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Asthma with fixed airway obstruction (FAO) is associated with significant morbidity and rapid decline in lung function, making its treatment challenging. Quantitative computed tomography (QCT) along with data postprocessing is a useful tool to obtain detailed information on airway structure, parenchymal function, and computational flow features. In this study, we aim to identify the structural and functional differences between asthma with and without FAO. The FAO group was defined by a ratio of forced expiratory volume in 1 s (FEV 1 ) to forced vital capacity (FVC), FEV 1 /FVC <0.7. Accordingly, we obtained two sets of QCT images at inspiration and expiration of asthma subjects without (N = 24) and with FAO (N = 12). Structural and functional QCT-derived airway variables were extracted, including normalized hydraulic diameter, normalized airway wall thickness, functional small airway disease, and emphysema percentage. A one-dimensional (1D) computational fluid dynamics (CFD) model considering airway deformation was used to compare the pressure distribution between the two groups. The computational pressures showed strong correlations with the pulmonary function test (PFT)-based metrics. In conclusion, asthma participants with FAO had worse lung functions and higher-pressure drops than those without FAO., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: An imbalance in Matrix MetalloProteases (MMPs) and Tissue Inhibitors of MMPs (TIMPs) contributes to Chronic Obstructive Pulmonary Disease (COPD) development. Longitudinal studies investigating Single Nucleotide Polymorphisms (SNPs) in MMPs and TIMPs with respect to COPD development and lung function decline in the general population are lacking. Methods: We genotyped SNPs in MMP1 (G-1607GG), MMP2 (-1306 C/T), MMP9 (3 tagging SNPs), MMP12 (A-82G and Asn357Ser) and TIMP1 (Phe124Phe and Ile158Ile) in 1390 Caucasians with multiple FEV1 measurements from a prospective cohort study in the general population. FEV1 decline was analyzed using linear mixed effect models adjusted for confounders. Analyses of the X-chromosomal TIMP1 gene were stratified according to sex. All significant associations were repeated in an independent general population cohort (n = 1152). Results: MMP2 -1306 TT genotype carriers had excess FEV1 decline (-4.0 ml/yr, p = 0.03) compared to wild type carriers. TIMP1 Ile158Ile predicted significant excess FEV1 decline in both males and females. TIMP1 Phe124Phe predicted significant excess FEV1 decline in males only, which was replicated (p = 0.10) in the second cohort. The MMP2 and TIMP1 Ile158Ile associations were not replicated. Although power was limited, we did not find associations with COPD development. Conclusions: We for the first time show that TIMP1 Phe124Phe contributes to excess FEV1 decline in two independent prospective cohorts, albeit not quite reaching conventional statistical significance in the replication cohort. SNPs in MMPs evidently do not contribute to FEV1 decline in the general population. [ABSTRACT FROM AUTHOR]

