Neutrophils and Emerging Targets for Treatment in COPD
Neutrophils and Emerging Targets for Treatment in COPD
Since CS is the most important risk factor for the development of COPD, smoking cessation is the intervention with the greatest capacity to influence the progress of COPD. CS and nicotine seem to delay neutrophil death, contributing to the pathogenesis of the disease. Spontaneous modifying neutrophil death provides an important treatment strategy in tobacco-induced COPD.
At this moment, the main forms of pharmacological treatment consist of short- and long-acting β-antagonists to relax smooth muscles and thus dilate the airways, short- and long-acting anticholinergics, and combinations of short-acting β-antagonists plus anticholinergic. These medications are often referred to as bronchodilators. Though administration of bronchodilators alleviates the symptoms of COPD, it is clear they do not treat any of the underlying causes. In the absence of any alternatives, corticosteroids have long been prescribed to patients with COPD. A recent meta-analysis studied the effects of corticosteroids. The results indicated that though a small reduction of neutrophil numbers in BAL fluids was found, tissue biopsies showed no difference in neutrophil presence. Macrophage infiltration also did not show a significant change. However, T-cells were markedly reduced. In a small minority of COPD patients, T-cells are the major instigators of the disease and these results suggest patients with this subtype would benefit from corticosteroid treatment. However, for the majority of patients corticosteroids do not affect the development of COPD. Normally, the nuclear enzyme histone deacetylase (HDAC) counteracts increased expression of inflammatory genes. However, in COPD a decrease in HDAC activity has been shown to be associated with enhanced inflammation. It was shown that suppression of HDAC is linked to reduced sensitivity to corticosteroids, because the glucocorticoid receptor recruits HDAC to the transcriptional complex in order to decrease inflammatory gene transcription. Interestingly enough, the inhibition by corticosteroids of neutrophil activation by LPS as measured by NE release seems to only be lacking in individuals primed by CS. It has been suggested that exposure to CS primes the neutrophils, leading to a decreased sensitivity to inhibitory signals from the corticosteroids. This could be explained by the observation that CS increases neutrophil intracellular calcium. As neutrophil degranulation is calcium-dependent, this could explain the increased neutrophil reactivity found in COPD.
More promising results have been observed when patients were prescribed statins. These patients had reduced hospitalization for COPD exacerbations, a lower mortality from these exacerbations, lower cardiovascular mortality, a decrease in FEV1-decline and a decreased risk of lung cancer. Additionally, statin administration was associated with a 54% increase in exercise tolerance. It should be noted that this study so far is the only prospective COPD trial with statins published. All other studies are retrospective. Unlike corticosteroids, statins are able to decrease IL-8 and TNF-α levels, as well as neutrophil infiltration of the lungs. Furthermore, in murine models statins have been able to restore some endothelial cell function which led to an increased regeneration of alveolar cells. In addition, statins appear to have an antioxidant activity by decreasing ROS production by inflammatory cells. Given these results, and the estimation that currently 25–30% of COPD patients are prescribed statins, much can be improved regarding the treatment of COPD. Nonetheless, it should be kept in mind that, although they have many beneficial effects, statins decrease but not obliterate the symptoms of COPD. Hence, better medication is still needed.
Up till now, most patients with the A1AT deficiency subtype of COPD are treated as conventional COPD patients. The efficacy of intravenous administration of plasma derived or recombinant A1AT has not yet convincingly been demonstrated.
Phosphodiesterase (PDE) inhibitors have shown some anti-inflammatory effects on leukocytes involved in the pathogenesis of COPD. Roflumilast, a PDE4 inhibitor, is prescribed for COPD patients with severe airflow limitation, chronic bronchitis and a history of exacerbations. Also this type of COPD patient cannot be adequately controlled by long-acting bronchodilators. On the other hand, roflumilast has significant side effects making it not useful in some patients. Other interesting results were obtained with macrolide therapy, such as azithromycin in the treatment of exacerbations. However, these type of drugs seem only to have beneficial effects when administered for periods longer than 6 months. A more specific approach to target neutrophils is the use of monoclonal antibodies directed against IL-8. Indeed, neutralizing IL-8 was shown to improve dyspnea, but further clinical studies were suggested by the authors. From recent studies, it is known that TLR4 is an interesting target in COPD, but also intake of some micronutrients, including vitamins and carotenes are positively associated with the natural history of COPD, and ligands of PPAR-γ have anti-inflammatory potencies in tobacco-induced COPD.
Currently, many new drugs are under development, a number of which have already been mentioned (Table 2). It should be acknowledged that several drugs, aimed to inhibit inflammatory mediators and pathways have failed to show clinical effectiveness and/or in vivo safety (Table 2). Especially NE and MMP-9 are targeted, together with neutrophil infiltration. For example, inhibiting PI3Kδ decreases neutrophil infiltration in murine models of acute lung damage, and might therefore also be a target for the treatment of COPD. However, it seems that neutrophil signaling pathways are altered in COPD, which makes research much more difficult and has led to many of such promising targets yielding no results. A few drugs, mainly targeting neutrophil recruitment, have been developed for other diseases such as rheumatoid arthritis, but had too many side effects after systemic administration and were therefore discarded. Currently, studies are performed to investigate if some of these drugs, such as p38 inhibitors, can be used for COPD, where they can be administered locally via inhalation. A very promising new drug, ectoine is able to restore normal apoptosis of neutrophils, which would lead to both lower levels of neutrophils in the lung and to less instances of neutrophil necrosis, thus also decreasing the protease/antiprotease imbalance. Because this drug only restores the normal lifespan of neutrophils, it does not affect the normal functioning of this cell type, which has been the main drawback of many other drugs. However, so far it has only been tested in murine models, so further studies are needed to prove its effectiveness and safety in the treatment of humans with COPD.
