Christina Gratziou

Bronchial biopsy evidence for leukocyte infiltration and upregulation of leukocyte-endothelial cell adhesion molecules 6 hours after local allergen challenge of sensitized asthmatic airways.

We have examined the mucosal changes occurring in bronchial biopsies from six atopic asthmatics 5-6 h after local endobronchial allergen challenge and compared them with biopsies from saline-challenged segments from the same subjects at the same time point. All the subjects developed localized bronchoconstriction in the allergen-challenged segment and had a decrease in forced expiratory volume in 1 s (FEV1) (P < 0.01) and a decrease in their methacholine provocative concentration of agonist required to reduce FEV1 from baseline by 20% (P < 0.05) 24 h postchallenge. At 6 h we observed an increase in neutrophils (P = 0.03), eosinophils (P = 0.025), mast cells (P = 0.03), and CD3+ lymphocytes (P = 0.025), but not in CD4+ or CD8+ lymphocyte counts. We also detected an increase in endothelial intercellular adhesion molecule type 1 (P < 0.05) and E-selectin (P < 0.005), but not vascular cell adhesion molecule type 1 expression with a correlative increase in submucosal and epithelial LFA+ leucocytes (P < 0.01). Thus, in sensitized asthmatics, local endobronchial allergen instillation leads to an increased inflammatory cell infiltrate of the airway mucosa that involves upregulation of specific adhesion molecules expressed on the microvasculature.

Osteopontin Deficiency Protects against Airway Remodeling and Hyperresponsiveness in Chronic Asthma

RATIONALE Osteopontin (OPN) is a cytokine that is upregulated in epithelial cells and macrophages in the lungs of mice during chronic allergen challenge and airway remodeling and also in lungs of patients with asthma. However, it remains unclear whether OPN has an in vivo effect on lung remodeling in allergic asthma. Based on its ability to induce smooth muscle and fibroblast proliferation and migration we hypothesize that OPN regulates lung remodeling and also affects subsequent airway hyperresponsiveness (AHR). OBJECTIVES Study the role of OPN in airway remodeling using OPN-knockout (KO) mice and a reversal approach administering recombinant mouse OPN (rOPN) in KO mice before challenge. METHODS A chronic allergen-challenge model of airway remodeling with OPN KO mice, KO mice treated with rOPN, and human bronchial smooth muscle were used. MEASUREMENTS AND MAIN RESULTS OPN deficiency protected mice against ova-induced AHR, which was associated with lower collagen and mucus production, gob-5 mRNA expression, submucosal cell area infiltration, and proliferation. Administration of rOPN to KO mice, just at the final five allergen challenges, exacerbated AHR and all the remodeling characteristics measured. In addition, rOPN increased the expression of IL-13 and pro-matrix metalloproteinase-9 in the lungs. Moreover, we demonstrated that rOPN induces proliferation of human BSM through binding to its alpha(v)beta3 integrin receptor and activation of PI3K/Akt downstream signaling pathway. CONCLUSIONS We conclude that OPN deficiency protects against remodeling and AHR. Thus our data reveal OPN as a novel therapeutic target for airway remodeling and associated AHR in chronic asthma.

Statement on smoking cessation in COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quit

Chronic obstructive pulmonary disease (COPD), lung cancer, asthma and pulmonary tuberculosis are common pulmonary diseases that are caused or worsened by tobacco smoking. Growing observational evidence suggests that symptoms and prognosis of these conditions improve upon smoking cessation. Despite increasing numbers of (small) randomised controlled trials suggesting intensive smoking cessation treatments work in people with pulmonary diseases many patients are not given specific advice on the benefits or referred for intensive cessation treatments and, therefore, continue smoking. This is a qualitative review regarding smoking cessation in patients with COPD and other pulmonary disorders, written by a group of European Respiratory Society experts. We describe the epidemiological links between smoking and pulmonary disorders, the evidence for benefits of stopping smoking, how best to assess tobacco dependence and what interventions currently work best to help pulmonary patients quit. Finally, we describe characteristics and management of any “hardcore” smoker who finds it difficult to quit with standard approaches. Smoking cessation is crucial for respiratory patients: every patient must be given advice and help to quit http://ow.ly/ITgsW

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.

