Do differences in sport participation contribute to socioeconomic health inequalities? Evidence from the Lifelines cohort study on all-cause mortality, diabetes and obesity.

Little is known about the role of sport participation in socioeconomic health inequalities. We studied the association between different aspects of sport participation with all-cause mortality, type 2 diabetes mellitus (T2DM) and obesity, including inequalities between socioeconomic subpopulations. Using the Dutch Lifelines cohort study (n = 84,230), we assessed the associations of sport participation, as well as the amount, intensity, type and number of sports, with all-cause mortality, T2DM and obesity in individuals. We studied the effect of sport participation on health outcomes within and between educational categories. Outcomes were compared with moderate to vigorous physical activity (MVPA). Sport participation was significantly associated with lower mortality (HR = 0.81), T2DM (HR = 0.70), and obesity (HR = 0.77). No significant additional effects of the amount or intensity of sport participation were found, while participating in teams sport was associated with significantly lower mortality (HR = 0.53) compared with other types of sport. These effects were similar among educational categories. Sport participation explained between 11% (T2DM and obesity) and 22% (mortality) of health inequalities between educational categories. This was more than twice the effect size of MVPA. The sensitivity analysis with net income as the socioeconomic indicator showed similar results. Our results suggest that to reduce socioeconomic differences in health, public health policies should focus on increasing sport participation in groups with a low socioeconomic status, rather than increasing the amount or intensity of sport participation, or MVPA in general.

The impact of the Covid-19 crisis on socioeconomic differences in physical activity behavior: Evidence from the Lifelines COVID-19 cohort study.

Covid-19 and measures to contain spreading the disease have led to changed physical activity behavior. This study aims to investigate the relationship between socioeconomic status (SES) and changes in the amount of moderate to vigorous physical activity (MVPA) during the Covid-19 crisis. Using the Dutch Lifelines Covid-19 cohort study (n = 17,749), the amount of MVPA was measured at 15 time-points between March and December 2020, and compared with the amount before the Covid19 pandemic. For SES, the population was stratified in three education and income levels. Logistic regression models were used to estimate the odds ratio (OR) and confidence interval (CI) of altered MVPA for low and high SES groups, with the middle SES category as the reference group. A clear socioeconomic gradient in changes in MVPA behavior was observed. Low educated individuals had significantly higher odds (OR = 1.14; CI: 1.03-1.27) of decreasing MVPA, while the high educated had significantly lower odds of decreased MVPA (OR = 0.84, CI: 0.79-0.90). Both low education (OR = 0.87; CI: 0.77-0.98) and low income (OR = 0.85; CI 0.78-0.92) had significantly lower odds to increase MVPA, while high education (OR = 1.21, CI: 1.12-1.30) and high income (OR = 1.17; CI: 1.07-1.28) had significantly higher odds to increase MVPA. Most findings were consistent over the full research period. Socioeconomic inequalities in MVPA have increased during the Covid-19 pandemic, even when Covid-19 containment measures were relaxed. Our findings suggest that future public health policies need to increase efforts to improve physical activity behavior with an even larger focus on low SES groups.

How are lifestyle factors associated with socioeconomic differences in health care costs? Evidence from full population data in the Netherlands.

INTRODUCTION: There is a strong socioeconomic gradient in health care costs. However, little is known about the role of lifestyle factors in the association between health care costs and socioeconomic status (SES). This study investigates variation in the association between lifestyle indicators and health care costs between and within neighborhoods with similar SES. METHOD: Using 2016 whole-population data for all 790 neighborhoods of the Netherlands, we estimated the association between neighborhood average health care cost performance (i.e., health care costs adjusted for population age and gender) and neighborhood socioeconomic status (NSES) and four lifestyle indicators - smoking, alcohol consumption, exercise and sport club membership. Additionally, using regression analysis, we explored the multivariate relationship between average health care cost performance, NSES and lifestyle indicators. RESULTS: Neighborhoods with proportionally fewer smokers and more sport club members had significantly lower average health care costs. Remarkably, neighborhoods with more people who complied with the recommended maximum alcohol consumption had significantly higher health care costs. These findings were consistent within and between neighborhoods with different SES levels. Neighborhoods with more compliance with exercise guidelines had lower health care costs. However, this relationship was inconsistent across different NSES levels, with the largest cost reductions found in the most deprived neighborhoods. CONCLUSION: Our findings suggest that prevention policies aimed at reducing the number of smokers and increasing sport club membership may reduce health care costs across all NSES groups, while increasing compliance with physical exercise norms may be effective mainly in low SES neighborhoods.

