Molecular Mechanisms of Inflammation During Exacerbations of Chronic Obstructive Pulmonary Disease

Kersul, Ana L.; Iglesias, Amanda; Ríos, Ángel; Noguera, Aina; Forteza, Aina; Serra, Enrique; Agustí, Alvar; Cosío, Borja G.

doi:10.1016/S1579-2129(11)70043-X

Article information

Abstract

Bibliography

Download PDF

Statistics

Abstract

Introduction

Exacerbations of chronic obstructive pulmonary disease (COPD) are characterised by an inflammatory and systemic response that persists for some time after their clinical resolution. The mechanisms of this inflammatory process are not well known.

Objectives

To explore the inflammatory changes and possible mechanisms during COPD exacerbation.

Methods

We determined the inflammatory cell concentrations in blood and sputum, nitric oxide in exhaled air (FeNO), C-reactive protein (CRP) in plasma, cytokines (IL-6, 8, 1β, 10, 12, TNF-α) and SLPI (leukocyte protease inhibitor) and total antioxidant status (TAS) in blood and sputum, the activity of nuclear kappa B factor (NF-κ B) and of the histone deacetylase enzyme (HDAC) in 17 patients during COPD exacerbation and in stable phase, as well as in 17 smoker and 11 non-smoker controls.

Results

COPD exacerbations are characterised by high levels of FeNO (p<0.05), plasma CRP (p<0.001) and IL-8, IL-1B, IL-10 in sputum (p<0.05) greater activation of NF-κ appaB in sputum macrophages compared with stable COPD and controls. During the stable phase, there continue to be high levels of oxidative stress, SLPI, IL-8, IL-6 and TNF-alfa, with no observed changes in either HDAC activity or in the amount of neutrophils in sputum, despite presenting a significant improvement (p<0.05) in lung function.

Conclusions

Changes were observed in different pulmonary and systemic inflammatory markers during COPD exacerbation, which did not completely resolve during stable phase. However, current treatment does not allow for HDAC activity to be modified, which limits its anti-inflammatory effects.

Keywords:

COPD exacerbation

Inflammation

Histone acetylation

Resumen

Introducción

Las agudizaciones de la enfermedad pulmonar obstructiva crónica (AEPOC) se caracterizan por una respuesta inflamatoria pulmonar y sistémica, que persiste tiempo después de la resolución clínica. Los mecanismos de este proceso inflamatorio no son bien conocidos.

Objetivos

Investigar los cambios inflamatorios y sus mecanismos durante las agudizaciones de la EPOC.

Métodos

Se determinaron las concentraciones de células inflamatorias en sangre y esputo, óxido nítrico en aire exhalado (FeNO), proteína C reactiva (PCR) en plasma, citocinas (interleucinas [IL] 6, 8, 1β, 10, 12, TNF-α) y SLPI (inhibidor de la leucoproteasa), marcadores de estrés oxidativo, la actividad del factor nuclear kappa B (NF-κ appaB) y de la enzima histona deacetilasa (HDAC) a 17 pacientes durante una AEPOC, en fase estable y a 17 controles fumadores y 11 no fumadores.

Resultados

Las AEPOC se caracterizaron por presentar niveles elevados de FeNO (p < 0,05), PCR en plasma (p < 0,001) e IL-8, IL-1β, IL-10 en esputo (p < 0,05) y mayor activación de NF-κ appaB en macrófagos de esputo en comparación con EPOC estable y controles. Durante la fase estable persisten niveles elevados de estrés oxidativo, SLPI, IL-8, IL-6 y TNF-alfa, sin objetivarse cambios en la actividad HDAC ni en la cantidad de neutrófilos en esputo a pesar de presentar una mejoría significativa (p < 0,05) de la función pulmonar.

Conclusiones

Durante las AEPOC se observan cambios en marcadores inflamatorios pulmonares y sistémicos que no se resuelven por completo en fase estable. El tratamiento actual no permite modificar la actividad HDAC lo que limita sus efectos antiinflamatorios.

Palabras clave:

Exacerbación de EPOC

Inflamación

Acetilación de histonas

Full text is only aviable in PDF

References

[1.]

K.F. Rabe, S. Hurd, A. Anzueto, P.J. Barnes, S.A. Buist, P. Calverley, et al.

Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.

Am J Respir Crit Care Med, 176 (2007), pp. 532-555

http://dx.doi.org/10.1164/rccm.200703-456SO | Medline

[2.]

T.A. Seemungal, G.C. Donaldson, E.A. Paul, J.C. Bestall, D.J. Jeffries, J.A. Wedzicha.

Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease.

