Efrossini Dima

Interleukin-18 in induced sputum: Association with lung function in chronic obstructive pulmonary disease

BACKGROUND It has been shown that interleukin (IL)-18 levels in induced sputum are reduced in asthmatic and healthy smokers. However, in chronic obstructive pulmonary disease (COPD) patients, recent data show an overproduction in the lungs and increased serum levels of IL-18, suggesting that IL-18 may be involved in the pathogenesis of COPD. METHOD In order to assess the relation of IL-18 with pulmonary function and airway inflammation in COPD, IL-18, tumour necrosis factor-alpha, and IL-8 levels were measured by ELISA in sputum supernatants obtained from patients with bronchitis type COPD (n=28), and healthy subjects (18 smokers and 17 non-smokers). Cellular localization of IL-18 was assessed by immunocytochemistry. RESULTS The levels of IL-18 were significantly higher in sputum supernatants of COPD patients compared to healthy smokers and non-smokers (p<0.05). IL-18 production was localized to sputum macrophages. IL-18 levels were inversely correlated with FEV(1) (% predicted) (r=-0.572, p=0.002) and FEV(1)/FVC ratio in COPD smokers (r=-0.608, p=0.001). No correlations were found between IL-18 levels and inflammatory markers studied in induced sputum obtained from COPD patients, healthy smokers and non-smokers. CONCLUSION In patients with COPD, increased levels of IL-18 in induced sputum were associated with airflow limitation, suggesting that IL-18 may be implicated in the pathogenesis of COPD.

Effectiveness of pharmacotherapy and behavioral interventions for smoking cessation in actual clinical practice

Objectives: This study evaluated the effectiveness of behavioral interventions (brief counseling, nonspecific psychological support in groups — NSGS and cognitive behavioral group therapy — CBGT) in combination with bupropion SR for smoking cessation in the field, through a smoking cessation clinic. Methods: Two-hundred-and-five smokers were enrolled in a 19-week course during 2007/ 2008, and were randomly assigned to: bupropion SR combined with brief counseling (group A), bupropion SR combined with NSGS (group B), bupropion SR combined with CBGT (group C), or CBGT as the only approach (group D). Results: Continuous abstinence rates at the end of therapy were 53.2% for group A, 62.9% for group B, 50.0% for group C, and 22.2% (p < 0.05) for group D. Sustained abstinence rates in 12 months were 29.6%, 28.1%, 34.3% and 19.4% (p > 0.05), respectively. Conclusions: Bupropion SR is an effective aid for smoking cessation in clinical practice. NSGT increased the chances for success at the end of therapy when combined with bupropion SR, while CBGT as monotherapy was less effective compared with the approaches including pharmacotherapy. It is suggested that smoking cessation interventions in real-life healthcare settings should be implemented through comprehensive programs using pharmacotherapy where applicable, combined with NSGT, and integrated by specialized healthcare professionals.

Pulmonary function tests, sputum induction, and bronchial provocation tests: diagnostic tools in the challenge of distinguishing asthma and COPD phenotypes in clinical practice

Background: Despite a number of important differences in the pathogenesis, course, and prognosis, asthma and chronic obstructive pulmonary disease (COPD) have many features in common. Furthermore, smoking induces considerable overlap in pathogenesis and clinical features between these conditions. This study aimed to reveal what inflammatory patterns prevail in clinically established diagnosis groups, including overlap phenotypes of asthma and COPD, and to evaluate the correlation with airway reversibility and hyperreactivity in these overlapping conditions. Methods: A total of 110 patients (17 healthy subjects; 16 “healthy” smokers; 46 asthma patients: 24 smokers and 22 non-smokers; and 31 COPD patients: 10 COPD patients with reversibility and 21 without) participated in the study. Induced sputum, reversibility testing, methacholine and adenosine 5’monophosphate (AMP) provocation challenges, and skin prick testing were performed. Airways inflammation was assessed by differential cell counts, and cytokines (interleukin-8 [IL-8] and tumor necrosis factor-alpha [TNF-α]) were measured in induced sputum by enzyme-linked immunosorbent assay (ELISA). Results: COPD patients with reversibility had increased sputum neutrophils, IL-8, and TNF-α levels compared to smoking asthmatics. No difference was found in inflammatory cells and cytokines between COPD subgroups. Sputum neutrophilia was inversely correlated with the change in forced expiratory volume in one second (ΔFEV1) in smoking asthmatic patients (r = −0.563, P = 0.036). No correlation was found between airway hyperresponsiveness (AHR), either with methacholine or AMP, and inflammation in asthmatic patients, regardless of smoking. Reversibility was not correlated with inflammation in COPD patients. However, the response to AMP challenge was correlated with sputum neutrophils (r = 0.844, P = 0.001). Conclusion: Although overlaps exist in the disease characteristics of asthma and COPD, the combination of lung function testing, sputum induction, and AHR reveals information that facilitates the distinction between these diseases, allowing clinicians to better tailor their therapy.