In recent years considerable insight has been gained in the optimal management of adult asthma. In asthma patients who have persistent symptoms despite the daily use of (a low dose) inhaled corticosteroids (ICS), adding a longacting β2-agonist to ICS improves asthma control and decreases the number of exacerbations. Currently two different LABAs are available, ie formoterol and salmeterol. The most important difference between both LABAs is a more rapid onset of action of formoterol (2-5 minutes) when compared to salmeterol (15-30 minutes). Partly based on these pharmacological differences, two major different approaches have been put forward to asthma management. The fi rst approach (Gaining Optimal Asthma Control) is promoted by the producers of fl uticasone/salmeterol and recommends to step up ICS to the dose needed to achieve optimal asthma control in order to keep the patient symptom free and to prevent exacerbations. The second approach is promoted by the producers of budesonide/formoterol and recommends a low maintenance dose which can be adjusted up or down according to the clinical control of asthma. Initially, a treatment strategy with Adjustable Maintenance Dosing with budesonide/formoterol was introduced. At a later time, this concept was changed to the Symbicort Maintenance And Reliever Therapy (SMART) approach. The aim of this manuscript is to review the current literature on the management of asthma with ICS and LABAs and to discuss the different treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown. Methods: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality. Results: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93). Conclusions: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2-3 years. [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend inhaled corticosteroids (ICS) as maintenance treatment for patients with chronic obstructive pulmonary disease (COPD) with a post-bronchodilator forced expiratory volume in 1 second (FEV1) <50% predicted and frequent exacerbations, although they have only a small preventive effect on the accelerated decline in lung function. Combined treatment with ICS and long acting 132 agonists (LABA) may provide benefit to the stability of COPD, but it is unknown if withdrawal of CS will result in disease deterioration. Methods: The effects of 1 year withdrawal of the ICS fluticasone propionate (FP) after a 3 month run-in treatment period with FP combined with the LABA salmeterol (S) (500 μg FP +50 μg S twice daily; SFC) were investigated in patients with COPD in a randomised, double blind study. 497 patients were enrolled from 39 centres throughout the Netherlands; 373 were randomised and 293 completed the study. Results: The drop out rate after randomisation was similar in the two groups. Withdrawal of FR resulted in a sustained decrease in FEV1: mean (SE) change from baseline -4.4 (0.9)% (S) v -0.1 (0.9)% (SFC); adjusted difference 4.1 (95% CI 1.6 to 6.6) percentage points (p<0.001). Corresponding figures for the FEV1/FVC ratio were -3.7 (0.8)% (5) v 0.0 (0.8)% (SFC) (p=0.002). The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups, respectively (adjusted rate ratio 1.2; 95% CI 0.9 to 1.5; p =0.15). The mean annual incidence rate of mild exacerbations was 1.3 (5) v 0.6 (SFC), p =0.020. An immediate and sustained increase in dyspnoea score (scale 0-4; mean difference between groups 0.17 (0.04), p<0.001) and in the percentage of disturbed nights (6 (2) percentage points, p<0.001) occurred after withdrawal of fluticasone. Conclusions: Withdrawal of FP in COPD patients using SFC resulted in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights. This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration, even under treatment with a LABA. [ABSTRACT FROM AUTHOR]

Compared with the effects of chronic smoke exposure on lung function and airway inflammation, there are few data on the acute effects of smoking. A review of the literature identified 123 studies investigating the acute effects of cigarette smoking on inflammation and oxidative stress in human, animal, and in vitro models. An acute smoking model is a relatively easy and sensitive method of investigating the specific effects of cigarette smoke on oxidative stress and inflammation. Acute smoke exposure can result in tissue damage, as suggested by increased products of lipid peroxidation and degradation products of extracellular matrix proteins. Acute cigarette smoke has a suppressive effect on the number of eosinophils and several inflammatory cytokines, possibly due to the anti- inflammatory effect of carbon monoxide. An acute smoking model can supplement other ways of studying the effects of smoking and is an as yet underinvestigated method for intervention studies in smoking related diseases. [ABSTRACT FROM AUTHOR]

Background: It has been shown that treatment with a long acting beta2 agonist in addition to a glucocorticoid is beneficial in the treatment of asthma. In asthma inflammatory cells, particularly eosinophils, migrate into the pulmonary tissue and airway lumen by means of adhesion molecules expressed on resident tissue cells--that is, fibroblasts--and become activated by cytokines and adhesive interactions. A study was undertaken to determine whether an interaction exists between the long acting beta2 agonist formoterol and the glucocorticoid budesonide on inhibition of adhesion molecule expression, as well as chemo/cytokine production by human lung fibroblasts.Methods: Lung fibroblasts were preincubated with therapeutically relevant drug concentrations of 10(-8) M to 10(-10) M. Cells were stimulated with interleukin (IL)-1beta (1 or 10 U/ml) for 8 hours and supernatants were collected for measurement of GM-CSF and IL-8 concentrations. The cells were fixed and subjected to a cell surface ELISA technique to measure the expression of ICAM-1 and VCAM-1.Results: Formoterol exerted an additive effect on the inhibition of IL-1beta stimulated ICAM-1 and VCAM-1 upregulation and GM-CSF production by budesonide in concentrations of 10(-9) M and above (p<0.05). IL-8 production was not influenced by formoterol.Conclusion: Formoterol exerts an additive effect on the anti-inflammatory properties of budesonide. In vitro data support the finding that the combination of budesonide and formoterol in asthma treatment strengthens the beneficial effect of either drug alone. [ABSTRACT FROM AUTHOR]

