35. Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I (2008) SIRT1, an antiinflammatory and
antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 177:861–870. https://doi.org/10.1164/rccm.200708-1269OC
36. Osoata GO, Yamamura S, Ito M, Vuppusetty C, Adcock IM, Barnes PJ, Ito K (2009) Nitration
of distinct tyrosine residues causes inactivation of histone deacetylase 2. Biochem Biophys
Res Commun 384:366–371. https://doi.org/10.1016/j.bbrc.2009.04.128
37. Adenuga D, Yao H, March TH, Seagrave J, Rahman I (2009) Histone deacetylase 2 is
phosphorylated, ubiquitinated, and degraded by cigarette smoke. Am J Respir Cell Mol Biol
40:464–473. https://doi.org/10.1165/rcmb.2008-0255OC
38. Barnes PJ (2009) Targeting the epigenome in the treatment of asthma and chronic obstructive
pulmonary disease. Proc Am Thorac Soc 6:693–696. https://doi.org/10.1513/pats.200907071DP
39. Barnes PJ (2009) Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol
71:451–464. https://doi.org/10.1146/annurev.physiol.010908.163257
40. Rao NAS, McCalman MT, Moulos P, Francoijs KJ, Chatziioannou A, Kolisis FN, Alexis MN,
Mitsiou DJ, Stunnenberg HG (2011) Coactivation of GR and NFKB alters the repertoire of
their binding sites and target genes. Genome Res 21:1404–1416. https://doi.org/10.1101/gr.
118042.110
41. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ (2004) Theophylline restores
histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med
200:689–695. https://doi.org/10.1084/jem.20040416
42. Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ (2002) A molecular
mechanism of action of theophylline: induction of histone deacetylase activity to decrease
inflammatory gene expression. Proc Natl Acad Sci U S A 99:8921–8926. https://doi.org/10.
1073/pnas.132556899
43. To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T, Elliott WM, Hogg JC, Adcock IM, Barnes
PJ (2010) Targeting phosphoinositide-3-kinase-δ with theophylline reverses corticosteroid
insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
182:897–904. https://doi.org/10.1164/rccm.200906-0937OC
44. Abramson M, Sim MR (2006) Theophylline for COPD. Thorax 61:741–742. https://doi.org/
10.1136/thx.2005.056200
45. Marwick JA, Ito K, Adcock IM, Kirkham PA (2007) Oxidative stress and steroid resistance in
asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy.
Expert Opin Ther Targets 11:745–755. https://doi.org/10.1517/14728222.11.6.745
46. Scanlon PD, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS, Tashkin DP (2000)
Smoking cessation and lung function in mild-to- moderate chronic obstructive pulmonary
disease: the lung health study. Am J Respir Crit Care Med 161:381–390
47. Wu J, Sin DD (2011) Improved patient outcome with smoking cessation: when is it too late?
Int J COPD 6:259–267. https://doi.org/10.2147/COPD.S10771
48. Lührs H, Gerke T, Müller JG, Melcher R, Schauber J, Boxberger F, Scheppach W, Menzel T
(2002) Butyrate inhibits NF-κB activation in lamina propria macrophages of patients with
ulcerative colitis. Scand J Gastroenterol 37:458–466. https://doi.org/10.1080/
003655202317316105
49. Faraco G, Cavone L (2011) The therapeutic potential of HDAC inhibitors in the treatment of
multiple sclerosis. Mol Med 17:1. https://doi.org/10.2119/molmed.2011.00077
50. Grabiec AM, Krausz S, de Jager W, Burakowski T, Groot D, Sanders ME, Prakken BJ,
Maslinski W, Eldering E, Tak PP, Reedquist KA (2010) Histone deacetylase inhibitors
suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and
tissue. J Immunol 184:2718–2728. https://doi.org/10.4049/jimmunol.0901467
51. Leus NGJ, Van Den Bosch T, Van Der Wouden PE, Krist K, Ourailidou ME, Eleftheriadis N,
Kistemaker LEM, Bos S, Gjaltema RAF, Mekonnen SA, Bischoff R, Gosens R, Haisma HJ,
Dekker FJ (2017) HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7
macrophages and reduces cigarette smoke-induced airway inflammation in mice. Sci Rep
