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• W2018496905 abstract "Chronic obstructive pulmonary disease (COPD) is a smoking-induced chronic inflammatory disease that affects mainly the lungs. In susceptible subjects airways inflammation becomes autonomous in part through pathogen-associated molecular patterns and tissue-derived damage-associated molecular patterns activating mainly Toll-like receptors expressed by multiple inflammatory cells.1Bezemer G.F. Sagar S. van Bergenhenegouwen J. Georgiou N.A. Garssen J. Kraneveld A.D. et al.Dual role of Toll-like receptors in asthma and chronic obstructive pulmonary disease.Pharmacol Rev. 2012; 64: 337-358Crossref PubMed Scopus (94) Google Scholar The current consensus is that the chronic inflammatory process in patients with COPD requires treatment to stop the ongoing cycle of infection, inflammation, and host tissue damage.2Vestbo J. Hurd S.S. Agustí A.G. Jones P.W. Vogelmeier C. Anzueto A. et al.Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.Am J Respir Crit Care Med. 2013; 187: 347-365Crossref PubMed Scopus (3773) Google ScholarThe inflammatory response in patients with COPD is dominated by neutrophils,3Hoenderdos K. Condliffe A. The neutrophil in chronic obstructive pulmonary disease.Am J Respir Cell Mol Biol. 2013; 48: 531-539Crossref PubMed Scopus (241) Google Scholar which circulate in greater numbers in patients with COPD. Moreover, there are now compelling data to indicate that these cells play a key pathogenic role in this condition and represent an important therapeutic target. Critically, the neutrophils in patients with COPD are different compared to cells isolated from healthy subjects. In particular, they display (1) aberrant chemotactic responses, (2) enhanced protease content, (3) intrinsic “priming” leading to greater agonist-induced reactive oxygen species generation, (4) enhanced IL-8 and leukotriene B4–driven migration to the airways and lung parenchyma,3Hoenderdos K. Condliffe A. The neutrophil in chronic obstructive pulmonary disease.Am J Respir Cell Mol Biol. 2013; 48: 531-539Crossref PubMed Scopus (241) Google Scholar and (5) a seemingly acquired resistance to the normal anti-inflammatory effects of corticosteroids.4Adcock I.M. Ito K. Glucocorticoid pathways in chronic obstructive pulmonary disease therapy.Proc Am Thorac Soc. 2005; 2: 313-319Crossref PubMed Scopus (49) Google Scholar As a consequence, it is generally agreed that inhibition or “normalization” of neutrophil function in patients with COPD might represent an important therapeutic strategy.2Vestbo J. Hurd S.S. Agustí A.G. Jones P.W. Vogelmeier C. Anzueto A. et al.Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.Am J Respir Crit Care Med. 2013; 187: 347-365Crossref PubMed Scopus (3773) Google ScholarCompared with other chronic inflammatory diseases, COPD is characterized by a further and possibly unique feature: oxidative stress, which originates from the inhalation of smoke and cellular sources, such as the phagocyte nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2).5Kirkham P.A. Barnes P.J. Oxidative stress in COPD.Chest. 2013; 144: 266-273Crossref PubMed Scopus (441) Google Scholar This oxidative environment is thought to have a negative effect on myeloid cell function (including the induction of corticosteroid resistance). However, it is important to note that steroid resistance is also observed in other chronic inflammatory settings and hence is not specific to COPD.Milara et al6Milara J. Lluch J. Almudever P. Freire J. Xiaozhong Q. Cortijo J. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2014; 134: 314-322.e9Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar have performed an extensive study into the putative mechanisms of steroid resistance in circulating neutrophils from patients with COPD and how these can be countered. They conclude that roflumilast N-oxide (RNO), the active metabolite of the phosphodiesterase IV inhibitor roflumilast, in addition to having direct (likely cyclic AMP mediated) anti-inflammatory and bronchodilator effects, also reverses the steroid insensitivity of neutrophils in patients with COPD. With certain caveats, their experiments support the hypothesis that oxidative stress downregulates steroid sensitivity in neutrophils and that this is almost completely reversible by cotreatment with RNO. Although these findings are of interest and align with certain clinical studies relating to the efficacy of these and other nonselective phosphodiesterase inhibitors in smokers with asthma,7Spears M. Donnelly I. Jolly L. Brannigan M. Ito K. McSharry C. et al.Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study.Eur Respir J. 2009; 33: 1010-1017Crossref PubMed Scopus (98) Google Scholar the article still lacks a clear hypothesis regarding how glucocorticosteroid (GCS) resistance evolves and the precise mechanism whereby RNO restores the sensitivity these cells to corticosteroids.A number of mechanisms have been proposed to explain the resistance of immune cells and lung epithelial cells of patients with COPD to steroids, including the following:1.familial GCS resistance (eg, through inactivating mutations in the glucocorticoid receptor [GR] α or functional single nucleotide polymorphisms, which affect GR transcription)8Charmandari E. Kino T. Ichijo T. Chrousos G.P. Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder.J Clin Endocrinol Metab. 2008; 93: 1563-1572Crossref PubMed Scopus (141) Google Scholar;2.reduced expression or enhanced degradation of GRα (eg, through the actions of IL-6, IL-8, TNF-α, and nitric oxide)9Hamid Q.A. Wenzel S.E. Hauk P.J. Tsicopoulos A. Wallaert B. Lafitte J.J. et al.Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.Am J Respir Crit Care Med. 1999; 159: 1600-1604Crossref PubMed Scopus (261) Google Scholar;3.impaired GRα activity (eg, through GRα phosphorylation induced by IL-2–, IL-4–, or IL-13–mediated p38 mitogen-activated protein kinase activation) or impaired GRα nuclear translocation (eg, through increased expression of the chaperone protein FKBP51)9Hamid Q.A. Wenzel S.E. Hauk P.J. Tsicopoulos A. Wallaert B. Lafitte J.J. et al.Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.Am J Respir Crit Care Med. 1999; 159: 1600-1604Crossref PubMed Scopus (261) Google Scholar;4.enhanced GRβ expression, which acts as a natural antagonist for GRα (eg, IL-17)10Barnes P.J. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2013; 131: 636-645Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar;5.inhibition of GRα transrepressive activity through impaired histone deacetylase 2 activity, which reduces histone acetylation (eg, through the effects of oxidative stress, nitric oxide, and hypoxia)9Hamid Q.A. Wenzel S.E. Hauk P.J. Tsicopoulos A. Wallaert B. Lafitte J.J. et al.Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.Am J Respir Crit Care Med. 1999; 159: 1600-1604Crossref PubMed Scopus (261) Google Scholar;6.enhanced GCS efflux from cells (eg, because of increased activity of the drug efflux pump P-glycoprotein 170)9Hamid Q.A. Wenzel S.E. Hauk P.J. Tsicopoulos A. Wallaert B. Lafitte J.J. et al.Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.Am J Respir Crit Care Med. 1999; 159: 1600-1604Crossref PubMed Scopus (261) Google Scholar; and7.the presence of parallel competing pathways, in which the intensity of the inflammatory response (eg, nuclear factor κB, activator protein 1, c-Jun N-terminal kinase 1, signal transducer and activator of transcription 5, and Janus kinase 3) saturates out any beneficial effect of GCS.9Hamid Q.A. Wenzel S.E. Hauk P.J. Tsicopoulos A. Wallaert B. Lafitte J.J. et al.Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.Am J Respir Crit Care Med. 1999; 159: 1600-1604Crossref PubMed Scopus (261) Google ScholarThe study by Milara et al6Milara J. Lluch J. Almudever P. Freire J. Xiaozhong Q. Cortijo J. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2014; 134: 314-322.e9Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar adds new information to this debate by showing that there is clear synergism between the anti-inflammatory effects of low concentrations of GCSs and RNO and the capacity of RNO to normalize a very diverse array of processes thought to underlie GCS resistance in neutrophils from patients with COPD. These include reversing the increases in phosphoinositide 3-kinase δ, macrophage migration inhibitory factor, and GRβ expression at the mRNA level observed in neutrophils from patients with COPD and restoring histone deacetylase activity and MKP-1 expression. Unfortunately, the authors do not integrate these findings into a unifying hypothesis as to how such different processes are controlled by RNO. There are also a number of technical issues regarding this study, including the use of a cohort of patients with COPD with very mild disease (mean FEV1/forced vital capacity ratio, 69.2% ± 11%), when a number of studies have suggested that patients with severe disease and frequent exacerbations derive the most clinical benefit from roflumilast.11Yu T. Fain K. Boyd C.M. Singh S. Weiss C.O. Li T. et al.Benefits and harms of roflumilast in moderate to severe COPD.Thorax. 