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

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

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