Increased Physical Activity in Preparation for a Women-Only Mass Participation Sport Event: A Framework for Estimating the Health Impact.

Mass participation sporting events (MPSEs) are increasing in popularity. However, little research exists into the potential value of these events for improving public health by enhancing physical activity (PA). The aim of this study is to estimate the health impact of increased physical activity as a result of preparing for an MPSE. Participants of a mass participation women-only running event were asked if they performed additional PA in preparation of the event, including the length (weeks) and intensity (min per week). Additionally, self-reported change in health status was evaluated. Based on these results, we have developed a framework for estimating the cumulatively gained quality adjusted life years (QALYs) and monetary value thereof. Of the respondents (N = 468; mean age 42.3 ± 11.9 years), 32% performed additional vigorous PA in preparation of the event, with an average of 63 min per week over 8.8 weeks. Performing additional vigorous PA significantly improved the odds of self-rated health. The estimated total health impact of participants preparing for the Marikenloop was 6.6 QALYs gained with a corresponding monetary value between EUR 133,000 and EUR 532,000. We believe our health impact framework helps to understand that MPSEs can be a notable part of the public health domain.

Neighborhood Socioeconomic Status and Health Care Costs: A Population-Wide Study in the Netherlands.

Objectives. To identify disparities in several types of insured health care costs in the Netherlands across neighborhoods with different socioeconomic statuses and to assess the room for improvement. Methods. We used 2015 Dutch whole-population registry data to estimate the age- and gender-specific cost structure by neighborhood for total, specialist, pharmaceutical, and mental health care. Classifying neighborhoods by the quintile of their neighborhood socioeconomic status (NSES), we determined differences in observed and expected health care costs for several scenarios of NSES improvement. Results. From low to high NSES, we found a clear downward gradient in health care costs. Total health care costs would drop by 7.3% if each neighborhood's cost structure was equal to that of the most affluent neighborhoods. The potential for cost reduction appeared highest for females, for age groups between 40 and 60 years, and for pharmaceutical care. Conclusions. Low NSES is associated with relatively high health care costs, and represents considerable potential for cost savings in health care. Public Health Implications. Our research suggests that policies aimed at improving the socioeconomic determinants of health locally may be pivotal in containing health care costs.

Physical Activity Characteristics across GOLD Quadrants Depend on the Questionnaire Used.

BACKGROUND: The GOLD multidimensional classification of COPD severity combines the exacerbation risk with the symptom experience, for which 3 different questionnaires are permitted. This study investigated differences in physical activity (PA) in the different GOLD quadrants and patient's distribution in relation to the questionnaire used. METHODS: 136 COPD patients (58±21% FEV1 predicted, 34F/102M) completed COPD assessment test (CAT), clinical COPD questionnaire (CCQ) and modified Medical Research Council (mMRC) questionnaire. Exacerbation history, spirometry and 6MWD were collected. PA was objectively measured for 2 periods of 1 week, 6 months apart, in 5 European centres; to minimise seasonal and clinical variation the average of these two periods was used for analysis. RESULTS: GOLD quadrants C+D had reduced PA compared with A+B (3824 [2976] vs. 5508 [4671] steps.d-1, p<0.0001). The choice of questionnaire yielded different patient distributions (agreement mMRC-CAT κ = 0.57; CCQ-mMRC κ = 0.71; CCQ-CAT κ = 0.72) with different clinical characteristics. PA was notably lower in patients with an mMRC score ≥2 (3430 [2537] vs. 5443 [3776] steps.d-1, p <0.001) in both the low and high risk quadrants. CONCLUSIONS: Using different questionnaires changes the patient distribution and results in different clinical characteristics. Therefore, standardization of the questionnaire used for classification is critical to allow comparison of different studies using this as an entry criterion. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01388218.

