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1.	Ahmadi, Zainab, et al. (author) Hypo- and hypercapnia predict mortality in oxygen-dependent chronic obstructive pulmonary disease : a population-based prospective study 2014 In: Respiratory Research. - : BioMed Central. - 1465-9921 .- 1465-993X. ; 15:1, s. 30- Journal article (peer-reviewed)abstract BACKGROUND: The prognostic role of the arterial blood gas tension of carbon dioxide (PaCO2) in severe Chronic Obstructive Pulmonary Disease (COPD) remains unknown. The aim of this study was to estimate the association between PaCO2 and mortality in oxygen-dependent COPD. METHODS: National prospective study of patients starting long-term oxygen therapy (LTOT) for COPD in Sweden between October 1, 2005 and June 30, 2009, with all-cause mortality as endpoint. The association between PaCO2 while breathing air, PaCO2 (air), and mortality was estimated using Cox regression adjusted for age, sex, arterial blood gas tension of oxygen (PaO2), World Health Organization performance status, body mass index, comorbidity, and medications. RESULTS: Of 2,249 patients included, 1,129 (50%) died during a median 1.1 years (IQR 0.6-2.0 years) of observation. No patient was lost to follow-up. PaCO2 (air) independently predicted adjusted mortality (p < 0.001). The association with mortality was U-shaped, with the lowest mortality at approximately PaCO2 (air) 6.5 kPa and increased mortality at PaCO2 (air) below 5.0 kPa and above 7.0 kPa. CONCLUSION: In oxygen-dependent COPD, PaCO2 (air) is an independent prognostic factor with a U-shaped association with mortality.
2.	Aldonyte, Ruta, et al. (author) Circulating monocytes from healthy individuals and COPD patients. 2003 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 4:1, s. 11-11 Journal article (peer-reviewed)abstract Background: Chronic obstructive pulmonary disease (COPD) is characterized by incompletely reversible airflow obstruction associated with inflammation in which monocytes/macrophages are the predominant inflammatory cells. The only known genetic factor related to COPD is inherited PiZZ deficiency of alpha1-antitrypsin (AAT), an inhibitor of serine proteases. Methods: We investigated the basal and LPS-stimulated release of pro-inflammatory molecules from blood monocytes isolated from age and gender matched healthy (n = 30) and COPD (n = 20) individuals with and without AAT deficiency. Results: After 18 h of cell culture the basal release of MMP-9 was 2.5-fold, p < 0.02 greater, whereas IL-8 was 1.8-fold (p < 0.01) lower from COPD patient monocytes than from controls. LPS-stimulated release of IL-6 and MCP-1 was greater from COPD patient's monocytes relative to controls, while activation of control cells resulted in enhanced secretion of ICAM-1 and MMP-9 compared to COPD patients. Independent of disease status, monocytes from PiZZ AAT carriers released less TNFalpha (by 2.3-fold, p < 0.03). Conclusions: The basal and LPS-stimulated secretion of specific pro-inflammatory molecules from circulating monocytes differs between healthy and COPD subjects. These findings may be valuable for further studies on the mechanisms involved in recruitment and activation of inflammatory cells in COPD.
3.	Andersson, Cecilia K, et al. (author) Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis 2011 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 12:139 Journal article (peer-reviewed)abstract Background: Although mast cells are regarded as important regulators of inflammation and tissue remodelling, their role in cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF) has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with CF, IPF and never smoking controls. Methods: Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with CF (20 lung regions; 5 patients), IPF (21 regions; 7 patients) and controls (16 regions; 8 subjects). In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of IL-6 and TGF-beta. Results: In the alveolar parenchyma in lungs from patients with CF, MCTC numbers increased in areas showing cellular inflammation or fibrosis compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in CF lungs showed elevated expression of IL-6. In CF, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with IPF, a significantly elevated MCTC density was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-beta. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in IPF. Both the density, as well as the percentage, of MCTC correlated positively with the degree of fibrosis. The increased density of MCTC, as well as MCTC expression of TGF-beta, correlated negatively with patient lung function. Conclusions: The present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased alveolar parenchyma, represents a significant component of the histopathology in CF and IPF. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.
4.	Andersson Sjöland, Annika, et al. (author) Fibrocytes and the tissue niche in lung repair 2011 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 12 Research review (peer-reviewed)abstract Human fibrocytes are bone marrow-derived mesenchymal progenitor cells that express a variety of markers related to leukocytes, hematopoietic stem cells and a diverse set of fibroblast phenotypes. Fibrocytes can be recruited from the circulation to the tissue where they further can differentiate and proliferate into various mesenchymal cell types depending on the tissue niche. This local tissue niche is important because it modulates the fibrocytes and coordinates their role in tissue behaviour and repair. However, plasticity of a niche may be co-opted in chronic airway diseases such as asthma, idiopathic pulmonary fibrosis and obliterative bronchiolitis. This review will therefore focus on a possible role of fibrocytes in pathological tissue repair processes in those diseases.
5.	Andersson Sjöland, Annika, et al. (author) Fibrocytes are associated with vascular and parenchymal remodelling in patients with obliterative bronchiolitis. 2009 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 10:Oct 30 Journal article (peer-reviewed)abstract BACKGROUND: The aim of the present study was to explore the occurrence of fibrocytes in tissue and to investigate whether the appearance of fibrocytes may be linked to structural changes of the parenchyme and vasculature in the lungs of patients with obliterative bronchiolitis (OB) following lung or bone marrow transplantation. METHODS: Identification of parenchyme, vasculature, and fibrocytes was done by histological methods in lung tissue from bone marrow or lung-transplanted patients with obliterative bronchiolitis, and from controls. RESULTS: The transplanted patients had significantly higher amounts of tissue in the alveolar parenchyme (46.5 +/- 17.6%) than the controls (21.7 +/- 7.6%) (p < 0.05). The patients also had significantly increased numbers of fibrocytes identified by CXCR4/prolyl4-hydroxylase, CD45R0/prolyl4-hydroxylase, and CD34/prolyl4-hydroxylase compared to the controls (p < 0.01). There was a correlation between the number of fibrocytes and the area of alveolar parenchyma; CXCR4/prolyl 4-hydroxylase (p < 0.01), CD45R0/prolyl 4-hydroxylase (p < 0.05) and CD34/prolyl 4-hydroxylase (p < 0.05). In the pulmonary vessels, there was an increase in the endothelial layer in patients (0.31 +/- 0.13%) relative to the controls (0.037 +/- 0.02%) (p < 0.01). There was a significant correlation between the number of fibrocytes and the total area of the endothelial layer CXCR4/prolyl 4-hydroxylase (p < 0.001), CD45R0/prolyl 4-hydroxylase (p < 0.001) and CD34/prolyl 4-hydroxylase (p < 0.01). The percent areas of the lumen of the vessels were significant (p < 0.001) enlarged in the patient with OB compared to the controls. There was also a correlation between total area of the lumen and number of fibrocytes, CXCR4/prolyl 4-hydroxylase (p < 0.01), CD45R0/prolyl 4-hydroxylase (p < 0.001) and CD34/prolyl 4-hydroxylase (p < 0.01). CONCLUSION: Our results indicate that fibrocytes are associated with pathological remodelling processes in patients with OB and that tissue fibrocytes might be a useful biomarker in these processes.
6.	Bateman, Eric D., et al. (author) Overall asthma control achieved with budesonide/formoterol maintenance and reliever therapy for patients on different treatment steps 2011 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 12 Journal article (peer-reviewed)abstract Background: Adjusting medication for uncontrolled asthma involves selecting one of several options from the same or a higher treatment step outlined in asthma guidelines. We examined the relative benefit of introducing budesonide/formoterol (BUD/FORM) maintenance and reliever therapy (Symbicort SMART (R) Turbuhaler (R)) in patients previously prescribed treatments from Global Initiative for Asthma (GINA) Steps 2, 3 or 4. Methods: This is a post hoc analysis of the results of five large clinical trials (> 12000 patients) comparing BUD/FORM maintenance and reliever therapy with other treatments categorised by treatment step at study entry. Both current clinical asthma control during the last week of treatment and exacerbations during the study were examined. Results: At each GINA treatment step, the proportion of patients achieving target levels of current clinical control were similar or higher with BUD/FORM maintenance and reliever therapy compared with the same or a higher fixed maintenance dose of inhaled corticosteroid/long-acting beta(2)-agonist (ICS/LABA) (plus short-acting beta(2)-agonist [SABA] as reliever), and rates of exacerbations were lower at all treatment steps in BUD/FORM maintenance and reliever therapy versus same maintenance dose ICS/LABA (P < 0.01) and at treatment Step 4 versus higher maintenance dose ICS/LABA (P < 0.001). BUD/FORM maintenance and reliever therapy also achieved significantly higher rates of current clinical control and significantly lower exacerbation rates at most treatment steps compared with a higher maintenance dose ICS + SABA (Steps 2-4 for control and Steps 3 and 4 for exacerbations). With all treatments, the proportion of patients achieving current clinical control was lower with increasing treatment steps. Conclusions: BUD/FORM maintenance and reliever therapy may be a preferable option for patients on Steps 2 to 4 of asthma guidelines requiring a more effective treatment and, compared with other fixed dose alternatives, is most effective in the higher treatment steps.
7.	Bryborn, Malin, et al. (author) Comprehensive evaluation of genetic variation in S100A7 suggests an association with the occurrence of allergic rhinitis. 2008 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 9:Mar 28 Journal article (peer-reviewed)abstract BACKGROUND: S100A7 is a calcium-binding protein with chemotactic and antimicrobial properties. S100A7 protein levels are decreased in nasal lavage fluid from individuals with ongoing allergic rhinitis, suggesting a role for S100A7 in allergic airway inflammation. The aims of this study were to describe genetic variation in S100A7 and search for associations between this variation and allergic rhinitis. METHODS: Peripheral blood was collected from 184 atopic patients with a history of pollen-induced allergic rhinitis and 378 non-atopic individuals, all of Swedish origin. DNA was extracted and the S100A7 gene was resequenced in a subset of 47 randomly selected atopic individuals. Nine polymorphisms were genotyped in 184 atopic and 378 non-atopic individuals and subsequently investigated for associations with allergic rhinitis as well as skin prick test results. Haplotypes were estimated and compared in the two groups. RESULTS: Thirteen polymorphisms were identified in S100A7, of which 7 were previously undescribed. rs3014837 (G/C), which gives rise to an Asp --> Glu amino acid shift, had significantly increased minor allele frequency in atopic individuals. The major haplotype, containing the major allele at all sites, was more common in non-atopic individuals, while the haplotype containing the minor allele at rs3014837 was equally more common among the atopic individuals. Additionally, heterozygotes at this site had significantly higher scores in skin prick tests for 9 out of 11 tested allergens, compared to homozygotes. CONCLUSION: This is the first study describing genetic variation, associated with allergy, in S100A7. The results indicate that rs3014837 is linked to allergic rhinitis in our Swedish population and render S100A7 a strong candidate for further investigations regarding its role in allergic inflammation.