Vascular endothelial growth factor: an angiogenic factor reflecting airway inflammation in healthy smokers and in patients with bronchitis type of chronic obstructive pulmonary disease?

BackgroundPatients with bronchitis type of chronic obstructive pulmonary disease (COPD) have raised vascular endothelial growth factor (VEGF) levels in induced sputum. This has been associated with the pathogenesis of COPD through apoptotic and oxidative stress mechanisms. Since, chronic airway inflammation is an important pathological feature of COPD mainly initiated by cigarette smoking, aim of this study was to assess smoking as a potential cause of raised airway VEGF levels in bronchitis type COPD and to test the association between VEGF levels in induced sputum and airway inflammation in these patients.Methods14 current smokers with bronchitis type COPD, 17 asymptomatic current smokers with normal spirometry and 16 non-smokers were included in the study. VEGF, IL-8, and TNF-α levels in induced sputum were measured and the correlations between these markers, as well as between VEGF levels and pulmonary function were assessed.ResultsThe median concentrations of VEGF, IL-8, and TNF-α were significantly higher in induced sputum of COPD patients (1,070 pg/ml, 5.6 ng/ml and 50 pg/ml, respectively) compared to nonsmokers (260 pg/ml, 0.73 ng/ml, and 15.4 pg/ml, respectively, p < 0.05) and asymptomatic smokers (421 pg/ml, 1.27 ng/ml, p < 0.05, and 18.6 pg/ml, p > 0.05, respectively). Significant correlations were found between VEGF levels and pack years (r = 0.56, p = 0.046), IL-8 (r = 0.64, p = 0.026) and TNF-α (r = 0.62, p = 0.031) levels both in asymptomatic and COPD smokers (r = 0.66, p = 0.027, r = 0.67, p = 0.023, and r = 0.82, p = 0.002, respectively). No correlation was found between VEGF levels in sputum and pulmonary function parameters.ConclusionVEGF levels are raised in the airways of both asymptomatic and COPD smokers. The close correlation observed between VEGF levels in the airways and markers of airway inflammation in healthy smokers and in smokers with bronchitis type of COPD is suggestive of VEGF as a marker reflecting the inflammatory process that occurs in smoking subjects without alveolar destruction.

Tuberculosis care among refugees arriving in Europe: a ERS/WHO Europe Region survey of current practices

No evidence exists on tuberculosis (TB) and latent TB infection (LTBI) management policies among refugees in European countries. A questionnaire investigating screening and management practices among refugees was sent to 38 national TB programme representatives of low and intermediate TB incidence European countries/territories of the WHO European Region. Out of 36 responding countries, 31 (86.1%) reported screening for active TB, 19 for LTBI, and eight (22.2%) reporting outcomes of LTBI treatment. Screening for TB is based on algorithms including different combinations of symptom-based questionnaires, bacteriology and chest radiography and LTBI screening on different combinations of tuberculin skin test and interferon-γ release assays. In 22 (61.1%) countries, TB and LTBI screening are performed in refugee centres. In 22 (61.1%) countries, TB services are organised in collaboration with the private sector. 27 (75%) countries answered that screening for TB is performed as per national and international guidelines, while 19 (52.7%) gave the same answer with regards to LTBI screening. Infection control measures are inadequate in several of the countries surveyed. There is need for improved coordination of TB screening in Europe to implement the End TB Strategy and achieve TB elimination. TB/LTBI detection and management in refugees in low/intermediate incidence European countries: policies and practice http://ow.ly/aNx8301yx3j

Respiratory, cardiovascular and other physiological consequences of smoking cessation