Background: The beta2 adrenoceptor and its 5' untranslated region contain a number of genetic variants. The aim of this study was to investigate the potential for genetic variation at this locus to influence the expression of beta2 adrenoceptors on circulating peripheral blood mononuclear cells (PBMCs).Methods: Genotype was determined in 96 individuals with asthma for four polymorphisms at the beta2 adrenoceptor locus. Beta2 adrenoceptor binding and cyclic AMP responses to isoprenaline in PBMCs were determined and the relationship between genotype/haplotype and beta2 adrenoceptor expression and response to isoprenaline examined.Results: Beta2 adrenoceptor promoter polymorphisms were found to be common in white subjects. Strong linkage disequilibrium exists across this locus, resulting in the occurrence of several common haplotypes. No single polymorphism or haplotype was correlated with the level of beta2 adrenoceptor expression or cyclic AMP responses to isoprenaline in vitro.Conclusion: Beta2 adrenoceptor polymorphisms, when considered in isolation or by extended haplotypes, do not determine the basal level of expression or coupling of beta2 adrenoceptors in PBMCs from asthmatic subjects. [ABSTRACT FROM AUTHOR]

Background: The β2 adrenoceptor and its 5' untranslated region contain a number of genetic variants. The aim of this study was to investigate the potential for genetic variation at this locus to influence the expression of β2 adrenoceptors on circulating peripheral blood mononuclear cells (PBMCs). Methods: Genotype was determined in 96 individuals with asthma for four polymorphisms at the β2 adrenoceptor locus. β2 adrenoceptor binding and cyclic AMP responses to isoprenaline in PBMCs were determined and the relationship between genotype/haplotype and β2 adrenoceptor expression and response to isoprenaline examined. Results: β2 adrenoceptor promoter polymorphisms were found to be common in white subjects. Strong linkage disequilibrium exists across this locus, resulting in the occurrence of several common hoplotypes. No single polymorphism or haplotype was correlated with the level of β2 adrenoceptor expression or cyclic AMP responses to isoprenaline in vitro. Conclusion: β2 adrenoceptor polymorphisms, when considered in isolation or by extended haplosypes, do not determine the basal level of expression or coupling of β2 adrenoceptors in PBMCs from asthmatic subjects. [ABSTRACT FROM AUTHOR]

Background: To study bronchial responsiveness to adenosine 5'-monophosphate (AMP) in population surveys, repeatability of a rapid dosimetric method with quadrupling doses was evaluated.Methods: Volunteers with symptoms of airway respiratory allergy or asthma were invited for AMP challenges on two occasions. After each dose the fall in forced expiratory volume in one second (FEV(1)) compared with the post-saline value was determined. The cumulative doses of AMP needed to cause a fall in FEV(1) of 20% (PD(20)), 15% (PD(15)), and 10% (PD(10)) were calculated. Agreement was evaluated by means of kappa values. After excluding systematic differences in PD values on two occasions (t test), repeatability of a single estimation of the chosen PD values was calculated and expressed in doubling doses (DD).Results: In 28 of 76 subjects a PD(20) was estimated on the two visits, in 29 subjects a PD(15) was estimated, and in 32 a PD(10) was obtained. Kappa values for a positive threshold were 0.89 for a cut off level for a 20% fall in FEV(1), 0.78 for a 15% fall in FEV(1), and 0.76 for a fall in FEV(1) of 10%. The PD values did not differ between the two visits and 95% repeatability of a single estimation was +/-1.7 DD for PD(20), +/-2.2 DD for PD(15), and +/-2.4 DD for PD(10). The quadrupling dose method reduced time by 40% in non-hyperresponsive subjects and no adverse effects were observed.Conclusion: The short dosimeter protocol with quadrupling doses for AMP challenges is a rapid, reproducible tool for estimating bronchial responsiveness in population surveys. [ABSTRACT FROM AUTHOR]