8.	Bryborn, Malin, et al. (author) Psoriasin, one of several new proteins identified in nasal lavage fluid from allergic and non-allergic individuals using 2-dimensional gel electrophoresis and mass spectrometry 2005 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 6:118 Journal article (peer-reviewed)abstract Background: Extravasation and luminal entry of plasma occurs continuously in the nose. This process is markedly facilitated in patients with symptomatic allergic rhinitis, resulting in an increased secretion of proteins. Identification of these proteins is an important step in the understanding of the pathological mechanisms in allergic diseases. DNA microarrays have recently made it possible to compare mRNA profiles of lavage fluids from healthy and diseased patients, whereas information on the protein level is still lacking. Methods: Nasal lavage fluid was collected from 11 patients with symptomatic allergic rhinitis and 11 healthy volunteers. 2-dimensional gel electrophoresis was used to separate proteins in the lavage fluids. Protein spots were picked from the gels and identified using mass spectrometry and database search. Selected proteins were confirmed with western blot. Results: 61 spots were identified, of which 21 were separate proteins. 6 of these proteins (psoriasin, galectin-3, alpha enolase, intersectin-2, Wnt-2B and hypothetical protein MGC33648) had not previously been described in nasal lavage fluids. The levels of psoriasin were markedly down-regulated in allergic individuals. Prolactin-inducible protein was also found to be down-regulated, whereas different fragments of albumin together with Ig gamma 2 chain c region, transthyretin and splice isoform 1 of Wnt-2B were up-regulated among the allergic patients. Conclusion: The identification of proteins in nasal lavage fluid with 2-dimensional gelelectrophoresis in combination with mass spectrometry is a novel tool to profile protein expression in allergic rhinitis and it might prove useful in the hunt for new therapeutic targets or diagnostic markers for allergic diseases. Psoriasin is a potent chemotactic factor and its down-regulation during inflammation might be of importance for the outcome of the disease.
9.	Cardell, Lars-Olaf, et al. (author) Downregulation of peroxisome proliferator-activated receptors (PPARs) in nasal polyposis 2005 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 6:1 Journal article (peer-reviewed)abstract Background: Peroxisome proliferator-activated receptor (PPAR) alpha, beta delta and gamma are nuclear receptors activated by fatty acid metabolites. An anti-inflammatory role for these receptors in airway inflammation has been suggested. Methods: Nasal biopsies were obtained from 10 healthy volunteers and 10 patients with symptomatic allergic rhinitis. Nasal polyps were obtained from 22 patients, before and after 4 weeks of local steroid treatment (fluticasone). Real-time RT-PCR was used for mRNA quantification and immunohistochemistry for protein localization and quantification. Results: mRNA expression of PPAR alpha, PPAR beta delta, PPAR gamma was found in all specimens. No differences in the expression of PPARs were obtained in nasal biopsies from patients with allergic rhinitis and healthy volunteers. Nasal polyps exhibited lower levels of PPAR alpha and PPAR gamma than normal nasal mucosa and these levels were, for PPAR gamma, further reduced following steroid treatment. PPAR gamma immunoreactivity was detected in the epithelium, but also found in smooth muscle of blood vessels, glandular acini and inflammatory cells. Quantitative evaluation of the epithelial immunostaining revealed no differences between nasal biopsies from patients with allergic rhinitis and healthy volunteers. In polyps, the PPAR gamma immunoreactivity was lower than in nasal mucosa and further decreased after steroid treatment. Conclusion: The down-regulation of PPAR gamma, in nasal polyposis but not in turbinates during symptomatic seasonal rhinitis, suggests that PPAR gamma might be of importance in long standing inflammations.
10.	Ekberg, Marie, et al. (author) Mortality in GOLD stages of COPD and its dependence on symptoms of chronic bronchitis 2005 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 6, s. 98-106 Journal article (peer-reviewed)abstract Background: The GOLD classification of COPD severity introduces a stage 0 ( at risk) comprising individuals with productive cough and normal lung function. The aims of this study were to investigate total mortality risks in GOLD stages 0 - 4 with special focus on stage 0, and furthermore to assess the influence of symptoms of chronic bronchitis on mortality risks in GOLD stages 1 - 4. Method: Between 1974 and 1992, a total of 22 044 middle-aged individuals participated in a health screening, which included a spirometry as well as recording of respiratory symptoms and smoking habits. Individuals with comorbidity at baseline ( diabetes, stroke, cancer, angina pectoris, or heart infarction) were excluded from the analyses. Hazard ratios (HR 95% CI) of total mortality were analyzed in GOLD stages 0 - 4 with individuals with normal lung function and without symptoms of chronic bronchitis as a reference group. HR: s in smoking individuals with symptoms of chronic bronchitis within the stages 1 - 4 were calculated with individuals with the same GOLD stage but without symptoms of chronic bronchitis as reference. Results: The number of deaths was 3674 for men and 832 for women based on 352 324 and 150 050 person-years respectively. The proportion of smokers among men was 50% and among women 40%. Self reported comorbidity was present in 4.6% of the men and 6.6% of the women. Among smoking men, Stage 0 was associated with an increased mortality risk, HR; 1.65 ( 1.32 - 2.08), of similar magnitude as in stage 2, HR; 1.41 ( 1.31 - 1.70). The hazard ratio in stage 0 was significantly higher than in stage 1 HR; 1.13 ( 0.98 - 1.29). Among male smokers with stage 1; HR: 2.04 ( 1.34 - 3.11), and among female smokers with stage 2 disease; HR: 3.16 ( 1.38 - 7.23), increased HR: s were found in individuals with symptoms of chronic bronchitis as compared to those without symptoms of chronic bronchitis. Conclusion: Symptoms fulfilling the definition of chronic bronchitis were associated with an increased mortality risk among male smokers with normal pulmonary function ( stage 0) and also with an increased risk of death among smoking individuals with mild to moderate COPD ( stage 1 and 2).
11.	Fattahi, Fatemeh, et al. (author) Atopy is a risk factor for respiratory symptoms in COPD patients: results from the EUROSCOP study 2013 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 14 Journal article (peer-reviewed)abstract Background: The pathogenesis of COPD is complex and remains poorly understood. The European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP) investigated long-term effects of budesonide; 18% of the COPD participants were atopic. So far effects of atopy on the long-term course of COPD have not been elucidated. Methods: Factors related to the presence of atopy (positive phadiatop) in 1277 mild-to-moderate COPD patients participating in EUROSCOP were analysed using regression analysis. Incidence and remission of respiratory symptoms during 3-year follow-up were analysed using generalised estimating equations models, and association of atopy with lung function decline using linear mixed effects models. Results: Independent predisposing factors associated with the presence of atopy were: male gender (OR: 2.21; 95% CI: 1.47-3.34), overweight/obese (OR: 1.41; 95% CI: 1.04-1.92) and lower age (OR: 0.98; 95% CI: 0.96-0.99). Atopy was associated with a higher prevalence of cough (OR: 1.71; 95% CI: 1.26-2.34) and phlegm (OR: 1.50; 95% CI: 1.10-2.03), but not with lung function levels or FEV1 decline. Atopic COPD patients not treated with budesonide had an increased incidence of cough over time (OR: 1.79, 95% CI: 1.03-3.08, p = 0.038), while those treated with budesonide had increased remission of cough (OR: 1.93, 95% CI: 1.11-3.37, p = 0.02) compared to non-atopic COPD patients. Conclusions: Atopic COPD patients are more likely male, have overweight/obesity and are younger as compared with non-atopic COPD patients. Atopy in COPD is associated with an increased incidence and prevalence of respiratory symptoms. If atopic COPD patients are treated with budesonide, they more often show remission of symptoms compared to non-atopic COPD patients who are treated with budesonide. We recommend including atopy in the diagnostic work-up and management of COPD.
12.	Fransson, Mattias, et al. (author) Expression of Toll-like receptor 9 in nose, peripheral blood and bone marrow during symptomatic allergic rhinitis. 2007 In: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X .- 1465-9921. ; 8 Journal article (peer-reviewed)abstract BACKGROUND: Allergic rhinitis is an inflammatory disease of the upper airway mucosa that also affects leukocytes in bone marrow and peripheral blood. Toll-like receptor 9 (TLR9) is a receptor for unmethylated CpG dinucleotides found in bacterial and viral DNA. The present study was designed to examine the expression of TLR9 in the nasal mucosa and in leukocytes derived from different cellular compartments during symptomatic allergic rhinitis. METHODS: The study was based on 32 patients with seasonal allergic rhinitis and 18 healthy subjects, serving as controls. Nasal biopsies were obtained before and after allergen challenge. Bone marrow, peripheral blood and nasal lavage fluid were sampled outside and during pollen season. The expression of TLR9 in tissues and cells was analyzed using immunohistochemistry and flow cytometry, respectively. RESULTS: TLR9 was found in several cell types in the nasal mucosa and in different leukocyte subpopulations derived from bone marrow, peripheral blood and nasal lavage fluid. The leukocyte expression was generally higher in bone marrow than in peripheral blood, and not affected by symptomatic allergic rhinitis. CONCLUSION: The widespread expression of TLR9 in the nasal mucosa along with its rich representation in leukocytes in different compartments, demonstrate the possibility for cells involved in allergic airway inflammation to directly interact with bacterial and viral DNA.
13.	Fransson, Mattias, et al. (author) Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis 2005 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 6:100 Journal article (peer-reviewed)abstract BACKGROUND: Toll-like receptors enable the host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharide, viral RNA, CpG-containing DNA and flagellin. Toll-like receptors have also been shown to play a pivotal role in both innate and adaptive immune responses. The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. The present study was designed to examine the expression of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with intermittent allergic rhinitis, focusing on changes induced by exposure to pollen. METHODS: 27 healthy controls and 42 patients with seasonal allergic rhinitis volunteered for the study. Nasal biopsies were obtained before and during pollen season as well as before and after allergen challenge. The seasonal material was used for mRNA quantification of Toll-like receptors 2, 3 and 4 with real-time polymerase chain reaction, whereas specimens achieved in conjunction with allergen challenge were used for immunohistochemical localization and quantification of corresponding proteins. RESULTS: mRNA and protein representing Toll-like receptors 2, 3 and 4 could be demonstrated in all specimens. An increase in protein expression for all three receptors could be seen following allergen challenge, whereas a significant increase of mRNA only could be obtained for Toll-like receptor 3 during pollen season. CONCLUSION: The up-regulation of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with symptomatic allergic rhinitis supports the idea of a role for Toll-like receptors in allergic airway inflammation.
