Exhaled Interleukine-6 and 8-isoprostane in chronic obstructive pulmonary disease: effect of carbocysteine lysine salt monohydrate (SCMC-Lys)

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Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by an airways inflammation and by an enhanced generation of reactive oxygen species. The aim of our study was to assess the inflammation and the oxidative stress in airways of COPD patients with acute exacerbation of disease and in stability. Furthermore, we investigated the anti-inflammatory and antioxidant effects of 6 months treatment with carbocysteine lysine salt monohydrate (SCMC-Lys) in COPD. We studied 30 mild acute COPD, 10 mild stable COPD and 15 healthy subjects. 8-isoprostane and Interleukine-6 were measured in their breath condensate through immunoassay. Significantly higher concentrations of exhaled 8-isoprostane and Interleukine-6 were found in acute COPD patients compared to stable COPD and healthy controls (21.8±5.1 vs. 13.2±2.0 vs. 4.7±1.8 pg/ml and 7.4±0.9 vs. 5.8±0.2 vs. 2.7±0.6 pg/ml, p<0.0001). COPD patients treated with SCMC-Lys showed a marked reduction of exhaled 8-isoprostane and Interleukine-6 (8.9±1.5 and 4.6±0.8 pg/ml, p<0.0001). These findings suggest that there is an increase of 8-isoprostane and Interleukine-6 concentrations in the breath condensate of COPD patients compared to healthy controls especially during acute exacerbations of the disease. Moreover, we showed an anti-inflammatory and antioxidant effect of short-term administration of SCMC-Lys in COPD, suggesting the importance of a further placebo-controlled study that should evaluate the effects of this drug.

Introduction

Chronic obstructive pulmonary disease (COPD) is predicted to become the third most common cause of death and the fifth most common cause of disability in the word by 2020 (Lopez and Murray, 1998).

The airways inflammation and the increased production of reactive oxygen species in the lung play a key role in the pathogenesis of this widespread respiratory disease (Barnes, 2003, Paredi et al., 2002, MacNee, 2001). Although bronchoepitelial cells contain high levels of antioxidant to compete with such oxidants, in COPD, they are inadequate. Therefore, it is realized an oxidant-mediated epithelial injury that finish to damage the epithelial surface of airways by peroxidizing lipids, disrupting proteins and deoxyribonucleic acid (DNA; Brandolini et al., 2003, Kasielski and Nowak, 2001, Pinamonti et al., 1996).

Recent studies have shown an increase in inflammatory and oxidative stress markers such as Interleukin-6, Leukotriene B4 (LTB4), 8-isoprostane, hydrogen peroxide (H2O2) and ethane in breath condensate of COPD subjects (Biernacki et al., 2003, Carpagnano et al., 2003a, Carpagnano et al., 2003b, Dekhuijzen et al., 1996, Montuschi et al., 2000, Paredi et al., 2000). This new method to collect sample from airways, the breath condensate, has recently arouses interest in research and clinic for its simplicity, practicability, noninvasiveness and especially for the great acceptance by patients (Kharitonov and Barnes, 2001a, Kharitonov and Barnes, 2001b).

The inflammation and the oxidative stress further raise during periods of acute exacerbations of COPD that are known to represent the most common cause of hospitalization and of health care costs (Biernacki et al., 2003, Fletcher and Peto, 1977, Kanner et al., 2001). Also, the mucus hypersecretion, hallmark of COPD, seems to get worse during the exacerbations (Schreiber et al., 2002).

Notwithstanding the key role of mucous in aggravate airflow obstruction, the value of mucolytic therapy is unrecognized at a point that the European Respiratory Society and the American Thoracic Society COPD guidelines discouraged the use of mucolytic in treatment of patients with stable and/or acute COPD (American Thoracic Society Standards, 1995 guidelines; British Thoracic Society guidelines, 1997, Schreiber et al., 2002). Of late, the point of view of researchers and clinicians at this regard seems starting to change inasmuch as some thiol-containing mucolytic drugs (sodium 2-mercaptoethane sulphonate and N-acetylcysteine) showed associated with their therapeutical effect, anti-inflammatory and antioxidant capabilities (Gressier et al., 1994, Kasielski and Nowak, 2001).

Only recently also, the thioether group contained in carbocysteine lysine salt monohydrate (SCMC-Lys) has been found to have some capacities to reduce airways inflammation (Barnes, 2003, Pfeifer et al., 1997).

The purpose of the present work was to assess the inflammation and the oxidative stress in airways of COPD patients during an acute exacerbation of diseases and in stability. Furthermore, we studied the anti-inflammatory and antioxidant effects of SCMC-Lys in COPD patients measuring an inflammatory (Interleukine-6) and an oxidative stress marker (8-isoprostane) in their breath condensate before and after 6 months of SCMC-Lys administration.

Section snippets

Study population

We studied 40 ex-smoker patients with mild COPD (cigarette consumption 32±5 pack/years) and 15 nonsmoker healthy subjects with no history of lung disease (Table 1). All subjects were recruited from the Respiratory Disease Institute, University of Bari, and written informed consent was obtained from all subjects. The study was approved by the Institutional Ethics Committee. The diagnosis of COPD was based on GOLD Guidelines (Pauwels et al., 2001). All COPD patients were ex-smokers, had stopped

Results

All patients tolerated the SCMC-Lys without any complaints of side effects. The lung function parameters (FEV1, FVC), the blood gases and the plasmatic neutrophils and PCR showed an improvement in COPD patients hospitalized for acute exacerbation after 2 weeks of antibiotics but did not indicate any significant differences after treatment with SCMC-Lys (Table 2).

No amylase activity was detected in any exhaled breath condensate sample.

Discussion

This study showed significantly higher concentrations of 8-isoprostane and Interleukine-6 in the breath condensate of COPD subjects than in healthy controls, especially during an acute exacerbation of the disease. Both these markers presented a marked reduction after 6 months of daily administration of carbocysteine lysine salt monohydrate (SCMC-Lys) in COPD subjects. However, an improvement of lung function after mucolytic drug was not watched. Finally, a positive correlation was observed

Acknowledgement

Supported by Dompe' S-p.A., Research Center, via Campo di Pile, 67100, L'Aquila, Italy.

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