The PROactive instruments to measure physical activity in patients with chronic obstructive pulmonary disease.

No current patient-centred instrument captures all dimensions of physical activity in chronic obstructive pulmonary disease (COPD). Our objective was item reduction and initial validation of two instruments to measure physical activity in COPD.Physical activity was assessed in a 6-week, randomised, two-way cross-over, multicentre study using PROactive draft questionnaires (daily and clinical visit versions) and two activity monitors. Item reduction followed an iterative process including classical and Rasch model analyses, and input from patients and clinical experts.236 COPD patients from five European centres were included. Results indicated the concept of physical activity in COPD had two domains, labelled "amount" and "difficulty". After item reduction, the daily PROactive instrument comprised nine items and the clinical visit contained 14. Both demonstrated good model fit (person separation index >0.7). Confirmatory factor analysis supported the bidimensional structure. Both instruments had good internal consistency (Cronbach's α>0.8), test-retest reliability (intraclass correlation coefficient ≥0.9) and exhibited moderate-to-high correlations (r>0.6) with related constructs and very low correlations (r<0.3) with unrelated constructs, providing evidence for construct validity.Daily and clinical visit "PROactive physical activity in COPD" instruments are hybrid tools combining a short patient-reported outcome questionnaire and two activity monitor variables which provide simple, valid and reliable measures of physical activity in COPD patients.

The PROactive innovative conceptual framework on physical activity.

Although physical activity is considered an important therapeutic target in chronic obstructive pulmonary disease (COPD), what "physical activity" means to COPD patients and how their perspective is best measured is poorly understood. We designed a conceptual framework, guiding the development and content validation of two patient reported outcome (PRO) instruments on physical activity (PROactive PRO instruments). 116 patients from four European countries with diverse demographics and COPD phenotypes participated in three consecutive qualitative studies (63% male, age mean±sd 66±9 years, 35% Global Initiative for Chronic Obstructive Lung Disease stage III-IV). 23 interviews and eight focus groups (n = 54) identified the main themes and candidate items of the framework. 39 cognitive debriefings allowed the clarity of the items and instructions to be optimised. Three themes emerged, i.e. impact of COPD on amount of physical activity, symptoms experienced during physical activity, and adaptations made to facilitate physical activity. The themes were similar irrespective of country, demographic or disease characteristics. Iterative rounds of appraisal and refinement of candidate items resulted in 30 items with a daily recall period and 34 items with a 7-day recall period. For the first time, our approach provides comprehensive insight on physical activity from the COPD patients' perspective. The PROactive PRO instruments' content validity represents the pivotal basis for empirically based item reduction and validation.

Nitric oxide donors augment interleukin-1ß-induced vascular endothelial growth factor in airway smooth muscle cells.

Angiogenesis and microvascular leakage are features of chronic inflammatory diseases of which molecular mechanisms are poorly understood. We investigated the effects of interleukin-1ß (IL-1ß) on the expression and secretion of vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) in porcine airway smooth muscle cells (PASMC) in relation to a nitric oxide (NO) pathway. Serum-deprived (48 h) PASMC were stimulated with IL-1ß alone or with NO donor, L-arginine and/or NO synthase inhibitor L-NAME for 4 and 24 h. IL-1ß did not affect PlGF release, but augmented VEGF release (2.4-fold) after 24 h. VEGF release was inhibited by L-NAME (531.8 ± 52 pg/ml), but restored and further elevated by L-arginine (1,529 ± 287 pg/ml). IL-1ß up-regulated VEGF mRNA (1.8-fold) and this response was attenuated by L-NAME (1.1-fold) and augmented by L-arginine (3.8-fold) at 4 h. Restoration of a NO pathway by L-arginine in L-NAME-treated cells resulted in elevated VEGF mRNA levels (2.2-fold). [(3)H]Thymidine incorporation assay revealed enhanced porcine pulmonary artery endothelial cell proliferation in response to IL-1ß, VEGF and PlGF, and this mitogenic effect was not influenced via the NO pathway. Our results suggest that a NO pathway modulates VEGF synthesis during inflammation contributing to bronchial angiogenesis and vascular leakage.