Am J Respir Crit Care Med, 157 (1998), pp. 1418-1422

http://dx.doi.org/10.1164/ajrccm.157.5.9709032 | Medline

[3.]

S. Spencer, P.W. Jones.

Time course of recovery of health status following an infective exacerbation of chronic bronchitis.

Thorax, 58 (2003), pp. 589

Medline

[4.]

T.A. Seemungal, G.C. Donaldson, A. Bhowmik, D.J. Jeffries, J.A. Wedzicha.

Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease.

Am J Respir Crit Care Med, 161 (2000), pp. 1608-1613

http://dx.doi.org/10.1164/ajrccm.161.5.9908022 | Medline

[5.]

G.C. Donaldson, T.A. Seemungal, A. Bhowmik, J.A. Wedzicha.

Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease.

Thorax, 57 (2002), pp. 847-852

Medline

[6.]

P. Almagro, E. Calbo, D.E. Ochoa, B. Barreiro, S. Quintana, J.L. Heredia, et al.

Mortality after hospitalization for COPD.

Chest, 121 (2002), pp. 1441-1448

Medline

[7.]

J.J. Soler-Cataluna, M.A. Martínez-García, S.P. Román, E. Salcedo, M. Navarro, R. Ochando.

Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease.

Thorax, 60 (2005), pp. 925-931

http://dx.doi.org/10.1136/thx.2005.040527 | Medline

[8.]

A. Bhowmik, T.A. Seemungal, R.J. Sapsford, J.A. Wedzicha.

Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations.

Thorax, 55 (2000), pp. 114-120

Medline

[9.]

K. Fujimoto, M. Yasuo, K. Urushibata, M. Hanaoka, T. Koizumi, K. Kubo.

Airway inflammation during stable and acutely exacerbated chronic obstructive pulmonary disease.

Eur Respir J, 25 (2005), pp. 640-646

http://dx.doi.org/10.1183/09031936.05.00047504 | Medline

[10.]

A. Di Stefano, G. Caramori, T. Oates, A. Capelli, M. Lusuardi, I. Gnemmi, et al.

Increased expression of nuclear factor-kappaB in bronchial biopsies from smokers and patients with COPD.

Eur Respir J, 20 (2002), pp. 556-563

Medline

[11.]

A. Bowie, L.A. O’Neill.

Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries.

Biochem Pharmacol, 59 (2000), pp. 13-23

Medline

[12.]

P.J. Barnes.

Chronic obstructive pulmonary disease.

N Engl J Med, 343 (2000), pp. 269-280

http://dx.doi.org/10.1056/NEJM200007273430407 | Medline

[13.]

M. Grunstein.

Histone acetylation in chromatin structure and transcription.

Nature, 389 (1997), pp. 349-352

http://dx.doi.org/10.1038/38664 | Medline

[14.]

K. Ito, P.J. Barnes, I.M. Adcock.

Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12.

Mol Cell Biol, 20 (2000), pp. 6891-6903

Medline

[15.]

K. Ito, E. Jazwari, B. Cosio, P.J. Barnes, I.M. Adcock.

p65-activated histone acetyltransferase activity is repressed by glucocorticoids: Mifepristone fails to recruit HDAC2 to the p65/HAT complex.

J Biol Chem, 276 (2001), pp. 30208-30215

http://dx.doi.org/10.1074/jbc.M103604200 | Medline

[16.]

B.G. Cosio, A. Torrego, I.M. Adcock.

Molecular mechanisms of glucocorticoids.

Arch Bronconeumol, 41 (2005), pp. 34-41

Medline

[17.]

K. Ito, S. Lim, G. Caramori, K.F. Chung, P.J. Barnes, I.M. Adcock.

Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages.

FASEB J, 15 (2001), pp. 1110-1112

Medline

[18.]

B.G. Cosio, E. Jazrawi, P.J. Barnes, I.M. Adcock.

Oxidative stress augments cytokine production in different cell lines.

Am. J Respir. Crit Care Med, 165 (2002), pp. A88

[19.]

B.G. Cosio, E. Jazrawi, K. Ito, P.J. Barnes, I.M. Adcock.

Cigarette smoke decreases steroid responsiveness in monocytes: the role of histone deacetylases.

Am J Respir Crit Care Med, 167 (2003), pp. A804

[20.]

P.J. Barnes, K. Ito, I.M. Adcock.

Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase.

Lancet, 363 (2004), pp. 731-733

http://dx.doi.org/10.1016/S0140-6736(04)15650-X | Medline

[21.]

M. Carrera, E. Sala, B.G. Cosio, A.G. Agusti.

Hospital treatment of chronic obstructive pulmonary disease exacerbations: an evidence-based review.