14.	Greiff, Lennart, et al. (author) Effects of a dual CCR3 and H-1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis 2010 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11 Journal article (peer-reviewed)abstract Background: The CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation. Objective: To examine whether a dual CCR3 and H-1-receptor antagonist (AZD3778) affects allergic inflammation and symptoms in allergic rhinitis. Methods: Patients with seasonal allergic rhinitis were subjected to three seven days' allergen challenge series. Treatment with AZD3778 was given in a placebo and antihistamine-controlled design. Symptoms and nasal peak inspiratory flow (PIF) were monitored in the morning, ten minutes post challenge, and in the evening. Nasal lavages were carried out at the end of each challenge series and alpha(2)-macroglobulin, ECP, and tryptase were monitored as indices of allergic inflammation. Results: Plasma levels of AZD3778 were stable throughout the treatment series. AZD3778 and the antihistamine (loratadine) reduced rhinitis symptoms recorded ten minutes post challenge during this period. AZD3778, but not the anti-histamine, also improved nasal PIF ten minutes post challenge. Furthermore, scores for morning and evening nasal symptoms from the last five days of the allergen challenge series showed statistically significant reductions for AZD3778, but not for loratadine. ECP was reduced by AZD3778, but not by loratadine. Conclusions: AZD3778 exerts anti-eosinophil and symptom-reducing effects in allergic rhinitis and part of this effect can likely be attributed to CCR3-antagonism. The present data are of interest with regard to the potential use of AZD3778 in allergic rhinitis and to the relative importance of eosinophil actions to the symptomatology of allergic rhinitis.
15.	Hallberg, Jenny, et al. (author) Genetic and environmental influence on lung function impairment in Swedish twins 2010 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11 Journal article (peer-reviewed)abstract Background: The understanding of the influence of smoking and sex on lung function and symptoms is important for understanding diseases such as COPD. The influence of both genes and environment on lung function, smoking behaviour and the presence of respiratory symptoms has previously been demonstrated for each of these separately. Hence, smoking can influence lung function by co-varying not only as an environmental factor, but also by shared genetic pathways. Therefore, the objective was to evaluate heritability for different aspects of lung function, and to investigate how the estimates are affected by adjustments for smoking and respiratory symptoms. Methods: The current study is based on a selected sample of adult twins from the Swedish Twin Registry. Pairs were selected based on background data on smoking and respiratory symptoms collected by telephone interview. Lung function was measured as FEV1, VC and DLco. Pack years were quantified, and quantitative genetic analysis was performed on lung function data adjusting stepwise for sex, pack years and respiratory symptoms. Results: Fully adjusted heritability for VC was 59% and did not differ by sex, with smoking and symptoms explaining only a small part of the total variance. Heritabilities for FEV1 and DLco were sex specific. Fully adjusted estimates were 10 and 15% in men and 46% and 39% in women, respectively. Adjustment for smoking and respiratory symptoms altered the estimates differently in men and women. For FEV1 and DLco, the variance explained by smoking and symptoms was larger in men. Further, smoking and symptoms explained genetic variance in women, but was primarily associated with shared environmental effects in men. Conclusion: Differences between men and women were found in how smoking and symptoms influence the variation in lung function. Pulmonary gas transfer variation related to the menstrual cycle has been shown before, and the findings regarding DLco in the present study indicates gender specific environmental susceptibility not shown before. As a consequence the results suggest that patients with lung diseases such as COPD could benefit from interventions that are sex specific.
16.	Hallgren, Oskar, et al. (author) Altered fibroblast proteoglycan production in COPD 2010 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11 Journal article (peer-reviewed)abstract Background: Airway remodeling in COPD includes reorganization of the extracellular matrix. Proteoglycans play a crucial role in this process as regulators of the integrity of the extracellular matrix. Altered proteoglycan immunostaining has been demonstrated in COPD lungs and this has been suggested to contribute to the pathogenesis. The major cell type responsible for production and maintenance of ECM constituents, such as proteoglycans, are fibroblasts. Interestingly, it has been proposed that central airways and alveolar lung parenchyma contain distinct fibroblast populations. This study explores the hypothesis that altered depositions of proteoglycans in COPD lungs, and in particular versican and perlecan, is a result of dysregulated fibroblast proteoglycan production. Methods: Proliferation, proteoglycan production and the response to TGF-beta(1) were examined in vitro in centrally and distally derived fibroblasts isolated from COPD patients (GOLD stage IV) and from control subjects. Results: Phenotypically different fibroblast populations were identified in central airways and in the lung parenchyma. Versican production was higher in distal fibroblasts from COPD patients than from control subjects (p < 0.01). In addition, perlecan production was lower in centrally derived fibroblasts from COPD patients than from control subjects (p < 0.01). TGF-beta(1) triggered similar increases in proteoglycan production in distally derived fibroblasts from COPD patients and control subjects. In contrast, centrally derived fibroblasts from COPD patients were less responsive to TGF-beta(1) than those from control subjects. Conclusions: The results show that fibroblasts from COPD patients have alterations in proteoglycan production that may contribute to disease development. Distally derived fibroblasts from COPD patients have enhanced production of versican that may have a negative influence on the elastic recoil. In addition, a lower perlecan production in centrally derived fibroblasts from COPD patients may indicate alterations in bronchial basement membrane integrity in severe COPD.
17.	Larsen, Kristoffer, et al. (author) Functional and phenotypical comparison of myofibroblasts derived from biopsies and bronchoalveolar lavage in mild asthma and scleroderma 2006 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 7 Journal article (peer-reviewed)abstract Background: Activated fibroblasts, which have previously been obtained from bronchoalveolar lavage fluid (BALF), are proposed to be important cells in the fibrotic processes of asthma and scleroderma (SSc). We have studied the motility for BALF derived fibroblasts in patients with SSc that may explain the presence of these cells in the airway lumen. Furthermore, we have compared phenotypic alterations in activated fibroblasts from BALF and bronchial biopsies from patients with mild asthma and SSc that may account for the distinct fibrotic responses. Methods: Fibroblasts were cultured from BALF and bronchial biopsies from patients with mild asthma and SSc. The motility was studied using a cell migration assay. Western Blotting was used to study the expression of alpha-smooth muscle actin (alpha-SMA), ED-A fibronectin, and serine arginine splicing factor 20 (SRp20). The protein expression pattern was analyzed to reveal potential biomarkers using two-dimensional electrophoresis (2-DE) and sequencing dual matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-TOF). The Mann-Whitney method was used to calculate statistical significance. Results: Increased migration and levels of ED-A fibronectin were observed in BALF fibroblasts from both groups of patients, supported by increased expression of RhoA, Rac1, and the splicing factor SRp20. However, these observations were exclusively accompanied by increased expression of alpha-SMA in patients with mild asthma. Compared to BALF fibroblasts in mild asthma, fibroblasts in SSc displayed a differential protein expression pattern of cytoskeletal- and scavenger proteins. These identified proteins facilitate cell migration, oxidative stress, and the excessive deposition of extracellular matrix observed in patients with SSc. Conclusion: This study demonstrates a possible origin for fibroblasts in the airway lumen in patients with SSc and important differences between fibroblast phenotypes in mild asthma and SSc. The findings may explain the distinct fibrotic processes and highlight the motile BALF fibroblast as a potential target cell in these disorders.
18.	Larsson Callerfelt, Anna-Karin, et al. (author) Specific mediator inhibition by the NO donors SNP and NCX 2057 in the peripheral lung: implications for allergen-induced bronchoconstriction. 2009 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 10:Jun 4 Journal article (peer-reviewed)abstract BACKGROUND: The aim of this study was to examine potential therapeutic effect of the two NO donors NCX 2057 (3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid) 4-(nitrooxy)butyl ester) and SNP (sodium nitroprusside) on the early allergic airway response in the peripheral lung. METHODS: The experiments were performed in guinea pig lung parenchyma (GPLP) derived from ovalbumin (OVA) sensitized guinea pigs. The effects of NCX 2057 and SNP were evaluated by contractile responses and mediator release during OVA challenge. The generation of nitrite and nitrate was assessed by chemiluminescence. Statistical analysis was evaluated by ANOVA. RESULTS: Cumulatively increasing concentrations of OVA (1-10,000 ng/ml) induced concentration-dependent contractions of the GPLP that were reduced by NCX 2057 (100 microM, p < 0.001) and SNP (100 microM, p < 0.05). Antigen-induced eicosanoid release was decreased by NCX 2057 (100 microM, p < 0.001) but not by SNP (100 microM), whereas the release of histamine was reduced by SNP (100 microM, p < 0.001) but not by NCX 2057 (100 microM). In addition, NCX 2057 (0.1-100 microM), but not SNP (0.1-100 microM), relaxed leukotriene D4 (10 nM) precontracted GPLP (p < 0.01). The guanylyl cyclase inhibitor ODQ had no effect on the NCX 2057 mediated relaxation. SNP released significantly less nitrite than NCX 2057. CONCLUSION: Although both SNP and NCX 2057 reduced the release of pro-inflammatory mediators, their profiles were distinctly different. Furthermore, NCX 2057 also induced smooth muscle dilation in the GPLP. The findings point to specific anti-inflammatory effects of different NO donors in the peripheral lung tissue.
19.	Lei, Ying, et al. (author) The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice 2008 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 9 Journal article (peer-reviewed)abstract Background: Sidestream smoke is closely associated with airway inflammation and hyperreactivity. The present study was designed to investigate if the Raf-1 inhibitor GW5074 and the anti-inflammatory drug dexamethasone suppress airway hyperreactivity in a mouse model of sidestream smoke exposure. Methods: Mice were repeatedly exposed to smoke from four cigarettes each day for four weeks. After the first week of the smoke exposure, the mice received either dexamethasone intraperitoneally every other day or GW5074 intraperitoneally every day for three weeks. The tone of the tracheal ring segments was recorded with a myograph system and concentration-response curves were obtained by cumulative administration of agonists. Histopathology was examined by light microscopy. Results: Four weeks of exposure to cigarette smoke significantly increased the mouse airway contractile response to carbachol, endothelin-1 and potassium. Intraperitoneal administration of GW5074 or dexamethasone significantly suppressed the enhanced airway contractile responses, while airway epithelium-dependent relaxation was not affected. In addition, the smoke-induced infiltration of inflammatory cells and mucous gland hypertrophy were attenuated by the administration of GW5074 or dexamethasone. Conclusion: Sidestream smoke induces airway contractile hyperresponsiveness. Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.