Angiogenesis and vascular remodeling in chronic airway diseases.

Asthma and chronic obstructive pulmonary disease remain a global health problem, with increasing morbidity and mortality. Despite differences in the causal agents, both diseases exhibit various degrees of inflammatory changes, structural alterations of the airways leading to airflow limitation. The existence of transient disease phenotypes which overlap both diseases and which progressively decline the lung function has complicated the search for an effective therapy. Important characteristics of chronic airway diseases include airway and vascular remodeling, of which the molecular mechanisms are complex and poorly understood. Recently, we and others have shown that airway smooth muscle (ASM) cells are not only structural and contractile components of airways, rather they bear capabilities of producing large number of pro-inflammatory and mitogenic factors. Increase in size and number of blood vessels both inside and outside the smooth muscle layer as well as hyperemia of bronchial vasculature are contributing factors in airway wall remodeling in patients with chronic airway diseases, proposing for the ongoing mechanisms like angiogenesis and vascular dilatation. We believe that vascular changes directly add to the airway narrowing and hyper-responsiveness by exudation and transudation of proinflammatory mediators, cytokines and growth factors; facilitating trafficking of inflammatory cells; causing oedema of the airway wall and promoting ASM accumulation. One of the key regulators of angiogenesis, vascular endothelial growth factor in concerted action with other endothelial mitogens play pivotal role in regulating bronchial angiogenesis. In this review article we address recent advances in pulmonary angiogenesis and remodelling that contribute in the pathogenesis of chronic airway diseases.

Azithromycin attenuates fibroblast growth factors induced vascular endothelial growth factor via p38(MAPK) signaling in human airway smooth muscle cells.

The airways in asthma and COPD are characterized by an increase in airway smooth muscle (ASM) mass and bronchial vascular changes associated with increased expression of pro-angiogenic growth factors, such as fibroblast growth factors (FGF-1 and FGF-2) and vascular endothelial growth factor (VEGF). We investigated the contribution of FGF-1/-2 in VEGF production in ASM cells and assessed the influence of azithromycin and dexamethasone and their underlying signaling mechanisms. Growth-synchronized human ASM cells were pre-treated with MAPK inhibitors, U0126 for ERK1/2(MAPK) and SB239063 for p38(MAPK) as well as with dexamethasone or azithromycin, 30 min before incubation with FGF-1 or FGF-2. Expression of VEGF (VEGF-A, VEGF121, and VEGF165) was assessed by quantitative PCR, VEGF release by ELISA and MAPK phosphorylation by Western blotting. Both FGF-1 and FGF-2 significantly induced mRNA levels of VEGF-A, VEGF121, and VEGF165. The VEGF protein release was increased 1.8-fold (FGF-1) and 5.5-fold (FGF-2) as compared to controls. Rapid transient increase in ERK1/2(MAPK) and p38(MAPK) phosphorylation and subsequent release of VEGF from FGF-1 or FGF-2-treated ASM cells were inhibited by respective blockers. Furthermore, azithromycin and dexamethasone significantly reduced both the VEGF release and the activation of p38(MAPK) pathway in response to FGF-1 or FGF-2 treatment. Our Results demonstrate that FGF-1 and FGF-2 up-regulate VEGF production via ERK1/2(MAPK) and p38(MAPK) pathways. Both azithromycin and dexamethasone elicited their anti-angiogenic effects via p38(MAPK) pathway in vitro, thereby suggesting a possible therapeutic approach to tackle VEGF-mediated vascular remodeling.