ABSTRACT Background: Smoking cessation is associated with substantial reductions in tobacco-related morbidity and mortality. Based on the current literature, the beneficial effects of quitting are particularly evident on pulmonary and cardiovascular function, but the negative physiological effects of cessation are less well documented. Scope: The objective of this article was to review systematically data on the physiological effects of smoking cessation. Articles based upon clinical trials, randomised controlled trials and meta-analyses were selected from titles and abstracts obtained via a MEDLINE search (May 2003–May 2008). Additional studies were identified from the bibliographies of reviewed literature. Findings: Smoking cessation is associated with improved lung function and a reduction in the presence and severity of respiratory symptoms. These changes, apparent within months of quitting, are sustained with long-term abstinence. The underlying pathophysiologies of smoking-induced airway inflammation and endothelial dysfunction are partially reversed following cessation in healthy ex-smokers, but not in those with chronic obstructive pulmonary disease. Smoking cessation is also associated with substantially improved cardiovascular function and reduced risk of primary and secondary cardiovascular morbidity and mortality. Although the overall long-term health benefits are unquestionable, smoking cessation is also associated with other possible undesirable short-term physiological effects such as weight gain, hypertension, constipation and mouth ulcers; and altered activity of the enzyme cytochrome P450 1A2 (CYP1A2), which metabolises many commonly used drugs. Conclusion: The negative physiological effects of smoking cessation may adversely affect a smokers attempt to quit, and physicians should provide their smoking patients with motivation and regular encouragement and support when attempting to quit, whilst educating them on the health benefits of abstinence. Additionally, since cigarette smoke is a potent inducer of CYP1A2, patients attempting to quit smoking should have their dosages of drugs metabolised by this enzyme closely monitored.

Breath markers of oxidative stress and airway inflammation in Seasonal Allergic Rhinitis.

Oxidative stress (OS) is well documented in asthma, but so far little data has been reported in non-asthmatic patients with Seasonal Allergic Rhinitis (SAR). The aim of this study is to investigate the degree of OS and airway inflammation in patients with SAR, with and without concomitant Asthma (SAR +A), using breath markers in exhaled air and in Exhaled Breath Condensate (EBC). In addition, the effects of natural allergen exposure and intranasal steroid treatment on these markers were evaluated. Exhaled NO (eNO) and CO, combined with measurements of 8-Isoprostane (Iso-8), Leukotriene B4 (LTB4) and nitrate/nitrite in EBC, were performed in 23 patients, 11 with SAR and 12 with SAR+A, and 16 healthy subjects. Iso-8 and LTB4 were significantly increased in both groups of patients (median values 43.6 pg/ml and 138.4 pg/ml in SAR group; 38.9 pg/ml, and 164.6 pg/ml in SAR+A group respectively; p>0.05) compared to healthy subjects (18.6 pg/ml and 7.8 pg/ml; p<0.05). Nitrate/nitrite and eNO levels were elevated in both groups compared to controls, but were significantly higher in the SAR+A compared to SAR group (nitrate/nitrite 9 μM and 3.9 μM; p=0.025; and eNO 18.5 ppb and 12.5 ppb, respectively; p>0.05). Nasal steroids caused significant reduction in LTB4 and 8-isoprostane levels in both groups of patients (p<0.05), while nitrate levels and eNO concentration were little affected by nasal treatment. OS markers were decreased at normal levels out of pollen season. Natural allergen exposure induces OS and airway inflammation, as assessed by measurements of markers in EBC and exhaled air, in patients with SAR who have no clinical signs of lower airway involvement. Besides, intranasal steroid treatment may have a regulatory role in the OS.

Glucocorticoid and estrogen receptors are reduced in mitochondria of lung epithelial cells in asthma.

Mitochondrial glucocorticoid (mtGR) and estrogen (mtER) receptors participate in the coordination of the cell’s energy requirement and in the mitochondrial oxidative phosphorylation enzyme (OXPHOS) biosynthesis, affecting reactive oxygen species (ROS) generation and induction of apoptosis. Although activation of mtGR and mtER is known to trigger anti-inflammatory signals, little information exists on the presence of these receptors in lung tissue and their role in respiratory physiology and disease. Using a mouse model of allergic airway inflammation disease and applying confocal microscopy, subcellular fractionation, and Western blot analysis we showed mitochondrial localization of GRα and ERβ in lung tissue. Allergic airway inflammation caused reduction in mtGRα, mtERβ, and OXPHOS enzyme biosynthesis in lung cells mitochondria and particularly in bronchial epithelial cells mitochondria, which was accompanied by decrease in lung mitochondrial mass and induction of apoptosis. Confirmation and validation of the reduction of the mitochondrial receptors in lung epithelial cells in human asthma was achieved by analyzing autopsies from fatal asthma cases. The presence of the mitochondrial GRα and ERβ in lung tissue cells and especially their reduction in bronchial epithelial cells during allergic airway inflammation suggests a crucial role of these receptors in the regulation of mitochondrial function in asthma, implicating their involvement in the pathophysiology of the disease.

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.