20.	Mansson Kvarnhammar, Anne, et al. (author) Diminished levels of nasal S100A7 (psoriasin) in seasonal allergic rhinitis: an effect mediated by Th2 cytokines 2012 In: Respiratory Research. - : BioMed Central. - 1465-9921 .- 1465-993X. ; 13:2 Journal article (peer-reviewed)abstract Background: S100A7 is an antimicrobial peptide involved in several inflammatory diseases. The aim of the present study was to explore the expression and regulation of S100A7 in seasonal allergic rhinitis (SAR). less thanbrgreater than less thanbrgreater thanMethods: Nasal lavage (NAL) fluid was obtained from healthy controls before and after lipopolysaccharide (LPS) provocation, from SAR patients before and after allergen challenge, and from SAR patients having completed allergen-specific immunotherapy (ASIT). Nasal biopsies, nasal epithelial cells and blood were acquired from healthy donors. The airway epithelial cell line FaDu was used for in vitro experiments. Real-time RT-PCR and immunohistochemistry were used to determine S100A7 expression in nasal tissue and cells. Release of S100A7 in NAL and culture supernatants was measured by ELISA. The function of recombinant S100A7 was explored in epithelial cells, neutrophils and peripheral blood mononuclear cells (PBMC). less thanbrgreater than less thanbrgreater thanResults: Nasal administration of LPS induced S100A7 release in healthy non-allergic subjects. The level of S100A7 was lower in NAL from SAR patients than from healthy controls, and it was further reduced in the SAR group 6 h post allergen provocation. In contrast, ASIT patients displayed higher levels after completed treatment. S100A7 was expressed in the nasal epithelium and in glands, and it was secreted by cultured epithelial cells. Stimulation with IL-4 and histamine repressed the epithelial S100A7 release. Further, recombinant S100A7 induced activation of neutrophils and PBMC. less thanbrgreater than less thanbrgreater thanConclusions: The present study shows an epithelial expression and excretion of S100A7 in the nose after microbial stimulation. The levels are diminished in rhinitis patients and in the presence of an allergic cytokine milieu, suggesting that the antimicrobial defense is compromised in patients with SAR.
21.	Mared, Lena, et al. (author) Cheyne-Stokes respiration in patients hospitalised for heart failure 2004 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 5:14 Journal article (peer-reviewed)abstract Background: Previous studies showing a strong relationship between Cheyne-Stokes respiration and the severity of left ventricular systolic dysfunction have usually been done in selected patient populations with lower age and a higher proportion of males than the "typical" in-hospital patient with heart failure. The purpose of the present study was test the strength of this relationship in unselected patients admitted to hospital due to decompensated chronic heart failure. Methods: We evaluated 191 patients (32% women), mean age 73 years, ready for discharge from the heart failure unit in the University Hospital of Malmo, Sweden. The patients underwent echocardiography for determination of left ventricular ejection fraction and left ventricular inner diastolic diameter. A respiratory investigation during sleep was performed the last night before discharge. Results: We found that 66% of the patients had Cheyne-Stokes respiration more than 10% of the total recording time. Only 7 (3.6%) of the patients had predominantly obstructive apnoeas. There was a significant but very weak relationship between left ventricular ejection fraction and left ventricular inner diastolic diameter on one hand and Cheyne-Stokes respiration on the other. Age was a stronger determinant of Cheyne-Stokes respiration than any of the cardiac or other clinical variables. Conclusion: Although presence of Cheyne-Stokes respiration indicates left ventricular dysfunction, its severity seems only weakly related to the severity of heart failure. Age was found to be a stronger determinant, which may reflect the underlying age-dependency found also in healthy subjects. Due to age restrictions or other selection criteria, the importance of age may have been underestimated in many previous studies on factors associated with Cheyne-Stokes respiration.
22.	Matheu, Victor, et al. (author) Local therapy with CpG motifs in a murine model of allergic airway inflammation in IFN-beta knock-out mice. 2005 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 6:1, s. 25-25 Journal article (peer-reviewed)abstract BACKGROUND: CpG oligodeoxynucleotides (CpG-ODN) are capable of inducing high amounts of type I IFNs with many immunomodulatory properties. Furthermore, type-I IFNs have been proposed to play a key role in mediating effects of CpG-ODN. The precise role of IFN-beta in the immunomodulatory effects of CpG-ODN is not known. OBJECTIVE: Here, we aimed to elucidate the role of IFN-beta in the anti-allergic effect of CpG motifs. METHODS: We assessed the immune response in OVA-primed/OVA-challenged IFN-beta knockout (-/-) mice compared to wild type (WT) control, after intranasal and systemic treatment with synthetic CpG motifs. RESULTS: Vaccination with CpG-ODN reduced the number of cells in airways of OVA-sensitized WT but not IFN-beta-/- mice. Although airway eosinophilia was reduced in both treated groups, they were significantly higher in IFN-beta-/- mice. Other inflammatory cells, such as lymphocytes and macrophages were enhanced in airways by CpG treatment in IFN-beta-/- mice. The ratio of IFN-gamma/IL-4 cytokines in airways was significantly skewed to a Th1 response in WT compared to IFN-beta-/- group. In contrast, IL-4 and IgE were reduced with no differences between groups. Ag-specific T-cell proliferation, Th1-cytokines such as IFN-gamma, IL-2 and also IL-12 were significantly lower in IFN-beta-/- mice. Surprisingly, we discovered that intranasal treatment of mice with CpG-ODN results in mild synovitis particularly in IFN-beta-/- mice. CONCLUSION: Our results indicate that induction of Th1 response by therapy with CpG-ODN is only slightly and partially dependent on IFN-beta, while IFN-beta is not an absolute requirement for suppression of airway eosinophilia and IgE. Furthermore, our finding of mild synovitis is a warning for possible negative effects of CpG-ODN vaccination.
23.	Mori, Michiko, et al. (author) Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD 2013 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 14 Journal article (peer-reviewed)abstract Background: De novo lymphatic vessel formation has recently been observed in lungs of patients with moderate chronic obstructive pulmonary disease (COPD). However, the distribution of lymphatic vessel changes among the anatomical compartments of diseased lungs is unknown. Furthermore, information regarding the nature of lymphatic vessel alterations across different stages of COPD is missing. This study performs a detailed morphometric characterization of lymphatic vessels in major peripheral lung compartments of patients with different severities of COPD and investigates the lymphatic expression of molecules involved in immune cell trafficking. Methods: Peripheral lung resection samples obtained from patients with mild (GOLD stage I), moderate-severe (GOLD stage II-III), and very severe (GOLD stage IV) COPD were investigated for podoplanin-immunopositive lymphatic vessels in distinct peripheral lung compartments: bronchioles, pulmonary blood vessels and alveolar walls. Control subjects with normal lung function were divided into never smokers and smokers. Lymphatics were analysed by multiple morphological parameters, as well as for their expression of CCL21 and the chemokine scavenger receptor D6. Results: The number of lymphatics increased by 133% in the alveolar parenchyma in patients with advanced COPD compared with never-smoking controls (p < 0.05). In patchy fibrotic lesions the number of alveolar lymphatics increased 20-fold from non-fibrotic parenchyma in the same COPD patients. The absolute number of lymphatics per bronchiole and artery was increased in advanced COPD, but numbers were not different after normalization to tissue area. Increased numbers of CCL21- and D6-positive lymphatics were observed in the alveolar parenchyma in advanced COPD compared with controls (p < 0.01). Lymphatic vessels also displayed increased mean levels of immunoreactivity for CCL21 in the wall of bronchioles (p < 0.01) and bronchiole-associated arteries (p < 0.05), as well as the alveolar parenchyma (p < 0.001) in patients with advanced COPD compared with never-smoking controls. A similar increase in lymphatic D6 immunoreactivity was observed in bronchioles (p < 0.05) and alveolar parenchyma (p < 0.01). Conclusions: This study shows that severe stages of COPD is associated with increased numbers of alveolar lymphatic vessels and a change in lymphatic vessel phenotype in major peripheral lung compartments. This novel histopathological feature is suggested to have important implications for distal lung immune cell traffic in advanced COPD.
24.	Månsson, Anne, et al. (author) Toll-like receptors in cellular subsets of human tonsil T cells: altered expression during recurrent tonsillitis 2006 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 7 Journal article (peer-reviewed)abstract Background: The palatine tonsils have a pivotal role in immunological detection of airborne and ingested antigens like bacteria and viruses. They have recently been demonstrated to express Toll-like receptors ( TLRs), known to recognize molecular structures on such microbes and activate innate immune responses. Their activation might also provide a link between innate and adaptive immunity. In the present study, the expression profile of TLR1-TLR10 was characterized in human tonsil T cells, focusing on differences between subsets of CD4(+) T helper ( Th) cells and CD8(+) cytotoxic T lymphocytes (CTL). The study was also designed to compare the TLR expression in T cells from patients with recurrent tonsillitis and tonsillar hyperplasia. Methods: Tonsils were obtained from children undergoing tonsillectomy, and classified according to the clinical diagnoses and the outcome of tonsillar core culture tests. Two groups were defined; recurrently infected tonsils and hyperplastic tonsils that served as controls. Subsets of T cells were isolated using magnetic beads. The expression of TLR transcripts in purified cells was assessed using quantitative real-time RT-PCR. The corresponding protein expression was investigated using flow cytometry and immunohistochemistry. Results: T cells expressed a broad repertoire of TLRs, in which TLR1, TLR2, TLR5, TLR9 and TLR10 predominated. Also, a differential expression of TLRs in CD4(+) and CD8(+) T cells was obtained. TLR1 and TLR9 mRNA was expressed to a greater extent in CD4+ cells, whereas expression of TLR3 mRNA and protein and TLR4 protein was higher in CD8(+) cells. CD8(+) cells from infected tonsils expressed higher levels of TLR2, TLR3 and TLR5 compared to control. In contrast, CD4(+) cells exhibited a down-regulated TLR9 as a consequence of infection. Conclusion: The present study demonstrates the presence of a broad repertoire of TLRs in T cells, a differential expression in CD4(+) and CD8(+) cells, along with infection-dependent alterations in TLR expression. Collectively, these results support the idea that TLRs are of importance to adaptive immune cells. It might be that TLRs have a direct role in adaptive immune reactions against infections. Thus, further functional studies of the relevance of TLR stimulation on T cells will be of importance.