2013; ([Epub ahead of print])Google Scholar All patients were active smokers, and some were studied close to an exacerbation; their in vitro assays also relied on the use of pharmacologic concentrations of LPS (1 μg/mL), which even then induced much lower levels of IL-8 than anticipated.It is uncertain whether the abnormal neutrophil phenotype observed in patients with COPD is intrinsic or acquired and, if the latter, how and in which compartment this effect occurs. There is a clear imperative to progress these studies to the airway/alveolar neutrophil. The assumption that neutrophils from patients with COPD are intrinsically normal but influenced by local proinflammatory mediators is not necessarily valid because recent research has provided evidence for the existence of multiple neutrophil phenotypes,12Pillay J. Kamp V.M. van Hoffen E. Visser T. Tak T. Lammers J.W. et al.A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1.J Clin Invest. 2012; 122: 327-336Crossref PubMed Scopus (550) Google Scholar including myeloid-derived suppressor cells, which might be modulated by smoking.13Scrimini S. Pons J. Agustí A. Soriano J.B. Cosio B.G. Torrecilla J.A. et al.Differential effects of smoking and COPD upon circulating myeloid derived suppressor cells.Respir Med. 2013; 107: 1895-1903Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar If an MDSC type of neutrophil is indeed mobilized in patients with COPD, these cells could easily respond differently to RNO, reactive oxygen species, and GCSs. The second proposal is that oxidative stress is the dominant factor in driving the steroid resistance observed in blood neutrophils in patients with COPD and that RNO reverses this effect. Although attractive, the supportive evidence for neutrophil oxidative stress in vivo being secondary to a direct effect of cigarette smoking is not definitive. The authors themselves discuss the fact that similar effects on neutrophils have been seen in patients with inflammatory diseases that do not involve cigarette smoke. The alternative hypothesis, that neutrophil priming and the acquisition of steroid resistance occur in the circulation or bone marrow compartments as a result of exposure to inflammatory mediators, such as cytokines, chemokines, and bioactive lipids, seems more attractive.The importance of targeting the neutrophil for future anti-inflammatory therapy in patients with COPD is clear, and several options now exist, including phosphodiesterase IV, CXCR2, nuclear erythroid-related factor 2 (Nrf2), phosphoinositide 3-kinase δ, and elastase inhibition.14Malhotra D. Thimmulappa R.K. Mercado N. Ito K. Kombairaju P. Kumar S. et al.Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients.J Clin Invest. 2011; 121: 4289-4302Crossref PubMed Scopus (112) Google Scholar, 15Marwick J.A. Caramori G. Stevenson C.S. Casolari P. Jazrawi E. Barnes P.J. et al.Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice.Am J Respir Crit Care Med. 2009; 179: 542-548Crossref PubMed Scopus (209) Google Scholar However, it is uncertain at this stage whether inhibition of this cell type alone will be sufficient in a disease that involves multiple cell types and pathologic processes. Likewise, even if it is possible to restore the sensitivity of neutrophils to the anti-inflammatory effects of steroids, it is debatable whether GCS will ever become more attractive in treating patients with COPD because even in health the effects of steroids on neutrophils are at best modest and in some cases detrimental (eg, increasing the overall number of circulating neutrophils and delaying apoptotic cell death). These concerns are compounded by reports highlighting the effect of inhaled corticosteroids on the incidence of pneumonia. Indeed, given the effect of RNO on intracellular reactive oxygen species generation, the effects of RNO alone or in combination with corticosteroids on bacterial killing and infection risk will need to be carefully assessed.16Kew K.M. Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease.Cochrane Database Syst Rev. 2014; : CD010115PubMed Google ScholarIn conclusion, roflumilast shows effectiveness in the treatment of COPD, and the article by Milara et al6Milara J. Lluch J. Almudever P. Freire J. Xiaozhong Q. Cortijo J. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2014; 134: 314-322.e9Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar suggests a capacity, at least in vitro, to reverse the GCS-resident phenotype of neutrophils from patients with COPD; the mechanism of this effect remains to be defined. This article provides a new impetus to continue to try to target neutrophils in patients with COPD. Chronic obstructive pulmonary disease (COPD) is a smoking-induced chronic inflammatory disease that affects mainly the lungs. In susceptible subjects airways inflammation becomes autonomous in part through pathogen-associated molecular patterns and tissue-derived damage-associated molecular patterns activating mainly Toll-like receptors expressed by multiple inflammatory cells.1Bezemer G.F. Sagar S. van Bergenhenegouwen J. Georgiou N.A. Garssen J. Kraneveld A.D. et al.Dual role of Toll-like receptors in asthma and chronic obstructive pulmonary disease.Pharmacol Rev. 2012; 64: 337-358Crossref PubMed Scopus (94) Google Scholar The current consensus is that the chronic inflammatory process in patients with COPD requires treatment to stop the ongoing cycle of infection, inflammation, and host tissue damage.2Vestbo J. Hurd S.S. Agustí A.G. Jones P.W. Vogelmeier C. Anzueto A. et al.Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.Am J Respir Crit Care Med. 2013; 187: 347-365Crossref PubMed Scopus (3773) Google Scholar The inflammatory response in patients with COPD is dominated by neutrophils,3Hoenderdos K. Condliffe A. The neutrophil in chronic obstructive pulmonary disease.Am J Respir Cell Mol Biol. 2013; 48: 531-539Crossref PubMed Scopus (241) Google Scholar which circulate in greater numbers in patients with COPD. Moreover, there are now compelling data to indicate that these cells play a key pathogenic role in this condition and represent an important therapeutic target. Critically, the neutrophils in patients with COPD are different compared to cells isolated from healthy subjects. In particular, they display (1) aberrant chemotactic responses, (2) enhanced protease content, (3) intrinsic “priming” leading to greater agonist-induced reactive oxygen species generation, (4) enhanced IL-8 and leukotriene B4–driven migration to the airways and lung parenchyma,3Hoenderdos K. Condliffe A. The neutrophil in chronic obstructive pulmonary disease.Am J Respir Cell Mol Biol. 2013; 48: 531-539Crossref PubMed Scopus (241) Google Scholar and (5) a seemingly acquired resistance to the normal anti-inflammatory effects of corticosteroids.4Adcock I.M. Ito K. Glucocorticoid pathways in chronic obstructive pulmonary disease therapy.Proc Am Thorac Soc. 2005; 2: 313-319Crossref PubMed Scopus (49) Google Scholar As a consequence, it is generally agreed that inhibition or “normalization” of neutrophil function in patients with COPD might represent an important therapeutic strategy.2Vestbo J. Hurd S.S. Agustí A.G. Jones P.W. Vogelmeier C. Anzueto A. et al.Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.Am J Respir Crit Care Med. 2013; 187: 347-365Crossref PubMed Scopus (3773) Google Scholar Compared with other chronic inflammatory diseases, COPD is characterized by a further and possibly unique feature: oxidative stress, which originates from the inhalation of smoke and cellular sources, such as the phagocyte nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2).5Kirkham P.A. Barnes P.J. Oxidative stress in COPD.Chest. 2013; 144: 266-273Crossref PubMed Scopus (441) Google Scholar This oxidative environment is thought to have a negative effect on myeloid cell function (including the induction of corticosteroid resistance). However, it is important to note that steroid resistance is also observed in other chronic inflammatory settings and hence is not specific to COPD. Milara et al6Milara J. Lluch J. Almudever P. Freire J. Xiaozhong Q. Cortijo J. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2014; 134: 314-322.e9Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar have performed an extensive study into the putative mechanisms of steroid resistance in circulating neutrophils from patients with COPD and how these can be countered. They conclude that roflumilast N-oxide (RNO), the active metabolite of the phosphodiesterase IV inhibitor roflumilast, in addition to having direct (likely cyclic AMP mediated) anti-inflammatory and bronchodilator effects, also reverses the steroid insensitivity of neutrophils in patients with COPD. With certain caveats, their experiments support the hypothesis that oxidative stress downregulates steroid sensitivity in neutrophils and that this is almost completely reversible by cotreatment with RNO. Although these findings are of interest and align with certain clinical studies relating to the efficacy of these and other nonselective phosphodiesterase inhibitors in smokers with asthma,7Spears M. Donnelly I. Jolly L. Brannigan M. Ito K. McSharry C. et al.Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study.Eur Respir J. 2009; 33: 1010-1017Crossref PubMed Scopus (98) Google Scholar the article still lacks a clear hypothesis regarding how glucocorticosteroid (GCS) resistance evolves and the precise mechanism whereby RNO restores the sensitivity these cells to corticosteroids. A number of mechanisms have been proposed to explain the resistance of immune cells and lung epithelial cells of patients with COPD to steroids, including the following:1.familial GCS resistance (eg, through inactivating mutations in the glucocorticoid receptor [GR] α or functional single nucleotide polymorphisms, which affect GR transcription)8Charmandari E. Kino T. Ichijo T. Chrousos G.P. Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder.J Clin Endocrinol Metab. 2008; 93: 1563-1572Crossref PubMed Scopus (141) Google Scholar;2.reduced expression or enhanced degradation of GRα (eg, through the actions of IL-6, IL-8, TNF-α, and nitric oxide)9Hamid Q.A. Wenzel S.E. Hauk P.J. Tsicopoulos A. Wallaert B. Lafitte J.J. et al.Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.Am J Respir Crit Care Med. 1999; 159: 1600-1604Crossref PubMed Scopus (261) Google Scholar;3.impaired GRα activity (eg, through GRα phosphorylation induced by IL-2–, IL-4–, or IL-13–mediated p38 mitogen-activated protein kinase activation) or impaired GRα nuclear translocation (eg, through increased expression of the chaperone protein FKBP51)9Hamid Q.A. Wenzel S.E. Hauk P.J. Tsicopoulos A. Wallaert B. Lafitte J.J. et al.Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.Am J Respir Crit Care Med. 1999; 159: 1600-1604Crossref PubMed Scopus (261) Google Scholar;4.enhanced GRβ expression, which acts as a natural antagonist for GRα (eg, IL-17)10Barnes P.J. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2013; 131: 636-645Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar;5.inhibition of GRα transrepressive activity through impaired histone deacetylase 2 activity, which reduces histone acetylation (eg, through the effects of oxidative stress, nitric oxide, and hypoxia)9Hamid Q.A. Wenzel S.E. Hauk P.J. Tsicopoulos A. Wallaert B. Lafitte J.J. et al.Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.Am J Respir Crit Care Med. 1999; 159: 1600-1604Crossref PubMed Scopus (261) Google Scholar;6.enhanced GCS efflux from cells (eg, because of increased activity of the drug efflux pump P-glycoprotein 170)9Hamid Q.A. Wenzel S.E. Hauk P.J. Tsicopoulos A. Wallaert B. Lafitte J.J. et al.Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.Am J Respir Crit Care Med. 1999; 159: 1600-1604Crossref PubMed Scopus (261) Google Scholar; and7.the presence of parallel competing pathways, in which the intensity of the inflammatory response (eg, nuclear factor κB, activator protein 1, c-Jun N-terminal kinase 1, signal transducer and activator of transcription 5, and Janus kinase 3) saturates out any beneficial effect of GCS.9Hamid Q.A. Wenzel S.E. Hauk P.J. Tsicopoulos A. Wallaert B. Lafitte J.J. et al.Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.Am J Respir Crit Care Med. 1999; 159: 1600-1604Crossref PubMed Scopus (261) Google Scholar The study by Milara et al6Milara J. Lluch J. Almudever P. Freire J. Xiaozhong Q. Cortijo J. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2014; 134: 314-322.e9Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar adds new information to this debate by showing that there is clear synergism between the anti-inflammatory effects of low concentrations of GCSs and RNO and the capacity of RNO to normalize a very diverse array of processes thought to underlie GCS resistance in neutrophils from patients with COPD. These include reversing the increases in phosphoinositide 3-kinase δ, macrophage migration inhibitory factor, and GRβ expression at the mRNA level observed in neutrophils from patients with COPD and restoring histone deacetylase activity and MKP-1 expression. Unfortunately, the authors do not integrate these findings into a unifying hypothesis as to how such different processes are controlled by RNO. There are also a number of technical issues regarding this study, including the use of a cohort of patients with COPD with very mild disease (mean FEV1/forced vital capacity ratio, 69.2% ± 11%), when a number of studies have suggested that patients with severe disease and frequent exacerbations derive the most clinical benefit from roflumilast.11Yu T. Fain K. Boyd C.M. Singh S. Weiss C.O. Li T. et al.Benefits and harms of roflumilast in moderate to severe COPD.Thorax. 2013; ([Epub ahead of print])Google Scholar All patients were active smokers, and some were studied close to an exacerbation; their in vitro assays also relied on the use of pharmacologic concentrations of LPS (1 μg/mL), which even then induced much lower levels of IL-8 than anticipated. It is uncertain whether the abnormal neutrophil phenotype observed in patients with COPD is intrinsic or acquired and, if the latter, how and in which compartment this effect occurs. There is a clear imperative to progress these studies to the airway/alveolar neutrophil. The assumption that neutrophils from patients with COPD are intrinsically normal but influenced by local proinflammatory mediators is not necessarily valid because recent research has provided evidence for the existence of multiple neutrophil phenotypes,12Pillay J. Kamp V.M. van Hoffen E. Visser T. Tak T. Lammers J.W. et al.A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1.J Clin Invest. 