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Differential regulation of neurotrophin expression in human bronchial smooth muscle cells
Cecilia Kemi, Johan Grunewald, Anders Eklund, Caroline Olgart H?glund
Respiratory Research , 2006, DOI: 10.1186/1465-9921-7-18
Abstract: Basal and cytokine (IL-1β, IFN-γ, IL-4)-stimulated neurotrophin expression in HBSMC cultured in vitro was quantified. The mRNA expression was quantified by real-time RT-PCR and the protein secretion into the cell culture medium by ELISA.We observed a constitutive NGF, BDNF and NT-3 expression. IL-1β stimulated a transient increase of NGF, while the increase of BDNF had a later onset and was more sustained. COX-inhibitors (indomethacin and NS-398) markedly decreased IL-1β-stimulated secretion of BDNF, but not IL-1β-stimulated NGF secretion. IFN-γ increased NGF expression, down-regulated BDNF expression and synergistically enhanced IL-1β-stimulated NGF expression. In contrast, IL-4 had no effect on basal NGF and BDNF expression, but decreased IL-1β-stimulated NGF expression. NT-3 was not altered by the tested cytokines.Taken together, our data indicate that, in addition to the contractile capacity, HBSMC can express NGF, BDNF and NT-3. The expression of these neurotrophins may be differently regulated by inflammatory cytokines, suggesting a dynamic interplay that might have a potential role in airway inflammation.Allergic asthma is characterised by an inflammatory airway obstruction induced by specific allergen [1]. In addition, structural cells of the allergic airways are often hyperresponsive to non-specific stimuli, which synergises with the inflammatory response to aggravate disease [2]. While the pathogenesis of allergen-induced inflammatory airway obstruction is relatively well understood [1], we know much less about the regulation of airway hyperresponsiveness. According to current models, it involves proliferation and phenotypic changes of structural cells (e.g. smooth muscle cells, fibroblasts) and nerve cells in the airways, which contribute to enhanced airway resistance [2,3].Neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) were initially discovered as factors that regulate development, dif
Cell Recovery in Bronchoalveolar Lavage Fluid in Smokers Is Dependent on Cumulative Smoking History
Reza Karimi, G?ran Tornling, Johan Grunewald, Anders Eklund, C. Magnus Sk?ld
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034232
Abstract: Background Smoking is a risk factor for various lung diseases in which BAL may be used as a part of a clinical investigation. Interpretation of BAL fluid cellularity is however difficult due to high variability, in particular among smokers. In this study we aimed to evaluate the effect of smoking on BAL cellular components in asymptomatic smokers. The effects of smoking cessation, age and gender were also investigated in groups of smokers and exsmokers. Methods We performed a retrospective review of BAL findings, to our knowledge the largest single center investigation, in our department from 1999 to 2009. One hundred thirty two current smokers (48 males and 84 females) and 44 ex-smokers (16 males and 28 females) were included. A group of 295 (132 males and 163 females) never-smokers served as reference. Result The median [5–95 pctl] total number of cells and cell concentration in current smokers were 63.4 [28.6–132.1]×106 and 382.1 [189.7–864.3]×106/L respectively and correlated positively to the cumulative smoking history. Macrophages were the predominant cell type (96.7% [90.4–99.0]) followed by lymphocytes (2% [0.8–7.7]) and neutrophils (0.6% [0–2.9]). The concentration of all inflammatory cells was increased in smokers compared to never smokers and ex-smokers. BAL fluid recovery was negatively correlated with age (p<0.001). Smoking men had a lower BAL fluid recovery than smoking women. Conclusion Smoking has a profound effect on BAL fluid cellularity, which is dependent on smoking history. Our results performed on a large group of current smokers and ex-smokers in a well standardized way, can contribute to better interpretation of BAL fluid cellularity in clinical context.