25.	Nihlberg, Kristian, et al. (author) Tissue fibrocytes in patients with mild asthma: A possible link to thickness of reticular basement membrane? 2006 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 7 Journal article (peer-reviewed)abstract Background: Myofibroblasts, proposed as being derived from circulating fibrocytes, are considered to be important cells in thickening of the basement membrane in patients with asthma. We have studied the correlation of tissue fibrocyte levels to basement membrane thickness and the presence of fibrocytes in bronchoalveolar lavage fluid (BALF) in steroid-naive patients with mild asthma and controls. Methods: Patients with mild asthma (n=9) were recruited and divided into two categories based on whether or not fibroblast-like cells could be established from BALF. Non-asthmatic healthy subjects (n=5) were used as controls. Colocalization of the fibrocyte markers CD34, CD45RO, procollagen I, and alpha-smooth muscle actin (alpha-SMA) were identified in bronchial biopsies from patients and controls by confocal microscopy. Kruskall-Wallis method was used to calculate statistical significance and Spearman coefficient of rank correlation was used to assess the degree of association. Results: In patients with BALF fibroblasts, a 14-fold increase of tissue cells expressing CD34/CD45RO/alpha-SMA and a 16-fold increase of tissue cells expressing CD34/procollagen I was observed when compared to controls (p<0.05). In contrast, patients without BALF fibroblasts displayed a 2-fold increase when compared to controls (p<0.05). Fibrocytes were localized close to the basement membrane which was significantly thicker in patients with BALF fibroblasts when compared to the other two groups of subjects. Furthermore, basement membrane thickness could be correlated to the number of fibrocytes in tissue (r=0.711). Fibroblasts-like cells were cultured from BALF where 17.6% of these cells expressed CD34, CD45RO and alpha-SMA. Conclusion: These findings indicate a correlation between recruited fibrocytes in tissue and thickness of basement membrane. Fibroblast progenitor cells may therefore be important in airway remodeling in steroid-naive patients with mild asthma.
26.	Nita, Izabela, et al. (author) Prolastin, a pharmaceutical preparation of purified human alpha 1-antitrypsin, blocks endotoxin-mediated cytokine release 2005 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 6:12 Journal article (peer-reviewed)abstract Background: alpha 1-antitrypsin (AAT) serves primarily as an inhibitor of the elastin degrading proteases, neutrophil elastase and proteinase 3. There is ample clinical evidence that inherited severe AAT deficiency predisposes to chronic obstructive pulmonary disease. Augmentation therapy for AAT deficiency has been available for many years, but to date no sufficient data exist to demonstrate its efficacy. There is increasing evidence that AAT is able to exert effects other than protease inhibition. We investigated whether Prolastin, a preparation of purified pooled human AAT used for augmentation therapy, exhibits antibacterial effects. Methods: Human monocytes and neutrophils were isolated from buffy coats or whole peripheral blood by the Ficoll-Hypaque procedure. Cells were stimulated with lipopolysaccharide (LPS) or zymosan, either alone or in combination with Prolastin, native AAT or polymerised AAT for 18 h, and analysed to determine the release of TNF alpha, IL-1 beta and IL-8. At 2-week intervals, seven subjects were submitted to a nasal challenge with sterile saline, LPS ( 25 mu g) and LPS-Prolastin combination. The concentration of IL-8 was analysed in nasal lavages performed before, and 2, 6 and 24 h after the challenge. Results: In vitro, Prolastin showed a concentration-dependent (0.5 to 16 mg/ml) inhibition of endotoxin-stimulated TNF alpha and IL-1 beta release from monocytes and IL-8 release from neutrophils. At 8 and 16 mg/ml the inhibitory effects of Prolastin appeared to be maximal for neutrophil IL- 8 release (5.3-fold, p < 0.001 compared to zymosan treated cells) and monocyte TNFa and IL- 1 release (10.7- and 7.3-fold, p < 0.001, respectively, compared to LPS treated cells). Furthermore, Prolastin (2.5 mg per nostril) significantly inhibited nasal IL- 8 release in response to pure LPS challenge. Conclusion: Our data demonstrate for the first time that Prolastin inhibits bacterial endotoxin-induced pro-inflammatory responses in vitro and in vivo, and provide scientific bases to explore new Prolastin-based therapies for individuals with inherited AAT deficiency, but also for other clinical conditions.
27.	Parr, David G., et al. (author) Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency 2009 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 10 Journal article (peer-reviewed)abstract Background: Computed tomography (CT) lung densitometry has been demonstrated to be the most sensitive and specific outcome measure for the assessment of emphysema-modifying therapy, but the optimum densitometric index has yet to be determined and targeted sampling may be more sensitive than whole lung assessment. The EXAcerbations and CT scan as Lung Endpoints (EXACTLE) trial aimed to clarify the optimum approach to the use of CT densitometry data for the assessment of alpha 1-antitrypsin (AAT) augmentation therapy on the progression of emphysema in AAT deficiency (AATD). Methods: Patients with AATD (n = 77) were randomised to weekly infusions of 60 mg/kg human AAT (Prolastin (R)) or placebo over 2 to 2.5 years. Lung volume was included as a covariate in an endpoint analysis and a comparison was made of different CT densitometric indices (15th percentile lung density [PD15], mean lung density [MLD] and voxel index at a threshold of -910 [VI-910] and -950 [VI-950] Hounsfield Units) obtained from whole lung scans at baseline and at 24 to 30 months. Targeted regional sampling was compared with whole lung assessment. Results: Whole lung analysis of the total change (baseline to last CT scan) compared with placebo indicated a concordant trend that was suggestive of a treatment effect for all densitometric indices (MLD [1.402 g/L, p = 0.204]; VI-910 [-0.611, p = 0.389]; VI-950 [-0.432, p = 0.452]) and that was significant using PD15 (1.472 g/L, p = 0.049). Assessment of the progression of emphysema in the apical, middle and basal regions of the lung by measurement with PD15 showed that this treatment effect was more evident when the basal third was sampled (1.722 g/L, p = 0.040). A comparison between different densitometric indices indicated that the influence of inspiratory variability between scans was greatest for PD15, but when adjustment for lung volume was made this index was the most sensitive measure of emphysema progression. Conclusion: PD15 is the most sensitive index of emphysema progression and of treatment modification. Targeted sampling may be more sensitive than whole lung analysis. Trial registration: Registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.
28.	Persson, Carl, et al. (author) Resolution of cell-mediated airways diseases 2010 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11 Research review (peer-reviewed)abstract "Inflammation resolution" has of late become a topical research area. Activation of resolution phase mechanisms, involving select post-transcriptional regulons, transcription factors, 'autacoids', and cell phenotypes, is now considered to resolve inflammatory diseases. Critical to this discourse on resolution is the elimination of inflammatory cells through apoptosis and phagocytosis. For major inflammatory diseases such as asthma and COPD we propose an alternative path to apoptosis for cell elimination. We argue that transepithelial migration of airway wall leukocytes, followed by mucociliary clearance, efficiently and non-injuriously eliminates pro-inflammatory cells from diseased airway tissues. First, it seems clear that numerous infiltrated granulocytes and lymphocytes can be speedily transmitted into the airway lumen without harming the epithelial barrier. Then there are a wide range of 'unexpected' findings demonstrating that clinical improvement of asthma and COPD is not only associated with decreasing numbers of airway wall inflammatory cells but also with increasing numbers of these cells in the airway lumen. Finally, effects of inhibition of transepithelial migration support the present hypothesis. Airway inflammatory processes have thus been much aggravated when transepithelial exit of leukocytes has been inhibited. In conclusion, the present hypothesis highlights risks involved in drug-induced inhibition of transepithelial migration of airway wall leukocytes. It helps interpretation of common airway lumen data, and suggests approaches to treat cell-mediated airway inflammation.
29.	Rydell-Törmänen, Kristina, et al. (author) Remodeling of extra-bronchial lung vasculature following allergic airway inflammation. 2008 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 9:18, FEb 8 Journal article (peer-reviewed)abstract BACKGROUND: We previously observed that allergen-exposed mice exhibit remodeling of large bronchial-associated blood vessels. The aim of the study was to examine whether vascular remodeling occurs also in vessels where a spill-over effect of bronchial remodeling molecules is less likely. METHODS: We used an established mouse model of allergic airway inflammation, where an allergic airway inflammation is triggered by inhalations of OVA. Remodeling of bronchial un-associated vessels was determined histologically by staining for alpha-smooth muscle actin, procollagen I, Ki67 and von Willebrand-factor. Myofibroblasts were defined as and visualized by double staining for alpha-smooth muscle actin and procollagen I. For quantification the blood vessels were divided, based on length of basement membrane, into groups; small (
30.	Sandström, Caroline, et al. (author) Endotoxin receptor CD14 in PiZ alpha-1-antitrypsin deficiency individuals 2008 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 9:34 Journal article (peer-reviewed)abstract Background: CD14, a receptor for lipopolysaccharides (LPS), is found in both a membrane-bound form (mCD14) and a soluble form (sCD14). It is suggested that sCD14 is mainly released from blood monocytes by serine protease-mediated shedding. Because alpha(1)-antitrypsin (AAT), an inhibitor of serine proteases, has been shown to regulate CD14 expression in human monocytes in vitro, we sought to investigate plasma levels of sCD14 and monocyte expression of mCD14 in subjects at age 30 years with normal MM and deficient PiZZ and PiSZ genotypes of AAT. Methods: Plasma levels of AAT and sCD14 were measured in 75 PiZZ and 34 PiSZ individuals with normal lung function identified from the Swedish neonatal AAT deficiency screening, and in 95 age matched PiMM controls. The mCD14 expression in monocytes from 9 PiZZ, 6 PiSZ and 11 PiMM subjects was analysed by FACS and Quantitative Real Time Reverse Transcription PCA. Results: As expected, plasma AAT concentrations were PiMM > PiSZ > PiZZ (p < 0.001). Plasma sCD14 levels were higher in PiZZ than in PiMM subjects (p < 0.01). The expression level of mCD14 was higher (1.89-fold) in monocytes isolated from PiZZ subjects compared to PiMM controls (p = 0.00189). Conclusion: This study is the first to show higher levels of plasma sCD14 and monocyte mCD14 expression in young, clinically healthy PiZZ AAT subjects.
