- TIMP
- Tissue inhibitor of matrix metal loproteinases
- IαB
- Inhibitor of nuclear factor κB
- IKK
- Inhibitor of IκB kinase
- EGF
- Epidermal growth factor
- CACC
- Calcium-activated chloride channel
- PI3Kγ
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Trans-4,4′-dihydroxystilbene ameliorates cigarette smoke-induced progression of chronic obstructive pulmonary disease via inhibiting oxidative stress and inflammatory response
2020, Free Radical Biology and MedicineCitation Excerpt :Furthermore, NF-κB pathway was activated in macrophages and epithelial cells of COPD patients [10,11]. Therefore, given the biological functions of Nrf2 and NF-κB, molecules with the capabilities of activating Nrf2-mediated antioxidant responses and inhibiting NF-κB-regulated inflammatory response are potential preventive and therapeutic agents against COPD [12,13]. Resveratrol is a naturally derived constituent distributed in grape, red wine, and some folk medicines, and has displayed diverse bioactivities and potential medical applications, covering anticancer, antioxidant, anti-inflammatory, neuroprotective, antidiabetic, and cardiovascular properties [14–17].
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