7:1–18. https://doi.org/10.1038/srep45047
448
M. R. H. Zwinderman et al.
antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 177:861–870. https://doi.org/10.1164/rccm.200708-1269OC
36. Osoata GO, Yamamura S, Ito M, Vuppusetty C, Adcock IM, Barnes PJ, Ito K (2009) Nitration
of distinct tyrosine residues causes inactivation of histone deacetylase 2. Biochem Biophys
Res Commun 384:366–371. https://doi.org/10.1016/j.bbrc.2009.04.128
37. Adenuga D, Yao H, March TH, Seagrave J, Rahman I (2009) Histone deacetylase 2 is
phosphorylated, ubiquitinated, and degraded by cigarette smoke. Am J Respir Cell Mol Biol
40:464–473. https://doi.org/10.1165/rcmb.2008-0255OC
38. Barnes PJ (2009) Targeting the epigenome in the treatment of asthma and chronic obstructive
pulmonary disease. Proc Am Thorac Soc 6:693–696. https://doi.org/10.1513/pats.200907071DP
39. Barnes PJ (2009) Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol
71:451–464. https://doi.org/10.1146/annurev.physiol.010908.163257
40. Rao NAS, McCalman MT, Moulos P, Francoijs KJ, Chatziioannou A, Kolisis FN, Alexis MN,
Mitsiou DJ, Stunnenberg HG (2011) Coactivation of GR and NFKB alters the repertoire of
their binding sites and target genes. Genome Res 21:1404–1416. https://doi.org/10.1101/gr.
118042.110
41. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ (2004) Theophylline restores
histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med
200:689–695. https://doi.org/10.1084/jem.20040416
42. Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ (2002) A molecular
mechanism of action of theophylline: induction of histone deacetylase activity to decrease
inflammatory gene expression. Proc Natl Acad Sci U S A 99:8921–8926. https://doi.org/10.
1073/pnas.132556899
43. To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T, Elliott WM, Hogg JC, Adcock IM, Barnes
PJ (2010) Targeting phosphoinositide-3-kinase-δ with theophylline reverses corticosteroid
insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
182:897–904. https://doi.org/10.1164/rccm.200906-0937OC
44. Abramson M, Sim MR (2006) Theophylline for COPD. Thorax 61:741–742. https://doi.org/
10.1136/thx.2005.056200
45. Marwick JA, Ito K, Adcock IM, Kirkham PA (2007) Oxidative stress and steroid resistance in
asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy.
Expert Opin Ther Targets 11:745–755. https://doi.org/10.1517/14728222.11.6.745
46. Scanlon PD, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS, Tashkin DP (2000)
Smoking cessation and lung function in mild-to- moderate chronic obstructive pulmonary
disease: the lung health study. Am J Respir Crit Care Med 161:381–390
47. Wu J, Sin DD (2011) Improved patient outcome with smoking cessation: when is it too late?
Int J COPD 6:259–267. https://doi.org/10.2147/COPD.S10771
48. Lührs H, Gerke T, Müller JG, Melcher R, Schauber J, Boxberger F, Scheppach W, Menzel T
(2002) Butyrate inhibits NF-κB activation in lamina propria macrophages of patients with
ulcerative colitis. Scand J Gastroenterol 37:458–466. https://doi.org/10.1080/
003655202317316105
49. Faraco G, Cavone L (2011) The therapeutic potential of HDAC inhibitors in the treatment of
multiple sclerosis. Mol Med 17:1. https://doi.org/10.2119/molmed.2011.00077
50. Grabiec AM, Krausz S, de Jager W, Burakowski T, Groot D, Sanders ME, Prakken BJ,
Maslinski W, Eldering E, Tak PP, Reedquist KA (2010) Histone deacetylase inhibitors
suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and
tissue. J Immunol 184:2718–2728. https://doi.org/10.4049/jimmunol.0901467
51. Leus NGJ, Van Den Bosch T, Van Der Wouden PE, Krist K, Ourailidou ME, Eleftheriadis N,
Kistemaker LEM, Bos S, Gjaltema RAF, Mekonnen SA, Bischoff R, Gosens R, Haisma HJ,
Dekker FJ (2017) HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7
macrophages and reduces cigarette smoke-induced airway inflammation in mice. Sci Rep
7:1–18. https://doi.org/10.1038/srep45047
448
M. R. H. Zwinderman et al.