31.	Stockley, Robert A., et al. (author) Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry 2010 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11 Journal article (peer-reviewed)abstract Background: Two randomised, double-blind, placebo-controlled trials have investigated the efficacy of IV alpha-1 antitrypsin (AAT) augmentation therapy on emphysema progression using CT densitometry. Methods: Data from these similar trials, a 2-center Danish-Dutch study (n = 54) and the 3-center EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (n = 65), were pooled to increase the statistical power. The change in 15(th) percentile of lung density (PD15) measured by CT scan was obtained from both trials. All subjects had 1 CT scan at baseline and at least 1 CT scan after treatment. Densitometric data from 119 patients (AAT [Alfalastin (R) or Prolastin (R)], n = 60; placebo, n = 59) were analysed by a statistical/endpoint analysis method. To adjust for lung volume, volume correction was made by including the change in log-transformed total lung volume as a covariate in the statistical model. Results: Mean follow-up was approximately 2.5 years. The mean change in lung density from baseline to last CT scan was -4.082 g/L for AAT and -6.379 g/L for placebo with a treatment difference of 2.297 (95% CI, 0.669 to 3.926; p = 0.006). The corresponding annual declines were -1.73 and -2.74 g/L/yr, respectively. Conclusions: The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency-related emphysema.
32.	Tanash, Hanan, et al. (author) Survival in severe alpha-1-antitrypsin deficiency (PiZZ) 2010 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11 Journal article (peer-reviewed)abstract Background: Previous studies of the natural history of alpha-1-antitrypsin (AAT) deficiency are mostly based on highly selected patients. The aim of this study was to analyse the mortality of PiZZ individuals. Methods: Data from 1339 adult PiZZ individuals from the Swedish National AAT Deficiency Registry, followed from 1991 to 2008, were analysed. Forty-three percent of these individuals were identified by respiratory symptoms (respiratory cases), 32% by liver diseases and other diseases (non-respiratory cases) and 25% by screening (screened cases). Smoking status was divided into two groups: smokers 737 (55%) and 602 (45%) never-smokers. Results: During the follow-up 315 individuals (24%) died. The standardised mortality rate (SMR) for respiratory cases was 4.70 (95% Confidence Interval (CI) 4.10-5.40), 3.0 (95% CI 2.35-3.70) for the non-respiratory cases and 2.30 (95% CI 1.46-3.46) for the screened cases. The smokers had a higher mortality risk than never-smokers, with a SMR of 4.80 (95% CI 4.20-5.50) for the smokers and 2.80(95% CI 2.30-3.40) for the never-smokers. The Rate Ratio (RR) was 1.70 (95% CI 1.35-2.20). Also among the screened cases, the mortality risk for the smokers was significantly higher than in the general Swedish population (SMR 3.40 (95% CI 1.98-5.40). Conclusion: Smokers with severe AAT deficiency, irrespective of mode of identification, have a significantly higher mortality risk than the general Swedish population.
33.	Uller, Lena, et al. (author) Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation. 2007 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 8:16 Journal article (peer-reviewed)abstract Background: Mast cell-derived prostaglandin D-2 (PGD(2)), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity receptor for prostaglandin D-2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology. Methods: Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A(2) receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. Results: TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia. Conclusion: This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban.
34.	Uller, Lena, et al. (author) Early phase resolution of mucosal eosinophilic inflammation in allergic rhinitis. 2010 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11:1 Journal article (peer-reviewed)abstract BACKGROUND: It is widely assumed that apoptosis of eosinophils is a central component of resolution of allergic airway disease. However, this has not been demonstrated in human allergic airways in vivo. Based on animal in vivo observations we hypothesised that steroid-induced resolution of human airway eosinophilic inflammation involves inhibition of CCL5 (RANTES), a CC-chemokine regulating eosinophil and lymphocyte traffic, and elimination of eosinophils without evident occurrence of apoptotic eosinophils in the diseased tissue. OBJECTIVE: To determine mucosal eosinophilia, apoptotic eosinophils, general cell apoptosis and cell proliferation, and expression of CCL5 and CCL11 (eotaxin) in human allergic airway tissues in vivo at resolution of established symptomatic eosinophilic inflammation. METHODS: Twenty-one patients with intermittent (birch and/or grass) allergic rhinitis received daily nasal allergen challenges for two seven days' periods separated by more than two weeks washout. Five days into these "artificial pollen seasons", nasal treatment with budesonide was instituted and continued for six days in a double blinded, randomized, placebo-controlled, and crossover design. This report is a parallel group comparison of nasal biopsy histochemistry data obtained on the final day of the second treatment period. RESULTS: Treatments were instituted when clinical rhinitis symptoms had been established. Compared to placebo, budesonide reduced tissue eosinophilia, and subepithelial more than epithelial eosinophilia. Steroid treatment also attenuated tissue expression of CCL5, but CCL11 was not reduced. General tissue cell apoptosis and epithelial cell proliferation were reduced by budesonide. However, apoptotic eosinophils were not detected in any biopsies, irrespective of treatment. CONCLUSIONS: Inhibition of CCL5-dependent recruitment of cells to diseased airway tissue, and reduced cell proliferation, reduced general cell apoptosis, but not increased eosinophil apoptosis, are involved in early phase steroid-induced resolution of human allergic rhinitis.
35.	Widegren, Henrik, et al. (author) Effects of intranasal TNFalpha on granulocyte recruitment and activity in healthy subjects and patients with allergic rhinitis. 2008 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 9:15 Journal article (peer-reviewed)abstract BACKGROUND: TNFalpha may contribute to the pathophysiology of airway inflammation. For example, we have recently shown that nasal administration of TNFalpha produces late phase co-appearance of granulocyte and plasma exudation markers on the mucosal surface. The objective of the present study was to examine indices of granulocyte presence and activity in response to intranasal TNFalpha challenge. METHODS: Healthy subjects and patients with allergic rhinitis (examined out of season) were subjected to nasal challenge with TNFalpha (10 microg) in a sham-controlled and crossover design. Nasal lavages were carried out prior to and 24 hours post challenge. Nasal biopsies were obtained post challenge. Nasal lavage fluid levels of myeloperoxidase (MPO) and eosinophil cationic protein (ECP) were analyzed as indices of neutrophil and eosinophil activity. Moreover, IL-8 and alpha2-macroglobulin were analyzed as markers of pro-inflammatory cytokine production and plasma exudation. Nasal biopsy numbers of neutrophils and eosinophils were monitored. RESULTS: Nasal lavage fluid levels of MPO recorded 24 hours post TNFalpha challenge were increased in healthy subjects (p = 0.0081) and in patients with allergic rhinitis (p = 0.0081) (c.f. sham challenge). Similarly, alpha2-macroglobulin was increased in healthy subjects (p = 0.014) and in patients with allergic rhinitis (p = 0.0034). Lavage fluid levels of ECP and IL-8 were not affected by TNFalpha challenge. TNFalpha increased the numbers of subepithelial neutrophils (p = 0.0021), but not the numbers of eosinophils. CONCLUSION: TNFalpha produces a nasal inflammatory response in humans that is characterised by late phase (i.e., 24 hours post challenge) neutrophil activity and plasma exudation.
36.	Zhang, Yaping, et al. (author) IL-1 beta induces murine airway 5-HT2A receptor hyperresponsiveness via a non-transcriptional MAPK-dependent mechanism 2007 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 8 Journal article (peer-reviewed)abstract Background: Interleukin 1 beta ( IL- I beta) is found in bronchoalveolar lavage fluids from asthmatic patients and plays an important role in normal immunoregulatory processes but also in pathophysiological inflammatory responses. The present study was designed to investigate if IL- I beta could be involved in the development of airway hyperresponsiveness and if transcriptional mechanisms, epithelium contractile factors and mitogen-activated protein kinase ( MAPK) pathways are involved in IL- I beta effect. Methods: The effect of IL- I beta on 5-hydroxytryptamine ( 5- HT) induced bronchoconstriction was evaluated in an in-vitro model for assessment of long-term effects of inflammatory mediators on the airway smooth muscle. Murine tracheal segments were cultured up to 8 days in the absence or presence of IL- I beta with subsequent evaluation in a myograph system, along with mRNA quantification, focusing on the role of the epithelium, acetylcholine release, transcriptional mechanisms and MAPK activity. Results: During control conditions, 5- HT induced a relatively weak contraction. Presence of IL- I beta increased this response in a time-and concentration-dependent way. The increased concentration-effect curves could be shifted rightwards in a parallel manner by ketanserin, a selective 5- HT2A receptor antagonist, indicating that the responses are mediated by 5- HT2A receptors. The mRNA levels of 5- HT2A receptors were not changed as a consequence of the IL- I beta treatment and actinomycin D, a general transcriptional inhibitor, failed to affect the contractile response, suggesting a non-transcriptional mechanism behind this phenomenon. Neither the removal of the epithelium nor the addition of atropine affected the IL- I beta induced enhancement of 5- HT2A receptor-mediated contractile response. Application of inhibitors for c-Jun N-terminal kinase ( JNK), p38 and extracellular signal-regulated kinase 1 and 2 ( ERK1/2) showed that the signaling pathways for JNK and ERK1/2 dominated only in cultured segments ( control) whereas JNK and p38 dominated in segments treated with IL- I beta. Conclusion: IL- I beta induces murine airway hyperresponsiveness, via a non-transcriptional up-regulation of 5- HT2A receptor-mediated contractile response. The increase of 5- HT contraction is unrelated to epithelial and cholinergic factors, but is dependent on IL- I beta- induced changes of MAPK pathways. The fact that IL- I beta can alter airway responses to contractile agents such as 5- HT, via alteration of the intracellular MAPK signal transduction pathways, might provide a new concept for future treatment of asthma.