Background: Inflammatory changes in the airways in chronic obstructive pulmonary disease (COPD) are largely attributed to smoking, yet they may be present even if patients do not currently smoke. The differences in inflammatory cells and the factors contributing to these differences were examined in the airways of patients with COPD who do not currently smoke.Methods: Eighteen non-atopic subjects with COPD (14 men) of mean (SD) age 62 (8) years and forced expiratory volume in one second (FEV(1)) 59 (13)% predicted and 11 non-atopic healthy subjects (eight men) of mean (SD) age 58 (8) years, FEV(1) 104 (11)% predicted were studied. Sputum induction and bronchoscopy with bronchoalveolar lavage (BAL) and biopsies were performed.Results: Patients with COPD had more mucosal EG2+ cells (eosinophils) (median (range) 40 (0-190) versus 5 (0-40) cells/mm(2), p = 0.049) and CD68+ cells (1115 (330-2920) versus 590 (450-1580) cells/mm(2), p = 0.03), and a tendency towards more CD4+ but not CD8+ lymphocytes than healthy controls. Furthermore, patients with COPD had higher percentages of sputum neutrophils (77 (29-94) versus 36 (18-60)%, p = 0.001) and eosinophils (1.2 (0-8.5) versus 0.2 (0-3.1)%, p = 0.008), BAL fluid eosinophils (0.4 (0-1.7) versus 0.2 (0-0.5)%, p = 0.03), and higher concentrations of sputum eosinophilic cationic protein (ECP) (838 (115-23 760) versus 121 (35-218) ng/ml, p<0.001). Concentrations of ECP expressed per eosinophil were not higher. Patients with COPD with high mucosal EG2+ cell numbers also had high mucosal CD4+ cell numbers. Sputum eosinophilia was associated with a decrease in FEV(1)/VC and BAL fluid eosinophilia with a decrease in mucosal NP57+ cells (neutrophils).Conclusions: Subjects with COPD who do not currently smoke have increased numbers of inflammatory cells. Eosinophils are increased in number in the airways in COPD but do not seem to be activated. The increased eosinophil numbers are probably due to recruitment as a result of ongoing inflammation. Macrophages and lymphocytes may play a part in this inflammation. [ABSTRACT FROM AUTHOR]

Understanding the puff-by-puff delivery mechanisms of key components of heated tobacco products is critical to developing product designs. This study investigates the puff-by-puff release patterns of key components in Natural Smoke Cigarettes (NSCs), which are designed to deliver nicotine without combustion by reducing oxygen content, utilizing a 30-s puff interval, a 2-s puff duration, and a 55 mL puff volume to simulate realistic smoking conditions. By establishing models to analyze the variation of nicotine, glycerol, 1,2-propylene glycol (PG), and water in different functional sections of the cigarette under controlled smoking conditions. These sections include the tobacco, hollow, cooling, and filter sections, constituting the structure of NSCs. In addition, the model calculates the port-by-port release of the components in the flue gas aerosol and compares it with the measured value. The results showed that: The retention amount in the tobacco section showed a steep decline in the first three puffs, with an overall exponential decrease. The amounts in the other sections were consistent, increasing in the first two puffs and then stabilizing. The retention amount decreased linearly with each puff, with a similar pattern across sections. The release amount peaked at the fourth to fifth puffs and then stabilized. The retention amount in the tobacco section declined exponentially in the first three puffs. It peaked in the second to third puffs in other sections, then decreased with each subsequent puff. The retention amount in the tobacco section showed a significant decline in the first puff, stabilizing at around 4 mg. In other sections, it peaked at the first puff and then rapidly declined. These findings can inform the development of reduced-harm smoking products and contribute to a better understanding of the dynamics of smoke generation. Additionally, the study offers a reference for the puff-by-puff release stability of NSCs and the improvement of consumers' sensory quality. [ABSTRACT FROM AUTHOR]

Although adipose stem cell (ASC)-derived extracellular vesicles (EVs) are as effective as ASCs in the suppression of Th2 cell-mediated eosinophilic inflammation, the role of identified pulmonary genes has not been well documented. Thus, we assessed the immunomodulatory effects of paraoxonase-1 (PON1) on allergic airway inflammation in a mouse model of asthma. Five-week-old female C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection and challenged intranasally with OVA. To evaluate the effect of PON1 on allergic airway inflammation, the intranasal and intraperitoneal injections of recombinant mouse serum PON1 (5 μg/50 μL) were performed before the OVA challenge. We evaluated airway hyperresponsiveness (AHR), total inflammatory cells, and eosinophils in the bronchoalveolar lavage fluid (BALF), lung histology, serum immunoglobulin (Ig), cytokine profiles of BALF and lung draining lymph nodes (LLNs), the expression of interleukin (IL)-25 and transforming growth factor (TGF)-β in mouse lung epithelial cell (MLE-12 cell), and dendritic cell (DC) differentiation. The intraperitoneal and intranasal administration of PON1 significantly decreased AHR, total inflammatory cells and eosinophils in BALF, eosinophilic airway inflammation, serum total, and OVA-specific IgE. PON1 treatment, which marked reduced IL-4, IL-5, and IL-13 in the BALF and LLN but significantly increased interferon-γ and TGF-β. Furthermore, PON1 treatment significantly decreased the expression of IL-25 and increased TGF-β in MLE-12 cells. The expressions of CD40, CD80, and CD86 in immature DCs were significantly increased by PON1 treatment. The administration of PON1 ameliorated allergic airway inflammation and improved AHR through the downregulation of IL-4, IL-5, and IL-13 and upregulation of TGF-β in asthmatic mice. Furthermore, PON1 treatment decreased Th2-mediated inflammation induced by Aspergillus protease antigen by decreasing IL-25 and increasing TGF-β. [ABSTRACT FROM AUTHOR]