Arch Bronconeumol, 41 (2005), pp. 220-229

Medline

[22.]

Standardization of Spirometry, 1994 Update.

American Thoracic Society.

Am J Respir Crit Care Med, 152 (1995), pp. 1107-1136

http://dx.doi.org/10.1164/ajrccm.152.3.7663792 | Medline

[23.]

A.G. Agusti, J.M. Villaverde, B. Togores, M. Bosch.

Serial measurements of exhaled nitric oxide during exacerbations of chronic obstructive pulmonary disease.

Eur Respir J, 14 (1999), pp. 523-528

Medline

[24.]

B.G. Cosio, A. Iglesias, A. Ríos, A. Noguera, E. Sala, K. Ito, et al.

Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD.

Thorax, 64 (2009), pp. 424-429

http://dx.doi.org/10.1136/thx.2008.103432 | Medline

[25.]

A. Barcelo, F. Barbe, P.M. de la, M. Vila, G. Pérez, J. Pierola, et al.

Antioxidant status in patients with sleep apnoea and impact of continuous positive airway pressure treatment.

Eur Respir J, 27 (2006), pp. 756-760

http://dx.doi.org/10.1183/09031936.06.00067605 | Medline

[26.]

G. Caramori, M. Romagnoli, P. Casolari, C. Bellettato, G. Casoni, P. Boschetto, et al.

Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations.

Thorax, 58 (2003), pp. 348-351

Medline

[27.]

E.M. Drost, K.M. Skwarski, J. Sauleda, N. Soler, J. Roca, A. Agusti, et al.

Oxidative stress and airway inflammation in severe exacerbations of COPD.

Thorax, 60 (2005), pp. 293-300

http://dx.doi.org/10.1136/thx.2004.027946 | Medline

[28.]

M. Saetta, G. Turato, P. Maestrelli, C.E. Mapp, L.M. Fabbri.

Cellular and structural bases of chronic obstructive pulmonary disease.

Am J Respir Crit Care Med, 163 (2001), pp. 1304-1309

http://dx.doi.org/10.1164/ajrccm.163.6.2009116 | Medline

[29.]

S. Gompertz, D.L. Bayley, S.L. Hill, R.A. Stockley.

Relationship between airway inflammation and the frequency of exacerbations in patients with smoking related COPD.

Thorax, 56 (2001), pp. 36-41

Medline

[30.]

J.A. Wedzicha, T.A. Seemungal.

COPD exacerbations: defining their cause and prevention.

Lancet, 370 (2007), pp. 786-796

http://dx.doi.org/10.1016/S0140-6736(07)61382-8 | Medline

[31.]

J.R. Hurst, W.R. Perera, T.M. Wilkinson, G.C. Donaldson, J.A. Wedzicha.

Exacerbation of chronic obstructive pulmonary disease: pan-airway and systemic inflammatory indices.

Proc Am Thorac Soc, 3 (2006), pp. 481-482

http://dx.doi.org/10.1513/pats.200603-059MS | Medline

[32.]

K. Ito, M. Ito, W.M. Elliott, B. Cosio, G. Caramori, O.M. Kon, et al.

Decreased histone deacetylase activity in chronic obstructive pulmonary disease.

N Engl J Med, 352 (2005), pp. 1967-1976

http://dx.doi.org/10.1056/NEJMoa041892 | Medline

[33.]

B.G. Cosio, L. Tsaprouni, K. Ito, E. Jazrawi, I.M. Adcock, P.J. Barnes.

Theophylline Restores Histone Deacetylase Activity and Steroid Responses in COPD Macrophages.

J Exp Med, 200 (2004), pp. 689-695

http://dx.doi.org/10.1084/jem.20040416 | Medline

[34.]

W.R. Perera, J.R. Hurst, T.M. Wilkinson, R.J. Sapsford, H. Mullerova, G.C. Donaldson, et al.

Inflammatory changes, recovery and recurrence at COPD exacerbation.

Eur Respir J, 29 (2007), pp. 527-534

http://dx.doi.org/10.1183/09031936.00092506 | Medline

[35.]

V.M. Pinto-Plata, G. Livnat, M. Girish, H. Cabral, P. Masdin, P. Linacre, et al.

Systemic cytokines, clinical and physiological changes in patients hospitalized for exacerbation of COPD.

Chest, 131 (2007), pp. 37-43

http://dx.doi.org/10.1378/chest.06-0668 | Medline

Indexed in:

Follow us:

Subscribe:

Indexed in:

Follow us:

Subscribe:

Subscribe to our newsletter