37.	Mincheva, Roxana, 1986, et al. (author) Frequent cough in unsatisfactory controlled asthma - results from the population-based West Sweden Asthma Study 2014 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-993X .- 1465-9921. ; 15:79 Journal article (peer-reviewed)abstract Background: Asthma is a complex disease presenting with variable symptoms which are sometimes hard to control. The purpose of the study was to describe the prevalence of asthma symptoms, use of asthma medications and allergic sensitization in subjects with asthma. We also related those indices to the level of asthma control, lung function and in particular, cough. Methods: An extensive questionnaire was sent to randomly selected adults from the West Sweden region. Clinical examinations and interview were performed in a subset. Of the participants, 744 were defined as having an ongoing asthma - reported ever having asthma or physician diagnosed asthma and one of the following - use of asthma medications, recurrent wheeze or attacks of shortness of breath with or without wheeze in the last 12 months. A respiratory disease-free control group of 847 subjects was also described. Results: According to GINA guidelines, 40.6% of the asthmatics had partly controlled and 17.8% had uncontrolled asthma. Asthmatic subjects reported significantly more symptoms in the last 12 months than the control group - wheezing (79.4 vs 9.2%), shortness of breath (36.1 vs 2.5%), wheezing with shortness of breath (58.7 vs 1.3%). Important complaints were morning cough (42.5 vs 15.5%), cough with sputum production (36.1 vs 6.8%) and longstanding cough (32.5 vs 11.1%), which bothered two thirds of the uncontrolled and one third of partly controlled subjects. Asthma medications were used by 87.5% of the asthmatics, although around 30% of them who had insufficiently controlled disease used only short-acting beta-agonists. Asthmatics also had lower lung function, reacted to lower doses of methacholine that the controls and 13.6% of them had a FEV1/FVC ratio below 0.7. Allergic rhinitis was reported by 73.8% of the asthmatics and they were more frequently sensitized to several common allergens. Conclusions: Approximately 60% of asthmatics from this population-based study had insufficiently controlled asthma and persistent complaints, despite a high use of asthma medications. These self-reported symptoms were supported by clinical examination data. Increased cough frequency is an indicator of a more severe and difficult to control disease and should be considered when asthma is characterized.
38.	Rydell-Törmänen, Kristina, et al. (author) Neutrophil cannibalism--a back up when the macrophage clearance system is insufficient. 2006 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 7:143, s. 143-143 Journal article (peer-reviewed)abstract Background: During a lipopolysaccharide-induced lung inflammation, a massive accumulation of neutrophils occurs, which is normally cleared by macrophage phagocytosis following neutrophil apoptosis. However, in cases of extensive apoptosis the normal clearance system may fail, resulting in extensive neutrophil secondary necrosis. The aim of this study was to explore the hypothesis that neutrophils, in areas of the lung with extensive cellular infiltration, contribute to clearance by phagocytosing apoptotic cells and/or cell debris derived from secondary necrosis. Methods: Intranasal lipopolysaccharide administration was used to induce lung inflammation in mice. The animals were sacrificed at seven time points following administration, bronchoalveolar lavage was performed and tissue samples obtained. Electron microscopy and histochemistry was used to assess neutrophil phagocytosis. Results: Electron microscopic studies revealed that phagocytosing neutrophils was common, at 24 h after LPS administration almost 50% of the total number of neutrophils contained phagosomes, and the engulfed material was mainly derived from other neutrophils. Histochemistry on bronchoalvolar lavage cells further showed phagocytosing neutrophils to be frequently occurring. Conclusion: Neutrophils are previously known to phagocytose invading pathogens and harmful particles. However, this study demonstrates that neutrophils are also able to engulf apoptotic neutrophils or cell debris resulting from secondary necrosis of neutrophils. Neutrophils may thereby contribute to clearance and resolution of inflammation, thus acting as a back up system in situations when the macrophage clearance system is insufficient and/or overwhelmed.
39.	Amin, Kawa, et al. (author) Uncoordinated production of Laminin-5 chains in airways epithelium of allergic asthmatics 2005 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 6, s. 110- Journal article (peer-reviewed)abstract BACKGROUND: Laminins are a group of proteins largely responsible for the anchorage of cells to basement membranes. We hypothesized that altered Laminin chain production in the bronchial mucosa might explain the phenomenon of epithelial cell shedding in asthma. The aim was to characterize the presence of Laminin chains in the SEBM and epithelium in allergic and non-allergic asthmatics.PATIENTS AND METHODS: Biopsies were taken from the bronchi of 11 patients with allergic and 9 patients with non-allergic asthma and from 7 controls and stained with antibodies against the Laminin (ln) chains alpha1-alpha5, beta1-beta2 and gamma1-gamma2.RESULTS: Lns-2,-5 and -10 were the main Laminins of SEBM. The layer of ln-10 was thicker in the two asthmatic groups while an increased thickness of lns-2 and -5 was only seen in allergic asthmatics. The ln gamma2-chain, which is only found in ln 5, was exclusively expressed in epithelial cells in association with epithelial injury and in the columnar epithelium of allergic asthmatics.CONCLUSION: The uncoordinated production of chains of ln-5 in allergic asthma could have a bearing on the poor epithelial cell anchorage in these patients.
40.	Andersson, Mikael, et al. (author) Physical activity level and its clinical correlates in chronic obstructive pulmonary disease : a cross-sectional study 2013 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 14, s. 128- Journal article (peer-reviewed)abstract Background: Decreased physical activity is associated with higher mortality in subjects with COPD. The aim of this study was to assess clinical characteristics and physical activity levels (PALs) in subjects with COPD. Methods: Seventy-three subjects with COPD (67 +/- 7 yrs, 44 female) with one-second forced expiratory volume percentage (FEV1%) predicted values of 43 +/- 16 were included. The ratio of total energy expenditure (TEE) and resting metabolic rate (RMR) was used to define the physical activity level (PAL) (PAL = TEE/RMR). TEE was assessed with an activity monitor (ActiReg), and RMR was measured by indirect calorimetry. Walking speed (measured over 30-meters), maximal quadriceps muscle strength, fat-free mass and systemic inflammation were measured as clinical characteristics. Hierarchical linear regression was applied to investigate the explanatory values of the clinical correlates to PAL. Results: The mean PAL was 1.47 +/- 0.19, and 92% of subjects were classified as physically very inactive or sedentary. The walking speed was 1.02 +/- 0.23 m/s, the quadriceps strength was 31.3 +/- 11.2 kg, and the fat-free mass index (FFMI) was 15.7 +/- 2.3 kg/m(2), identifying 42% of subjects as slow walkers, 21% as muscle-weak and 49% as FFM-depleted. The regression model explained 45.5% (p < 0.001) of the variance in PAL. The FEV1% predicted explained the largest proportion (22.5%), with further improvements in the model from walking speed (10.1%), muscle strength (7.0%) and FFMI (3.0%). Neither age, gender nor systemic inflammation contributed to the model. Conclusions: Apart from lung function, walking speed and muscle strength are important correlates of physical activity. Further explorations of the longitudinal effects of the factors characterizing the most inactive subjects are warranted.
41.	Arnardóttir, Ragnheiður Harpa, et al. (author) Peak exercise capacity estimated from incremental shuttle walking test in patients with COPD: A methodological study 2006 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 7, s. 127- Journal article (peer-reviewed)abstract Background: In patients with COPD, both laboratory exercise tests and field walking tests are used to assess physical performance. In laboratory tests, peak exercise capacity in watts ( W peak) and/or peak oxygen uptake (VO2 peak) are assessed, whereas the performance on walking tests usually is expressed as distance walked. The aim of the study was to investigate the relationship between an incremental shuttle walking test (ISWT) and two laboratory cycle tests in order to assess whether W peak could be estimated from an ISWT.Methods: Ninety-three patients with moderate or severe COPD performed an ISWT, an incremental cycle test (ICT) to measure W peak and a semi-steady-state cycle test with breath-by-breath gas exchange analysis (CPET) to measure VO2 peak. Routine equations for conversion between cycle tests were used to estimate W peak from measured VO2 peak (CPET). Conversion equation for estimation of W peak from ISWT was found by univariate regression.Results: There was a significant correlation between W peak and distance walked on ISWT x body weight (r=0.88, p<0.0001). The agreement between W peak measured by ICT and estimated from ISWT was similar to the agreement between measured W peak (ICT) and W peak estimated from measured VO2 peak by CPET.Conclusion: Peak exercise capacity measured by an incremental cycle test could be estimated from an ISWT with similar accuracy as when estimated from peak oxygen uptake in patients with COPD.
42.	Blidberg, K, et al. (author) Adhesion molecules in subjects with COPD and healthy non-smokers: a cross sectional parallel group study 2013 In: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X .- 1465-9921. ; 14, s. 47- Journal article (peer-reviewed)
43.	Byström, Jonas, et al. (author) Analysing the eosinophil cationic protein - a clue to the function of the eosinophil granulocyte 2011 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 12, s. 10- Research review (peer-reviewed)abstract Eosinophil granulocytes reside in respiratory mucosa including lungs, in the gastro-intestinal tract, and in lymphocyte associated organs, the thymus, lymph nodes and the spleen. In parasitic infections, atopic diseases such as atopic dermatitis and asthma, the numbers of the circulating eosinophils are frequently elevated. In conditions such as Hypereosinophilic Syndrome (HES) circulating eosinophil levels are even further raised. Although, eosinophils were identified more than hundred years ago, their roles in homeostasis and in disease still remain unclear. The most prominent feature of the eosinophils are their large secondary granules, each containing four basic proteins, the best known being the eosinophil cationic protein (ECP). This protein has been developed as a marker for eosinophilic disease and quantified in biological fluids including serum, bronchoalveolar lavage and nasal secretions. Elevated ECP levels are found in T helper lymphocyte type 2 (atopic) diseases such as allergic asthma and allergic rhinitis but also occasionally in other diseases such as bacterial sinusitis. ECP is a ribonuclease which has been attributed with cytotoxic, neurotoxic, fibrosis promoting and immune-regulatory functions. ECP regulates mucosal and immune cells and may directly act against helminth, bacterial and viral infections. The levels of ECP measured in disease in combination with the catalogue of known functions of the protein and its polymorphisms presented here will build a foundation for further speculations of the role of ECP, and ultimately the role of the eosinophil.