Bronchoalveolar Lavage Results Are Independent of Season, Age, Gender and Collection Site
Helga H. Olsen, Johan Grunewald, G?ran Tornling, C. Magnus Sk?ld, Anders Eklund
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043644
Abstract: Background Clinical interpretation of bronchoalveolar lavage fluid results is dependent on the availability of reference values for healthy individuals. Only a few studies have published such reference values and the applicability of results is restricted by small sample sizes and the limited representativeness of the study population. We aim to investigate the influence of age, gender, collection site and season on bronchoalveolar lavage fluid results and to establish reference values for use in clinical practice. Methodology/Principal Findings Bronchoalveolar lavage fluid data from 295 healthy never-smoking volunteers, investigated during 1990–2009, were analyzed retrospectively. 47 volunteers had 2–5 repeat lavages during the course of several years. Fluid recovery, total number of cells, cell concentration, and differential cell counts on cytospin prepared slides were recorded. Reference values, as represented by the 5th to the 95th percentile, were 72–96% for macrophages, 2–26% for lymphocytes, 0–4% for neutrophils and 0–1% for eosinophils. Basophils and mast cells were rare. When repeat lavages were performed, there was a relatively large intra-individual variability, mainly for macrophages and lymphocytes. An age dependent decrease of lavage fluid return was present, but there was no age dependent correlation with any of the other BALF parameters. The BALF cell parameters were independent of gender, season and site (lingula vs. middle lobe). Conclusions/Significance Our data show that bronchoalveolar lavage fluid cell differential count is independent of age, gender, season and collection site (RML or lingua). It therefore seems acceptable to use the same reference values for all never-smoking individuals.
Assessing Recent Smoking Status by Measuring Exhaled Carbon Monoxide Levels
AnnSofi Sandberg, C. Magnus Sk?ld, Johan Grunewald, Anders Eklund, ?sa M. Wheelock
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028864
Abstract: Background Cigarette smoke causes both acute and chronic changes of the immune system. Excluding recent smoking is therefore important in clinical studies with chronic inflammation as primary focus. In this context, it is common to ask the study subjects to refrain from smoking within a certain time frame prior to sampling. The duration of the smoking cessation is typically from midnight the evening before, i.e. 8 hours from sampling. As it has been shown that a proportion of current smokers underestimates or denies smoking, objective assessment of recent smoking status is of great importance. Our aim was to extend the use of exhaled carbon monoxide (CObreath), a well-established method for separating smokers from non-smokers, to assessment of recent smoking status. Methods and Findings The time course of CObreath decline was investigated by hourly measurements during one day on non-symptomatic smokers and non-smokers (6+7), as well as by measurements on three separate occasions on non-smokers (n = 29), smokers with normal lung function (n = 38) and smokers with chronic obstructive pulmonary disease (n = 19) participating in a clinical study. We used regression analysis to model the decay, and receiver operator characteristics analysis for evaluation of model performance. The decline was described as a mono-exponential decay (r2 = 0.7) with a half-life of 4.5 hours. CO decline rate depends on initial CO levels, and by necessity a generic cut-off is therefore crude as initial CObreath varies a lot between individuals. However, a cut-off level of 12 ppm could classify recent smokers from smokers having refrained from smoking during the past 8 hours with a specificity of 94% and a sensitivity of 90%. Conclusions We hereby describe a method for classifying recent smokers from smokers having refrained from smoking for >8 hours that is easy to implement in a clinical setting.
No evidence of altered alveolar macrophage polarization, but reduced expression of TLR2, in bronchoalveolar lavage cells in sarcoidosis
Maria Wikén, Farah Idali, Muntasir Al Hayja, Johan Grunewald, Anders Eklund, Jan Wahlstr?m
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-121