Transforming growth factor-beta 1 induces angiogenesis in vitro via VEGF production in human airway smooth muscle cells.

Increase in size and number of bronchial blood vessels as well as hyperaemia are factors that contribute to airway wall remodelling in patients with chronic airway diseases, such as asthma and chronic obstructive pulmonary diseases (COPD). Expression of transforming growth factor beta 1 (TGF-beta 1), a multifunctional cytokine as well as vascular endothelial growth factor (VEGF), a key angiogenic molecule, has been shown in the inflammed airways in patients with chronic airway diseases. TGF-beta 1 has been implicated in the regulation of extracellular matrix, leading to airway remodelling in patients with chronic airway diseases. However, the role of TGF-beta 1 in regulating VEGF expression in patients with chronic airway diseases, as well as the underlying mechanisms are not yet well established. We investigated whether TGF-beta 1 stimulates VEGF expression in vitro and hence could influence vascular remodelling. Cultured human airway smooth muscle cells (HASMC) were serum deprived for 60 h before incubation with 5ng/ml of TGF-beta 1 for different time points. Control cells received serum-free culture medium. TGF-beta 1 treatment resulted in time dependent HASMC cell proliferation with maximal values for DNA biosynthesis at 24 h and cell number at 48 h. Northern blot analysis of VEGF mRNA expression showed increased levels in cells treated with TGF-beta 1 for 4 to 8 h. TGF-beta 1 also induced a time-dependent release of VEGF proteins in the conditioned medium after 48 h of treatment. Furthermore, the ability of HASMC-released VEGF proteins to induce human umbilical vein endothelial cells proliferation was inhibited by VEGF receptor antagonist, confirming that TGF-beta 1 induced VEGF was biologically active. We conclude that TGF-beta 1 in addition to an extracellular matrix regulator also could play a key role in bronchial angiogenesis and vascular remodelling via VEGF pathway in asthma.

Targeting lung inflammation: novel therapies for the treatment of COPD.

Chronic obstructive pulmonary disease (COPD) is a global health problem. As understanding of pathology of COPD has increased it has been established that COPD is associated with the progressive pulmonary inflammation and destruction of lung parenchyma (emphysema) that relate to disease severity. Therefore, it is anticipated that drugs that reduce pulmonary inflammation will provide effective, disease modifying therapy for COPD. Several specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD; these include agents directed against cytokines and chemokines. Broad-range anti-inflammatory drugs are now in phase III development for COPD; they include inhibitors of phosphodiesterase 4 (PDE4). Other drugs that inhibit cell signaling include inhibitors of p38 mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and phosphoinositide-3-kinase (PI3K). There is also a search for inhibitors of proteinases and matrix metalloproteinases (MMPs) to prevent lung destruction and the development of emphysema. This review highlights studies on novel or potential anti-inflammatory agents that might be considered in the development of new future therapies for COPD.

Molecular mechanisms in chronic obstructive pulmonary disease: potential targets for therapy.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive airflow obstruction. Tobacco smoking is the main risk factor worldwide. In contrast to asthma, antiinflammatory therapies are rather ineffective in improving chronic symptoms and reducing inflammation, lung function decline, and airway remodeling. Specific drugs that are directed against the remodeling and chronic inflammation, thereby preventing lung tissue damage and progressive lung function decline, must be developed. Experimental models and expression studies suggest that anti-vascular endothelial growth factor (VEGF) receptor strategies may be of use in patients with emphysema, whereas anti-HER1-directed strategies may be more useful in patients with pulmonary mucus hypersecretion, as seen in chronic bronchitis and asthma. Growth factors and cytokines including VEGF, fibroblast growth factors, transforming growth factor-beta, tumor necrosis factor-alpha, CXCL1, CXCL8, and CCL2, and signal transduction proteins such as mitogen-activated protein kinase p38 and nuclear factor-kappaB, seem to be important pathogenetic molecules in COPD. Specific antagonists for these proteins may be effective for different inflammatory diseases. However, their efficacy for COPD therapy has not yet been demonstrated. Finally, other drugs such as retinoic acids may provide restoration of lung tissue structure. Such approaches, however, must await the first results of growth factor or cytokine antagonist therapy in chronic lung diseases.