It is important to understand the effects of environmental factors such as air pollution on mitochondrial structure and function, especially when these changes increase cardiovascular disease risk. Although lifestyle choices directly determine many mitochondrial diseases, increasingly, it is becoming clear that the structure and function of mitochondria may be affected by pollutants found in the atmosphere (e.g., gases, pesticides herbicide aerosols, or microparticles). To date, the role of such agents on mitochondria and the potential impact on cardiovascular fitness is neglected. Here we offer a review of airborne stressors and pollutants, that may contribute to impairments in mitochondrial function and structure to cause heart disease. [ABSTRACT FROM AUTHOR]

Patients with interstitial lung diseases (ILDs) associate a large variety of comorbidities that have a significant impact on their clinical outcomes and survival. Among these comorbidities is neurological impairment. This review highlights what is known about the cognitive function, central nervous system (CNS), depression, and anxiety in patients with specific forms of fibrosing ILDs, such as idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, connective tissue diseases, etc. The most common pathogenic mechanisms for neurocognitive dysfunction as well as the screening methods and tools for their identification are also described in this review. [ABSTRACT FROM AUTHOR]

Air pollution, characterized by high levels of particulate matter (PM), poses the greatest environmental threat to human health, causing an estimated 7 million deaths annually and accounting for 5 % of the global gross domestic product (GDP). While the health impacts of PM are influenced by the toxicity of its individual chemical constituents, the mortality burden of PM is solely based on its total mass concentration. This is because of a lack of large-scale, high-resolution data on PM chemical composition, needed for epidemiological assessments. Identifying which PM constituents are harmful to health has been the "holy grail" of atmospheric science since the landmark 1993 study on six US cities established a definitive link between PM and mortality. Ever since, atmospheric scientists have focused on understanding aerosol composition, emission sources, and formation pathways, while longitudinal epidemiological studies have required individual-level exposure data, employing land use regression models for the prediction of exposures at fine resolutions. In this opinion article, we argue that the time has come to shift the focus towards incorporating PM chemical composition into epidemiological health assessments, laying the foundation for the development of new regulatory metrics. This shift will enable the creation of targeted guidelines and subsequent regulations, prioritizing mitigation efforts against the most harmful anthropogenic emissions. Central to this shift is the availability of global, long-term, high-resolution data on PM chemical composition that are obtained through field observations and modelling outputs. In the article, we underscore key milestones within aerosol science that have been integral for advancing this foundational shift. Specifically, we examine emerging modelling tools for estimating exposure to individual PM components, present the type of ambient observations needed for model developments, identify key gaps in our fundamental understanding of emissions and their atmospheric transformation, and propose advancing cross-disciplinary collaboration between aerosol scientists and epidemiologists to understand the health impacts of individual PM components. We contend that aerosol science has now reached a pivotal moment in elucidating the differential health impacts of PM components, representing a first step towards their incorporation into air quality guidelines. [ABSTRACT FROM AUTHOR]