Abstract: Total BAL cells (cultured four or 24 h in medium, or stimulated 24 h with LPS) from 14 patients and six healthy subjects, sorted AMs from 22 patients (L?fgren's syndrome n = 11) and 11 healthy subjects, and sorted CD4+ T cells from 26 patients (L?fgren's syndrome n = 13) and seven healthy subjects, were included. Using real-time PCR, the relative gene expression of IL-10, IL-12p35, IL-12p40, IL-23p19, CCR2, CCR7, iNOS, CXCL10, CXCL11, CXCL16, CCL18, CCL20, CD80, and CD86, and innate immune receptors TLR2, TLR4, and TLR9, was quantified in sorted AMs, and for selected genes in total BAL cells, while IL-17A was quantified in T cells.We did not find evidence of a difference with regard to alveolar macrophage M1/M2 polarization between sarcoidosis patients and healthy controls. TLR2 gene expression was significantly lower in sorted AMs from patients, particular in L?fgren's patients. CCL18 gene expression in AMs was significantly higher in patients compared to controls. Additionally, the IL-17A expression was lower in L?fgren's patients' CD4+ T cells.Overall, there was no evidence for alveolar macrophage polarization in sarcoidosis. However, there was a reduced TLR2 mRNA expression in patients with L?fgren's syndrome, which may be of relevance for macrophage interactions with a postulated sarcoidosis pathogen, and for the characteristics of the ensuing T cell response.Sarcoidosis is a systemic T helper 1 (Th1) inflammatory disease [1,2], primarily affecting the lungs. The hallmark of disease is non-caseating granulomas where macrophages are essential components. These cells are very heterogeneous, characterized by plasticity and functional polarization, with, as here named, M1 and M2 types, at the extremes of a continuum. Due to micro-environmental signals, such as cytokines, chemokines and Toll-like receptor (TLR) ligands, macrophages differ in receptor expression, cytokine and chemokine production, as well as effector function [3,4]. Classical activation, that is IFNγ
Altered expression of T cell Immunoglobulin-Mucin (TIM) molecules in bronchoalveolar lavage CD4+ T cells in sarcoidosis
Farah Idali, Jan Wahlstr?m, Benita Dahlberg, Mohsen Khademi, Tomas Olsson, Anders Eklund, Johan Grunewald
Respiratory Research , 2009, DOI: 10.1186/1465-9921-10-42
Abstract: We used real-time polymerase chain reaction to investigate the differential gene expression of TIM-1 and TIM-3 as well as a few Th1 and Th2 cytokines (IL-2, IFN-γ, IL-4, IL-5 and IL-13) in CD4+ T cells isolated from bronchoalveolar lavage fluid (BALF) of patients (n = 28) and healthy controls (n = 8). Using flow cytometry, we were also able to analyse TIM-3 protein expression in 10 patients and 6 healthy controls.A decreased TIM-3 mRNA (p < 0.05) and protein (p < 0.05) expression was observed in patients, and the level of TIM-3 mRNA correlated negatively with the CD4/CD8 T cell ratio in BALF cells of patients. Compared to a distinct subgroup of patients i.e. those with L?fgren's syndrome, BALF CD4+ T cells from non- L?fgren's patients expressed decreased mRNA levels of TIM-1 (p < 0.05). mRNA expression of IL-2 was increased in patients (p < 0.01) and non-L?fgren's patients expressed significantly higher levels of IFN-γ mRNA (p < 0.05) versus patients with L?fgren's syndrome.These findings are the first data on the expression of TIM-1 and TIM-3 molecules in sarcoidosis. The reduced TIM-3 expression in the lungs of patients may result in a defective T cell ability to control the Th1 immune response and could thus contribute to the pathogenesis of sarcoidosis. The down-regulated TIM-1 expression in non-L?fgren'spatients is in agreement with an exaggerated Th1 response in these patients.Sarcoidosis is a T helper (Th) 1-mediated inflammatory disease with unknown aetiology, characterized by the formation of noncaseating granulomas, and involving accumulations of macrophages and T cells, primarily affecting the lungs [1]. In pulmonary sarcoidosis, an acute onset usually indicates a self-limiting disease course, whereas an insidious onset may be followed by persistent disease with a risk for fibrosis [1]. An imbalance in the expression of Th1/Th2 cytokines by alveolar cells has been suggested to be of importance for the outcome of a pulmonary immune response in sarcoidosis
Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients
Johan Grunewald, Boel Brynedal, Pernilla Darlington, Magnus Nisell, Kerstin Cederlund, Jan Hillert, Anders Eklund
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-25
Abstract: In this study we HLA typed a large patient population (n = 754) recruited from one single centre. Patients were sub-grouped into those with L?fgren's syndrome (LS) (n = 302) and those without (non-L?fgren's) (n = 452), and the majority of them were clinically classified into those with recovery within two years (resolving) and those with signs of disease for more than two years (non-resolving). PCR was used for determination of HLA-DRB1 alleles. Swedish healthy blood donors (n = 1366) served as controls.There was a dramatic difference in the distribution of HLA alleles in LS compared to non-LS patients (p = 4 × 10-36). Most notably, DRB1*01, DRB1*03 and DRB1*14, clearly differed in LS and non-LS patients. In relation to disease course, DRB1*07, DRB1*14 