Future therapeutic treatment of COPD: struggle between oxidants and cytokines.

Chronic obstructive pulmonary disease (COPD) is a global health problem. Being a progressive disease characterized by inflammation and predominantly caused by tobacco smoking, it deteriorates pulmonary and skeletal muscle functioning, and reduces physical behavior, societal participation and quality of life. During the last two decades studies were focused on the airway and systemic inflammation, oxidative stress, and airway and/or parenchymal remodeling. Macrophages, neutrophils and T cells are thought to be important key players, as well as structural cells like fibroblasts, epithelial, endothelial and smooth muscle cells. Mediators and proteins including cytokines, chemokines, growth factors, proteinases, and oxidants seem to be involved differentially in its pathogenesis. Current pharmacological treatments are directed to reducing airway inflammation, boosting the endogenous levels of anti-oxidants and relieving airway contraction and sputum production. Most agents were primarily used for treating asthma. But in contrast to asthma, these treatments are not very effective in COPD. As a result, novel more specifically acting interventional drugs with less side effects are being developed to treat chronic inflammatory diseases, including COPD. This review highlights studies on novel or potential drug antioxidants such as dietary antioxidants supplementation, N-acetyl-L-cysteine, N-acystelyn, endosteine, antioxidant enzyme mimetics, and anti-inflammatory agents like antagonists of cytokines, such as tumor necrosis factor (TNF)-alpha, CXCL8, and CCL2, and inhibitors of signal transduction proteins including phosphodiesterase 4, MAPK p38, P1-3k, and NFkappaB.

Enhanced bronchial expression of extracellular matrix proteins in chronic obstructive pulmonary disease.

Remodeling of airways and blood vessels is an important feature in chronic obstructive pulmonary disease (COPD). By using immunohistochemical analysis, we examined bronchial expression patterns of various extracellular matrix (ECM) components such as collagens (subtypes I, III, and IV), fibronectin, and laminin beta2 in patients with COPD (forced expiratory volume in 1 second [FEV1] or=85%; n = 16) and correlated expression data with lung function. Quantitative analysis revealed enhanced levels (P < .01) of total collagens I, III, and IV in surface epithelial basement membrane (SEBM) and collagens I and III in bronchial lamina propria (P < .02) and adventitia (P < .05) in COPD. Distinct and increased (P < .05) vascular expression of fibronectin accounts for intimal vascular fibrosis, whereas laminin beta2 (P < .05) was elevated in airway smooth muscle (ASM). FEV1 values inversely correlated with collagens in the SEBM, fibronectin in bronchial vessels, and laminin in the ASM. Our data suggest that COPD exhibits increased bronchial deposition of ECM proteins that contribute to deteriorated lung function and airway remodeling.

Expression of epidermal growth factors and their receptors in the bronchial epithelium of subjects with chronic obstructive pulmonary disease.

Smoking may affect epithelial repair and differentiation differentially in smokers with and without chronic obstructive pulmonary disease (COPD). We hypothesized that epithelial repair is disturbed in patients with COPD owing to higher expression of epidermal growth factor (EGF)-like factors and/or receptors. We studied epithelial expression of EGF, transforming growth factor a, amphiregulin, heregulin (HRG), betacellulin (BTC), and their receptors, EGFR, HER-2, and HER-3, by immunohistochemical analysis in resected bronchial tissue from 20 subjects with (forced expiratory volume in 1 second [FEV(1)] <75% of predicted value) and 18 without (FEV(1) >85% predicted value) COPD. All subjects underwent surgery for lung cancer. The proportion of intact, damaged, goblet, or squamous metaplastic epithelium was similar in subjects with and without COPD. Regardless of smoking status, HRG expression was higher in intact epithelium of patients with COPD than in those without. Subgroup analysis showed higher EGFR expression in intact epithelium (1.4 times; P pound .04) and higher EGF, BTC, and HRG expression in damaged epithelium (1.4-1.8 times; P

Effects of cigarette smoke condensate on proliferation and wound closure of bronchial epithelial cells in vitro: role of glutathione.