The evidence regarding the association between infant formula (IF) composition and the prevention of allergy and respiratory diseases remains sparse and inconclusive. This study aimed to evaluate whether some IF characteristics were associated with the risk of allergy or respiratory diseases in childhood. Among 1243 formula‐fed children from the EDEN mother–child cohort, IF characteristics concerning long‐chain polyunsaturated fatty acids (LCPUFAs) enrichment, prebiotic/probiotic enrichment, and hydrolysis of proteins were identified from the ingredients list. Eczema, wheezing, food allergy, asthma, and allergic rhinitis up to age 8 years were prospectively collected and summarized into four allergic and respiratory multimorbidity clusters. Associations between 4‐month IF characteristics and risk of allergy or respiratory diseases were tested using logistic regressions adjusted on main confounders. The consumption of LCPUFA‐enriched formula was not linked to allergic and respiratory multimorbidity clusters, but to a lower risk of any allergy, eczema, and wheezing. Probiotic‐enriched formula consumption was associated with a lower risk of belonging to the 'Allergy without asthma' cluster (odds ratio [OR] [95% confidence interval, CI] = 0.63 [0.40–0.99]), and consumption of a formula enriched in Bifidobacterium lactis was associated with a lower risk of any allergy (OR [95% CI] = 0.59 [0.41–0.85]). Partially hydrolysed formula (pHF) consumption was associated with a higher risk of belonging to the 'Allergy without asthma' cluster (OR [95% CI] = 2.73 [1.65–4.51]). This study confirms the positive association between pHF consumption and the risk of allergy found in previous observational studies and suggests that consumption of LCPUFA‐enriched or probiotic‐enriched formula was associated with a lower risk of allergy. Key messages: The study aimed to explore, among formula‐fed infants, the association between infant formula characteristics and allergic or respiratory multimorbidity clusters in early childhood.Probiotic‐enriched formula consumption was associated with a lower risk of belonging to the 'Allergy without asthma' cluster.Partially hydrolysed formula consumption was associated with a higher risk of belonging to the 'Allergy without asthma' cluster, even after exclusion of cases reported at 1 year. [ABSTRACT FROM AUTHOR]

Summary The role of exogenous nitric oxide (NO) on the expression of interleukin (IL)‐2, IL‐4, IL‐5 and interferon‐γ (IFN‐γ) by freshly isolated human T lymphocytes was investigated. The presence of NO, generated from any of the NO‐donor compounds, S‐nitroso‐N‐acetyl‐d,l‐penicillamine (SNAP), DPTA‐nonoate (DPTA) or DETA‐nonoate (DETA), added 15 min prior to T‐cell stimulation (for 24 hr) with anti‐CD3/anti‐CD28 monoclonal antibodies (mAbs), resulted in up to 50% inhibition of IL‐4, IL‐5 and IFN‐γ secretion. In contrast, IL‐2 secretion was not inhibited. Using the guanylate cyclase inhibitor, LY83583, it was shown that the inhibition of IL‐4 and IL‐5 was cGMP dependent, whereas additional mechanisms mediated the inhibition of IFN‐γ. Exposure of T cells to the NO‐donor compounds for 24 hr prior to stimulation resulted in a more pronounced inhibition of IFN‐γ secretion by DPTA and DETA (P < 0·01), despite the fact that NO generation could no longer be detected. Under these conditions, IL‐4 secretion was not inhibited and IL‐5 secretion was inhibited to a lesser extent (P < 0·01 for SNAP and DPTA, P > 0·05 for DETA). IL‐2 secretion was inhibited after 24 hr of preincubation with the NO‐donor compounds, whereas it was not directly affected by NO. The increased inhibitory effects on IFN‐γ and IL‐2 secretion could not be accounted for by the antiproliferative effects of the NO‐donor compounds, which were diminished after 24 hr of preincubation relative to 15 min of preincubation. For IFN‐γ, the inhibition was at least partially effected at the transcriptional level as shown by decreased mRNA accumulation. These data show that NO can modulate the balance between the expression, by human T‐lymphocytes, of T helper 1‐ and T helper 2‐type cytokines, through selective and persistent inhibition of the expression of IFN‐γ via a cGMP‐independent mechanism. [ABSTRACT FROM AUTHOR]