Treatment
Since CS is the most important risk factor for the development of COPD, smoking cessation is the intervention with the greatest capacity to influence the progress of COPD. CS and nicotine seem to delay neutrophil death, contributing to the pathogenesis of the disease. Spontaneous modifying neutrophil death provides an important treatment strategy in tobacco-induced COPD.
At this moment, the main forms of pharmacological treatment consist of short- and long-acting β-antagonists to relax smooth muscles and thus dilate the airways, short- and long-acting anticholinergics, and combinations of short-acting β-antagonists plus anticholinergic. These medications are often referred to as bronchodilators. Though administration of bronchodilators alleviates the symptoms of COPD, it is clear they do not treat any of the underlying causes. In the absence of any alternatives, corticosteroids have long been prescribed to patients with COPD. A recent meta-analysis studied the effects of corticosteroids. The results indicated that though a small reduction of neutrophil numbers in BAL fluids was found, tissue biopsies showed no difference in neutrophil presence. Macrophage infiltration also did not show a significant change. However, T-cells were markedly reduced. In a small minority of COPD patients, T-cells are the major instigators of the disease and these results suggest patients with this subtype would benefit from corticosteroid treatment. However, for the majority of patients corticosteroids do not affect the development of COPD. Normally, the nuclear enzyme histone deacetylase (HDAC) counteracts increased expression of inflammatory genes. However, in COPD a decrease in HDAC activity has been shown to be associated with enhanced inflammation. It was shown that suppression of HDAC is linked to reduced sensitivity to corticosteroids, because the glucocorticoid receptor recruits HDAC to the transcriptional complex in order to decrease inflammatory gene transcription. Interestingly enough, the inhibition by corticosteroids of neutrophil activation by LPS as measured by NE release seems to only be lacking in individuals primed by CS. It has been suggested that exposure to CS primes the neutrophils, leading to a decreased sensitivity to inhibitory signals from the corticosteroids. This could be explained by the observation that CS increases neutrophil intracellular calcium. As neutrophil degranulation is calcium-dependent, this could explain the increased neutrophil reactivity found in COPD.
More promising results have been observed when patients were prescribed statins. These patients had reduced hospitalization for COPD exacerbations, a lower mortality from these exacerbations, lower cardiovascular mortality, a decrease in FEV1-decline and a decreased risk of lung cancer. Additionally, statin administration was associated with a 54% increase in exercise tolerance. It should be noted that this study so far is the only prospective COPD trial with statins published. All other studies are retrospective. Unlike corticosteroids, statins are able to decrease IL-8 and TNF-α levels, as well as neutrophil infiltration of the lungs. Furthermore, in murine models statins have been able to restore some endothelial cell function which led to an increased regeneration of alveolar cells. In addition, statins appear to have an antioxidant activity by decreasing ROS production by inflammatory cells. Given these results, and the estimation that currently 25–30% of COPD patients are prescribed statins, much can be improved regarding the treatment of COPD. Nonetheless, it should be kept in mind that, although they have many beneficial effects, statins decrease but not obliterate the symptoms of COPD. Hence, better medication is still needed.
Up till now, most patients with the A1AT deficiency subtype of COPD are treated as conventional COPD patients. The efficacy of intravenous administration of plasma derived or recombinant A1AT has not yet convincingly been demonstrated.
Phosphodiesterase (PDE) inhibitors have shown some anti-inflammatory effects on leukocytes involved in the pathogenesis of COPD. Roflumilast, a PDE4 inhibitor, is prescribed for COPD patients with severe airflow limitation, chronic bronchitis and a history of exacerbations. Also this type of COPD patient cannot be adequately controlled by long-acting bronchodilators. On the other hand, roflumilast has significant side effects making it not useful in some patients. Other interesting results were obtained with macrolide therapy, such as azithromycin in the treatment of exacerbations. However, these type of drugs seem only to have beneficial effects when administered for periods longer than 6 months. A more specific approach to target neutrophils is the use of monoclonal antibodies directed against IL-8. Indeed, neutralizing IL-8 was shown to improve dyspnea, but further clinical studies were suggested by the authors. From recent studies, it is known that TLR4 is an interesting target in COPD, but also intake of some micronutrients, including vitamins and carotenes are positively associated with the natural history of COPD, and ligands of PPAR-γ have anti-inflammatory potencies in tobacco-induced COPD.
Currently, many new drugs are under development, a number of which have already been mentioned (Table 2). It should be acknowledged that several drugs, aimed to inhibit inflammatory mediators and pathways have failed to show clinical effectiveness and/or in vivo safety (Table 2). Especially NE and MMP-9 are targeted, together with neutrophil infiltration. For example, inhibiting PI3Kδ decreases neutrophil infiltration in murine models of acute lung damage, and might therefore also be a target for the treatment of COPD. However, it seems that neutrophil signaling pathways are altered in COPD, which makes research much more difficult and has led to many of such promising targets yielding no results. A few drugs, mainly targeting neutrophil recruitment, have been developed for other diseases such as rheumatoid arthritis, but had too many side effects after systemic administration and were therefore discarded. Currently, studies are performed to investigate if some of these drugs, such as p38 inhibitors, can be used for COPD, where they can be administered locally via inhalation. A very promising new drug, ectoine is able to restore normal apoptosis of neutrophils, which would lead to both lower levels of neutrophils in the lung and to less instances of neutrophil necrosis, thus also decreasing the protease/antiprotease imbalance. Because this drug only restores the normal lifespan of neutrophils, it does not affect the normal functioning of this cell type, which has been the main drawback of many other drugs. However, so far it has only been tested in murine models, so further studies are needed to prove its effectiveness and safety in the treatment of humans with COPD.