BACKGROUND: Increased airway epithelial proliferation is frequently observed in smokers. To elucidate the molecular mechanisms leading to these epithelial changes, we studied the effect of cigarette smoke condensate (CSC) on cell proliferation, wound closure and mitogen activated protein kinase (MAPK) activation. We also studied whether modulation of intracellular glutathione/thiol levels could attenuate CSC-induced cell proliferation. METHODS: Cells of the bronchial epithelial cell line NCI-H292 and subcultures of primary bronchial epithelial cells were used for the present study. The effect of CSC on epithelial proliferation was assessed using 5-bromo-2-deoxyuridine (BrdU) incorporation. Modulation of epithelial wound repair was studied by analysis of closure of 3 mm circular scrape wounds during 72 hours of culture. Wound closure was calculated from digital images obtained at 24 h intervals. Activation of mitogen-activated protein kinases was assessed by Western blotting using phospho-specific antibodies. RESULTS: At low concentrations CSC increased proliferation of NCI-H292 cells, whereas high concentrations were inhibitory as a result of cytotoxicity. Low concentrations of CSC also increased epithelial wound closure of both NCI-H292 and PBEC, whereas at high concentrations closure was inhibited. At low, mitogenic concentrations, CSC caused persistent activation of ERK1/2, a MAPK involved in cell proliferation. Inhibition of cell proliferation by high concentrations of CSC was associated with activation of the pro-apoptotic MAP kinases p38 and JNK. Modulation of intracellular glutathione (GSH)/thiol levels using N-acetyl-L-cysteine, GSH or buthionine sulphoximine (BSO), demonstrated that both the stimulatory and the inhibitory effects of CSC were regulated in part by intracellular GSH levels. CONCLUSION: These results indicate that CSC may increase cell proliferation and wound closure dependent on the local concentration of cigarette smoke and the anti-oxidant status. These findings are consistent with increased epithelial proliferation in smokers, and may provide further insight in the development of lung cancer.

Chronic obstructive pulmonary disease is associated with enhanced bronchial expression of FGF-1, FGF-2, and FGFR-1.

An important feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, the molecular mechanisms of which are poorly understood. In this study, the role of fibroblast growth factors (FGF-1 and FGF-2) and their receptor, FGFR-1, was assessed in bronchial airway wall remodelling in patients with COPD (FEV1 < 75%; n = 15) and without COPD (FEV1 > 85%; n = 16). FGF-1 and FGFR-1 were immunolocalized in bronchial epithelium, airway smooth muscle (ASM), submucosal glandular epithelium, and vascular smooth muscle. Quantitative digital image analysis revealed increased cytoplasmic expression of FGF-2 in bronchial epithelium (0.35 +/- 0.03 vs 0.20 +/- 0.04, p < 0.008) and nuclear localization in ASM (p < 0.0001) in COPD patients compared with controls. Elevated levels of FGFR-1 in ASM (p < 0.005) and of FGF-1 (p < 0.04) and FGFR-1 (p < 0.001) in bronchial epithelium were observed. In cultured human ASM cells, FGF-1 and/or FGF-2 (10 ng/ml) induced cellular proliferation, as shown by [3H]thymidine incorporation and by cell number counts. Steady-state mRNA levels of FGFR-1 were elevated in human ASM cells treated with either FGF-1 or FGF-2. The increased bronchial expression of fibroblast growth factors and their receptor in patients with COPD, and the mitogenic response of human ASM cells to FGFs in vitro suggest a potential role for the FGF/FGFR-1 system in the remodelling of bronchial airways in COPD.