Background: In general practice airway obstruction and the bronchodilator response are usually assessed using peak expiratory flow (PEF) measurements. A study was carried out in patients presenting with persistent cough to investigate to what extent PEF measurements are reliable when compared with tests using forced expiratory volume in one second (FEV(1)) as the measure of response.Methods: Data (questionnaire, physical examination, spirometry, PEF) were collected from 240 patients aged 18-75 years, not previously diagnosed with asthma or chronic obstructive pulmonary disease (COPD), who consulted their general practitioner with cough of at least two weeks duration. The relationship between low PEF (PEF < PEFpred - 1.64RSD) and low FEV(1) (FEV(1) < FEV(1)pred - 1.64RSD) was tested. A positive bronchodilator response after inhaling 400 microg salbutamol was defined as an increase in FEV(1) of > or = 9% predicted and was compared with an absolute increase in PEF with cut off values of 40, 60, and 80 l/min and DeltaPEF % baseline with cut off values of 10%, 15%, and 20%.Results: Forty eight patients (20%) had low FEV(1), 86 (35.8%) had low PEF, and 32 (13.3%) had a positive bronchodilator response. Low PEF had a positive predictive value (PPV) for low FEV(1) of 46.5% and a negative predictive value (NPV) of 95%. DeltaPEF of > or = 10%, > or = 15%, or > or = 20% baseline had PPVs of 36%, 52%, and 67%, respectively, and DeltaPEF of > or = 40, > or = 60, and > or = 80 l/min in absolute terms had PPVs of 39%, 45%, and 57%, respectively, for DeltaFEV(1) > or = 9% predicted; NPVs were high (88-93%).Conclusions: Although PEF measurements can reliably exclude airway obstruction and bronchodilator response, they are not suitable for use in the assessment of the bronchodilator response in the diagnostic work up of primary care patients with persistent cough. The clinical value of PEF measurements in the diagnosis of reversible obstructive airway disease should therefore be re-evaluated. [ABSTRACT FROM AUTHOR]

Background: Guidelines state that oral and inhaled corticosteroids are the cornerstone of asthma treatment. The effect of both types of treatment can be assessed by measuring lung and systemic parameters. Treatment for two weeks with either oral prednisolone (30 mg/day), high dose fluticasone propionate (2000 microg/day, FP2000), or lower dose FP (500 microg/day, FP500), both given by a dry powder inhaler, were compared.Methods: One hundred and twenty patients with asthma were treated for two weeks in a double blind parallel group design. Lung function, asthma symptoms, airway hyperresponsiveness (PC(20) methacholine and adenosine-5'-monophosphate), sputum eosinophil and eosinophilic cationic protein (ECP) levels were measured as lung parameters. In addition, morning serum blood cortisol, blood eosinophil, and serum ECP levels were measured as systemic parameters.Results: PC(20) methacholine and adenosine-5'-monophosphate showed significantly greater improvement with FP2000 (1.99 and 4.04 doubling concentrations (DC), respectively) than prednisolone (0.90 DC, p = 0.02; 2.15 DC, p = 0. 05) and marginally more than with FP500 (1.69 and 3.54 DC). Changes in sputum eosinophil and ECP concentrations showed similar trends; the decrease in ECP was significantly greater with FP2000 than with FP500. In contrast, the systemic parameters of steroid activity (cortisol, peripheral blood eosinophils, and serum ECP) decreased to a similar extent with FP2000 and prednisolone but significantly less with FP500.Conclusions: Oral prednisolone (30 mg/day) was inferior to FP2000 in improving airway hyperresponsiveness to both methacholine and AMP, with similar trends in forced expiratory volume in one second (FEV(1)), sputum eosinophil and ECP concentrations. Systemic effects were similar with prednisolone and FP2000 and less with FP500. [ABSTRACT FROM AUTHOR]

Background: Nitric oxide (NO) is involved in inflammation and host defence of the lung. It has been found in increased concentrations in the airways in asthmatic subjects but its levels in patients with chronic obstructive pulmonary disease (COPD) have not been investigated. A study was undertaken to determine whether markers of NO metabolism (NO in exhaled air, iNOS expression in sputum cells, and nitrite + nitrate (NO2-/NO3-) in sputum supernatant) are increased in subjects with COPD, and whether they correlate with inflammatory indices in induced sputum. The associations of these markers with smoking were also assessed.Methods: Sixteen subjects with COPD (median age 66 years, median forced expiratory volume in one second (FEV1) 63% predicted, eight current smokers) and 16 healthy subjects (median age 63 years, median FEV1 113% predicted, eight current smokers) participated in the study. NO was measured during tidal breathing and sputum was induced by inhalation of hypertonic saline.Results: No differences were observed between subjects with COPD and healthy controls in exhaled NO excretion rate (median 5.15 and 6.25 nmol/min), sputum macrophage iNOS expression (14% and 12%), and sputum supernatant NO2-/NO3- (46 and 73 microM). NO in exhaled air correlated with the percentage of sputum eosinophils in patients with COPD (rho = 0.65, p = 0.009) but not in healthy individuals. Exhaled NO and supernatant NO2-/NO3- levels were lower in healthy smokers than in healthy non/ex-smokers.Conclusions: Our findings indicate that NO metabolism is not increased in patients with stable COPD. The close association between exhaled NO levels and sputum eosinophils suggests a role for NO in airway inflammation in COPD. Studies performed during exacerbations may clarify this role. [ABSTRACT FROM AUTHOR]