VEGF and IL-18 in induced sputum of lung cancer patients

Cytokines are key players in the biological processes of malignant tumors and special interest has been focused on cytokines exerting tumor and anti-tumor properties, such as vascular endothelial growth factor (VEGF) and Interleukin-18 (IL-18). Aim of this study was to assess IL-18 and VEGF levels in induced sputum of lung cancer patients at diagnosis, and assess their possible association with the histological type of cancer, the stage and the overall patient survival. Seventy six patients with a diagnosis of lung cancer were recruited and were followed up for 48months. Thirteen healthy smokers and 16 healthy non-smokers were used as control groups. VEGF and IL-18 were measured by ELISA in sputum supernatants at the time of diagnosis. Lung cancer patients had significantly higher baseline IL-18 and VEGF levels compared to healthy controls (p<0.001). No difference was found in IL-18 and VEGF levels between the various stages in non-small cell lung cancer (NSCLC) and between limited and extended small cell lung cancer (SCLC). However, the ratio of VEGF/IL-18 was significantly higher in NSCLC compared to SCLC patients (p=0.018). In extended SCLC overall survival was inversely associated with baseline sputum VEGF levels (p=0.034) and estimated mortality risk was 1.14 (95% CI 1.006-1.283) for an increase of 100pg/ml in VEGF levels. Such association was not found regarding baseline IL-18 levels. VEGF levels in induced sputum may have a prognostic role in the survival of SCLC. The ratio VEGF/IL-18 in induced sputum differs between NSCLC and SCLC, indicating differences in angiogenesis mechanisms and/or immunological response in these two major histological types of lung cancer.

IL-18 in induced sputum and airway hyperresponsiveness in mild asthmatics: Effect of smoking

Interleukin 18 (IL-18) is a pro-inflammatory cytokine, which has been shown to be implicated in the induction of airway hyperresponsiveness (AHR) in murine asthma models. The association of IL-18 with AHR in human bronchial asthma is not clear as yet. As cigarette smoking modifies airway inflammation we aimed to assess the relationship of IL-18 with airway hyperresponsiveness (AHR) in non-smoking versus smoking asthmatics. IL-18 was measured in sputum supernatants obtained from asthmatic (24 smokers and 22 non-smokers) and healthy subjects (16 smokers and 17 non-smokers). All subjects were assessed by spirometry, skin-prick tests to common aeroallergens and bronchial provocation to methacholine (Mch). There was no significant difference in IL-18 levels between healthy and asthmatic smokers and between healthy and asthmatic non-smokers. IL-18 levels in sputum were significantly lower in healthy smokers compared to non-smokers (p=0.048); similarly, in asthmatic smokers as compared to non-smokers (p=0.037). An inverse correlation was found between IL-18 levels, FEV(1) (% pred) (r=-0.495, p=0.043), and PD(20)Mc(h) in non-smoking asthmatics (r=-0.621, p=0.024). A positive correlation was found in smoking asthmatics between IL-18 levels in sputum and FEV(1) (% pred) (r=0.627, p=0.002), FVC (% pred) (r=0.460, p=0.031), and PD(20)Mc(h) (r=0.809, p=0.005). Cigarette smoking reduced IL-18 levels in induced sputum in healthy and asthmatic smokers. IL-18 levels were correlated with airway obstruction and AHR in an inverse way in smoking and non-smoking asthmatics. These results suggest the implication of IL-18 in airway hyperresponsiveness characterizing bronchial asthma, which is modified by smoking.

Implication of Interleukin (IL)-18 in the pathogenesis of chronic obstructive pulmonary disease (COPD).

Interleukin (IL)-18 is a pro-inflammatory cytokine that was firstly described as an interferon (IFN)-γ-inducing factor. Similar to IL-1β, IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine. The platform for activating caspase-1 is known as the inflammasome, a multiple protein complex. Macrophages and dendritic cells are the primary sources for the release of active IL-18, whereas the inactive precursor remains in the intracellular compartment of mesenchymal cells. Finally, the IL-18 precursor is released from dying cells and processed extracellularly. IL-18 has crucial host defense and antitumor activities, and gene therapy to increase IL-18 levels in tissues protects experimental animals from infection and tumor growth and metastasis. Moreover, multiple studies in experimental animal models have shown that IL-18 over-expression results to emphysematous lesions in mice. The published data prompt to the hypothesis that IL-18 induces a broad spectrum of COPD-like inflammatory and remodeling responses in the murine lung and also induces a mixed type 1, type 2, and type 17 cytokine responses. The majority of studies identify IL-18 as a potential target for future COPD therapeutics to limit both the destructive and remodeling processes occurring in COPD lungs.

Acute effects of smoke exposure on airway and systemic inflammation in forest firefighters

Introduction The aim of this study was to assess respiratory health and airway and systemic inflammation in professional forest firefighters post firefighting. Methods A total of 60 firefighters who participated in forest firefighting operations in Greece during 2008 were included in the study. A questionnaire consisting of symptoms and exposure, pulmonary function, atopy, bronchial hyperresponsiveness, and markers of inflammation in induced sputum, serum, and bronchoalveolar lavage (BAL) fluid was assessed. Results A measurable eosinophilic and neutrophilic inflammation was shown to be induced in the bronchial airways after acute exposure during forest firefighting. This was associated with increased respiratory symptoms from the upper and lower respiratory tract and pulmonary function impairment. Additionally, a measurable systemic inflammatory response was demonstrated. This study showed that acute exposure during forest firefighting significantly augments the intensity of airway and systemic inflammation in relation to the baseline inflammatory background due to chronic exposure. Conclusion The repeated acute exposures during firefighting augment the burden of chronic airway and systemic inflammation and may eventually lead to allergic sensitization of the airways and increased incidence of rhinitis and asthma after prolonged exposure.