2012; 122: 327-336Crossref PubMed Scopus (550) Google Scholar including myeloid-derived suppressor cells, which might be modulated by smoking.13Scrimini S. Pons J. Agustí A. Soriano J.B. Cosio B.G. Torrecilla J.A. et al.Differential effects of smoking and COPD upon circulating myeloid derived suppressor cells.Respir Med. 2013; 107: 1895-1903Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar If an MDSC type of neutrophil is indeed mobilized in patients with COPD, these cells could easily respond differently to RNO, reactive oxygen species, and GCSs. The second proposal is that oxidative stress is the dominant factor in driving the steroid resistance observed in blood neutrophils in patients with COPD and that RNO reverses this effect. Although attractive, the supportive evidence for neutrophil oxidative stress in vivo being secondary to a direct effect of cigarette smoking is not definitive. The authors themselves discuss the fact that similar effects on neutrophils have been seen in patients with inflammatory diseases that do not involve cigarette smoke. The alternative hypothesis, that neutrophil priming and the acquisition of steroid resistance occur in the circulation or bone marrow compartments as a result of exposure to inflammatory mediators, such as cytokines, chemokines, and bioactive lipids, seems more attractive. The importance of targeting the neutrophil for future anti-inflammatory therapy in patients with COPD is clear, and several options now exist, including phosphodiesterase IV, CXCR2, nuclear erythroid-related factor 2 (Nrf2), phosphoinositide 3-kinase δ, and elastase inhibition.14Malhotra D. Thimmulappa R.K. Mercado N. Ito K. Kombairaju P. Kumar S. et al.Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients.J Clin Invest. 2011; 121: 4289-4302Crossref PubMed Scopus (112) Google Scholar, 15Marwick J.A. Caramori G. Stevenson C.S. Casolari P. Jazrawi E. Barnes P.J. et al.Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice.Am J Respir Crit Care Med. 2009; 179: 542-548Crossref PubMed Scopus (209) Google Scholar However, it is uncertain at this stage whether inhibition of this cell type alone will be sufficient in a disease that involves multiple cell types and pathologic processes. Likewise, even if it is possible to restore the sensitivity of neutrophils to the anti-inflammatory effects of steroids, it is debatable whether GCS will ever become more attractive in treating patients with COPD because even in health the effects of steroids on neutrophils are at best modest and in some cases detrimental (eg, increasing the overall number of circulating neutrophils and delaying apoptotic cell death). These concerns are compounded by reports highlighting the effect of inhaled corticosteroids on the incidence of pneumonia. Indeed, given the effect of RNO on intracellular reactive oxygen species generation, the effects of RNO alone or in combination with corticosteroids on bacterial killing and infection risk will need to be carefully assessed.16Kew K.M. Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease.Cochrane Database Syst Rev. 2014; : CD010115PubMed Google Scholar In conclusion, roflumilast shows effectiveness in the treatment of COPD, and the article by Milara et al6Milara J. Lluch J. Almudever P. Freire J. Xiaozhong Q. Cortijo J. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2014; 134: 314-322.e9Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar suggests a capacity, at least in vitro, to reverse the GCS-resident phenotype of neutrophils from patients with COPD; the mechanism of this effect remains to be defined. This article provides a new impetus to continue to try to target neutrophils in patients with COPD. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary diseaseJournal of Allergy and Clinical ImmunologyVol. 134Issue 2PreviewGlucocorticoid functions are markedly impaired in patients with chronic obstructive pulmonary disease (COPD). The phosphodiesterase 4 inhibitor roflumilast N-oxide (RNO) is the active metabolite of roflumilast approved as a treatment to reduce the risk of exacerbations in patients with severe COPD. Full-Text PDF" @default.
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• W2018496905 title "Future treatment in patients with chronic obstructive pulmonary disease: To reverse or not to reverse steroid resistance—that is the question" @default.
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