44.	Darlington, P, et al. (author) Cardiac involvement in Caucasian patients with pulmonary sarcoidosis 2014 In: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X .- 1465-9921. ; 15, s. 15- Journal article (peer-reviewed)
45.	Eliason, Gabriella, 1975-, et al. (author) Alterations in the muscle-to-capillary interface in patients with different degrees of chronic obstructive pulmonary disease 2010 In: Respiratory Research. - London, United Kingdom : BioMed Central. - 1465-9921 .- 1465-993X. ; 11 Journal article (peer-reviewed)abstract Background: It is hypothesized that decreased capillarization of limb skeletal muscle is implicated in the decreased exercise tolerance in COPD patients. We have recently demonstrated decreased number of capillaries per muscle fibre (CAF) but no changes in CAF in relation to fibre area (CAFA), which is based on the diffusion distance between the capillary and muscle fibre. The aim of the current study is to investigate the muscle-to-capillary interface which is an important factor involved in oxygen supply to the muscle that has previously been suggested to be a more sensitive marker for changes in the capillary bed compared to CAF and CAFA.Methods: 23 COPD patients and 12 age-matched healthy subjects participated in the study. Muscle-to-capillary interface was assessed in muscle biopsies from the tibialis anterior muscle using the following parameters:1) The capillary-to-fibre ratio (C:Fi) which is defined as the sum of the fractional contributions of all capillary contacts around the fibre2) The ratio between C:Fi and the fibre perimeter (CFPE-index)3) The ratio between length of capillary and fibre perimeter (LC/PF) which is also referred to as the index of tortuosity.Exercise capacity was determined using the 6-min walking test. Results: A positive correlation was found between CFPE-index and ascending disease severity with CFPE-index for type I fibres being significantly lower in patients with moderate and severe COPD. Furthermore, a positive correlation was observed between exercise capacity and CFPE-index for both type I and type IIa fibres.Conclusion: It can be concluded that the muscle-to-capillary interface is disturbed in the tibialis anterior muscle in patients with COPD and that interface is strongly correlated to increased disease severity and to decreased exercise capacity in this patient group.
46.	Franklin, Karl, et al. (author) Early life environment and snoring in adulthood 2008 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 9:1, s. 63- Journal article (peer-reviewed)abstract BACKGROUND: To our knowledge, no studies of the possible association of early life environment with snoring in adulthood have been published. We aimed to investigate whether early life environment is associated with snoring later in life. METHODS: A questionnaire including snoring frequency in adulthood and environmental factors in early life was obtained from 16,190 randomly selected men and women, aged 25-54 years, in Sweden, Norway, Iceland, Denmark and Estonia (response rate 74%). RESULTS: A total of 15,556 subjects answered the questions on snoring. Habitual snoring, defined as loud and disturbing snoring at least 3 nights a week, was reported by 18%. Being hospitalized for a respiratory infection before the age of two years (adjusted odds ratio (OR) = 1.27; 95% confidence interval (CI) 1.01-1.59), suffering from recurrent otitis as a child (OR = 1.18; 95%CI 1.05-1.33), growing up in a large family (OR = 1.04; 95%CI 1.002-1.07) and being exposed to a dog at home as a newborn (OR = 1.26; 95%CI 1.12-1.42) were independently related to snoring later in life and independent of a number of possible confounders in adulthood. The same childhood environmental factors except household size were also related with snoring and daytime sleepiness combined. CONCLUSION: The predisposition for adult snoring may be partly established early in life. Having had severe airway infections or recurrent otitis in childhood, being exposed to a dog as a newborn and growing up in a large family are environmental factors associated with snoring in adulthood.
47.	Gudmundsson, Gunnar, et al. (author) Mortality in COPD patients discharged from hospital : the role of treatment and co-morbidity 2006 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 7, s. 109- Journal article (peer-reviewed)abstract Background: The aim of this study was to analyse mortality and associated risk factors, with special emphasis on health status, medications and co-morbidity, in patients with chronic obstructive pulmonary disease ( COPD) that had been hospitalized for acute exacerbation.Methods: This prospective study included 416 patients from each of the five Nordic countries that were followed for 24 months. The St. George's Respiratory Questionnaire (SGRQ) was administered. Information on treatment and co-morbidity was obtained.Results: During the follow-up 122 (29.3%) of the 416 patients died. Patients with diabetes had an increased mortality rate [HR = 2.25 (1.28 - 3.95)]. Other risk factors were advanced age, low FEV1 and lower health status. Patients treated with inhaled corticosteroids and/or long-acting beta-2-agonists had a lower risk of death than patients using neither of these types of treatment.Conclusion: Mortality was high after COPD admission, with older age, decreased lung function, lower health status and diabetes the most important risk factors. Treatment with inhaled corticosteroids and long-acting bronchodilators may be associated with lower mortality in patients with COPD.
48.	Ivanov, Stefan, 1974, et al. (author) Interleukin-17A mRNA and protein expression within cells from the human bronchoalveolar space after exposure to organic dust 2005 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 6, s. 44- Journal article (peer-reviewed)abstract BACKGROUND: In mice, the cytokine interleukin (IL)-17A causes a local accumulation of neutrophils within the bronchoalveolar space. IL-17A may thereby also contribute to an increased local proteolytic burden. In the current study, we determined whether mRNA for IL-17A is elevated and protein expression of IL-17A occurs locally in inflammatory cells within the human bronchoalveolar space during severe inflammation caused by organic dust. We also assessed the expression of the elastinolytic protease MMP-9 in this airway compartment.METHODS: Six healthy, non-smoking human volunteers were exposed to organic dust in a swine confinement, a potent stimulus of neutrophil accumulation within the human bronchoalveolar space. Bronchoalveolar lavage (BAL) fluid was harvested 2 weeks before and 24 hours after the exposure and total and differential counts were conducted for inflammatory BAL cells. Messenger RNA for IL-17A was measured using reverse transcript polymerase chain reaction-enzyme linked immunoassay (RT-PCR-ELISA). Intracellular immunoreactivity (IR) for IL-17A and MMP-9, respectively, was determined in BAL cells.RESULTS: The exposure to organic dust caused more than a forty-fold increase of mRNA for IL-17A in BAL cells. IL-17A immunoreactivity was detected mainly in BAL lymphocytes, and the number of these IL-17A expressing lymphocytes displayed an eight-fold increase, even though not statistically significant. The increase in IL-17A mRNA was associated with a substantial increase of the number of BAL neutrophils expressing MMP-9 immunoreactivity.CONCLUSION: Exposure to organic dust increases local IL-17A mRNA and because there is intracellular expression in BAL lymphocytes, this suggests that IL-17A protein can originate from lymphocytes within the human bronchoalveolar space. The fact that the increased IL-17A mRNA is associated with an increased number of MMP-9-expressing neutrophils is compatible with IL-17A increasing the local proteolytic burden through its neutrophil-accumulating effect.
49.	Jonasson, Sofia, et al. (author) Different effects of deep inspirations on central and peripheral airways in healthy and allergen-challenged mice 2008 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 9:23 Journal article (peer-reviewed)abstract BACKGROUND: Deep inspirations (DI) have bronchodilatory and bronchoprotective effects in healthy human subjects, but these effects appear to be absent in asthmatic lungs. We have characterized the effects of DI on lung mechanics during mechanical ventilation in healthy mice and in a murine model of acute and chronic airway inflammation. METHODS: Balb/c mice were sensitized to ovalbumin (OVA) and challenged with nebulized OVA for 1 week or 12 weeks. Control mice were challenged with PBS. Mice were randomly selected to receive DI, which was given twice during the minute before assessment of lung mechanics. RESULTS: DI protected against bronchoconstriction of central airways in healthy mice and in mice with acute airway inflammation, but not when OVA-induced chronic inflammation was present. DI reduced lung resistance induced by methacholine from 3.8+/-0.3 to 2.8+/-0.1 cmH2OsmL-1 in healthy mice and 5.1+/-0.3 to 3.5+/-0.3 cmH2OsmL-1 in acute airway inflammation (both P < 0.001). In healthy mice, DI reduced the maximum decrease in lung compliance from 15.9+/-1.5% to 5.6+/-0.6% (P < 0.0001). This protective effect was even more pronounced in mice with chronic inflammation where DI attenuated maximum decrease in compliance from 44.1+/-6.6% to 14.3+/-1.3% (P < 0.001). DI largely prevented increased peripheral tissue damping (G) and tissue elastance (H) in both healthy (G and H both P < 0.0001) and chronic allergen-treated animals (G and H both P < 0.0001). CONCLUSIONS: We have tested a mouse model of potential value for defining mechanisms and sites of action of DI in healthy and asthmatic human subjects. Our current results point to potent protective effects of DI on peripheral parts of chronically inflamed murine lungs and that presence of DI may blunt airway hyperreactivity.
50.	Karimi, R, et al. (author) Lung density on high resolution computer tomography (HRCT) reflects degree of inflammation in smokers 2014 In: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X .- 1465-9921. ; 15, s. 23- Journal article (peer-reviewed)

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Type of publication: journal article (177); research review (4)

Type of content: peer-reviewed (177); other academic/artistic (4)

Author/Editor: Janson, Christer (18); Lötvall, Jan, 1956 (15); Bjermer, Leif (14); Erjefält, Jonas (13); Westergren-Thorsson, ... (9); Grunewald, J (9); show more...; Cardell, Lars-Olaf (9); Adner, Mikael (8); Löfdahl, Claes-Göran (8); Ekerljung, Linda, 19 ... (7); Eklund, A (6); Wheelock, AM (6); Lundbäck, Bo, 1948 (6); Blomberg, Anders, 19 ... (6); Uller, Lena (6); Larsson, Kjell (6); Lindberg, Anne (6); Piitulainen, Eeva (5); Lisspers, Karin, Doc ... (5); Gislason, Thorarinn (5); Melen, E (5); Eriksson, Leif (5); Mori, Michiko (5); Olin, Anna-Carin, 19 ... (5); Ställberg, Björn, Do ... (4); Nilsson, Peter (4); Hallgren, Oskar (4); Greiff, Lennart (4); Johansson, Gunnar (4); Ekström, Magnus (4); Uddman, Rolf (4); Rönmark, Eva (4); Andersson, Morgan (4); Linden, A (4); Gao, J. (3); Bucht, Anders (3); Dahlen, SE (3); Larsson, K (3); Palmberg, L (3); Ahlström-Emanuelsson ... (3); Persson, Carl (3); Tufvesson, Ellen (3); Lindberg, Eva (3); Janciauskiene, Sabin ... (3); Jansson, Lennart (3); Erjefält, Jonas S. (3); Vanfleteren, Lowie E ... (3); Nyren, S (3); Emilsson, Össur Ingi (3); Ganguly, K (3); show less...

University: Karolinska Institutet (73); Lund University (65); University of Gothenburg (40); Uppsala University (36); Umeå University (17); Royal Institute of Technology (4); show more...; Linköping University (4); Luleå University of Technology (2); Örebro University (2); Malmö University (2); University of Gävle (1); Mid Sweden University (1); Linnaeus University (1); Swedish University of Agricultural Sciences (1); show less...

Language: English (181)

Research subject (UKÄ/SCB): Medical and Health Sciences (129)

Year

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