and DRB1*15 generally associated with, while DRB1*01 and DRB1*03 protected against, a non-resolving disease. Interestingly, the clinical influence of DRB1*03 (good prognosis) dominated over that of DRB1*15 (bad prognosis).We found several significant differences between LS and non-LS patients and we therefore suggest that genetic association studies in sarcoidosis should include a careful clinical characterisation and sub-grouping of patients, in order to reveal true genetic associations. This may be particularly accurate to do in the heterogeneous non-LS group of patients.Sarcoidosis is an inflammatory disease of unknown aetiology. A genetic influence has been suggested by reports showing different susceptibilities and clinical manifestations between distinct ethnic groups [1]. In addition genetic linkage analyses have pointed out a significant linkage for the major histocompatibility complex (MHC) region [2], but also with minor peaks in specific regions of some other chromosomes [3]. One recently published genome wide association study described an association with the gene coding for Annexin A11, a protein with several important functions, including for apoptosis [4].Sarcoidosis is thus influenced by a multitude o
Neurotrophins and neurotrophin receptors in pulmonary sarcoidosis - granulomas as a source of expression
Charlotta Dagnell, Johan Grunewald, Marija Kramar, Helga Haugom-Olsen, G?ran P Elmberger, Anders Eklund, Caroline Olgart H?glund
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-156
Abstract: The concentrations of NGF, BDNF and NT-3 in bronchoalveolar lavage fluid (BALF) of 41 patients with newly diagnosed pulmonary sarcoidosis and 27 healthy controls were determined with ELISA. The localization of neurotrophins and neurotrophin receptors were examined by immunohistochemistry on transbronchial lung biopsies from sarcoidosis patients.The sarcoidosis patients showed significantly enhanced NT-3 and NGF levels in BALF, whereas BDNF was undetectable in both patients and controls. NT-3 levels in BALF were found higher in patients with non-L?fgren sarcoidosis as compared to patients with L?fgren's syndrome, and in more advanced disease stage. Epithelioid cells and multinucleated giant cells within the sarcoid granulomas showed marked immunoreactivity for NGF, BDNF and NT-3. Also, immunoreactivity for the neurotrophin receptor TrkA, TrkB and TrkC, was found within the granulomas. In addition, alveolar macrophages showed positive immunoreactivity for NGF, BDNF and NT-3 as well as for TrkA, TrkB and TrkC.This study provides evidence of enhanced neurotrophin levels locally within the airways of patients with sarcoidosis. Findings suggest that sarcoid granuloma cells and alveolar macrophages are possible cellular sources of, as well as targets for, neurotrophins in the airways of these patients.Sarcoidosis is an inflammatory granulomatous disease which primarily affects the lungs. The disease is characterized by an accumulation of CD4+ lymphocytes and the formation of non-caseating epithelioid cell granulomas in the affected organs. The granuloma consists of highly differentiated mononuclear phagocytes (epithelioid cells and multinucleated giant cells) surrounded by lymphocytes [1]. The disease either resolves spontaneously or develops into a more chronic disease where the sarcoid granulomas develop fibrotic changes, which in the airways may lead to a progressive loss of lung function. Factors that influence granuloma formation and the development of fibrosis are no
The Behavior of Nil-Groups under Localization and the Relative Assembly Map
Joachim Grunewald
Mathematics , 2006,
Abstract: We study the behavior of the Nil-subgroups of K-groups under localization. As a consequence we obtain that the relative assembly map from the family of finite subgroups to the family of virtually cyclic subgroups is rationally an isomorphism. Combined with the equivariant Chern character we obtain a complete computation of the rationalized source of the K-theoretic assembly map in terms of group homology and the K-groups of finite cyclic subgroups.
Combined Electroweak Analysis
Grunewald, Martin W.
High Energy Physics - Phenomenology , 2007, DOI: 10.1088/1742-6596/110/4/042008
Abstract: Recent developments in the measurement of precision electroweak measurements are summarised, notably new results on the mass of the top quark and mass and width of the W boson. Predictions of the Standard Model are compared to the experimental results which are used to constrain the input parameters of the Standard Model, in particular the mass of the Higgs boson. The agreement between measurements and expectations from theory is discussed. Invited talk presented at the EPS HEP 2007 conference Manchester, England, July 19th to 25th, 2007
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