Background: The role of inhaled corticosteroids in the long term management of chronic obstructive pulmonary disease (COPD) is still unclear. A meta-analysis of the original data sets of the randomised controlled trials published thus far was therefore performed. The main question was: "Are inhaled corticosteroids able to slow down the decline in lung function (FEV1) in COPD?"Methods: A Medline search of papers published between 1983 and 1996 was performed and three studies were selected, two of which were published in full and one in abstract form. Patients with "asthmatic features" were excluded from the original data. Ninety five of the original 140 patients treated with inhaled corticosteroids (81 with 1500 micrograms beclomethasone daily, six with 1600 micrograms budesonide daily, and eight with 800 micrograms beclomethasone daily) and 88 patients treated with placebo (of the initial 144 patients) were included in the analysis. The effect on FEV1 was assessed by a multiple repeated measurement technique in which points of time in the study and treatment effects (inhaled corticosteroids compared with placebo) were investigated.Results: No baseline differences were observed (mean age 61 years, mean FEV1 45% predicted). The estimated two year difference in prebronchodilator FEV1 was +0.034 l/year (95% confidence interval (CI) 0.005 to 0.063) in the inhaled corticosteroid group compared with placebo. The postbronchodilator FEV1 showed a difference of +0.039 l/year (95% CI -0.006 to 0.084). No beneficial effect was observed on the exacerbation rate. Worsening of the disease was the reason for drop out in four patients in the treatment group compared with nine in the placebo group. In the treatment group six of the 95 subjects dropped out because of an adverse effect which may have been related to the treatment compared with two of the 88 patients in the placebo group.Conclusions: This meta-analysis in patients with clearly defined moderately severe COPD showed a beneficial course of FEV1 during two years of treatment with relatively high daily dosages of inhaled corticosteroids. [ABSTRACT FROM AUTHOR]

The objective of this study was to compare the two most frequently used asthma-specific quality of life (QOL) questionnaires and two generic QOL questionnaries with clinical data in order to establish their ability to discriminate in asthma severity, also referred to as cross-sectional construct validity. We conducted a multicentre, randomized, placebo-controlled study investigating the long-term effects of the long-acting beta 2-agonist formoterol in asthma patients using inhaled corticosteroids and short-acting beta 2-agonists. Before randomization, the peak expiratory flow (PEF) and use of beta 2-agonists for relief of symptoms were recorded twice daily for 1 month. At the end of the run-in period, the forced expiratory volume in 1 s (FEV1), airway hyper-responsiveness (PC20 methacholine) and QOL were measured, using two asthma-specific questionnaires, the Asthma Quality of Life Questionnaire (AQLQ) and the Living with Asthma Quality of Life Questionnaire (LWAQ), as well as two generic questionnaires, the Short Form 36 (SF-36) and the Psychological General Well Being (PGWB) index. The quality of life of the patients (n = 110) was only mildly impaired. The mean symptom score was 3.6 on a scale of 0-21 and the mean FEV1 was 65% of that predicted. The correlations between the QOL parameters and objective measures of asthma severity, such as the FEV1, PEF and PC20, were low (0.01-0.37). The correlations between the QOL parameters and subjective measures of asthma severity, such as symptom scores (range 0.26-0.65) and beta 2-agonist use for the relief of symptoms (0.09-0.39), were higher. The correlations of the activity and symptoms domains of the AQLQ with diary-obtained symptom scores were r = 0.50 (p < 0.0001) and r = 0.65 (p < 0.0001), respectively. The correlation between the physical construct of the LWAQ and symptom scores was r = 0.42 (p < 0.001) and that between the physical sumscore of the SF-36 and symptom scores was r = 0.50 (p < 0.001). The correlation between the PGWB and symptom scores was r = 0.41 (p < 0.001). The relation between the FEV1, PEF and PC20 and QOL was very low. The QOL measurements related well to the symptom scores. The AQLQ had a better cross-sectional construct validity than the LWAQ. The cross-sectional construct validity of the SF-36 was surprisingly high for this group of patients and the SF-36 performed better than the PGWB and LWAQ. [ABSTRACT FROM AUTHOR]