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Resolution of cell-mediated airways diseases
Carl G Persson, Lena Uller
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-75
Abstract: Mechanisms active in development of cell-mediated airways disease such as asthma and chronic obstructive pulmonary disease (COPD) may differ from mechanisms involved in exacerbations of these diseases. Different mechanisms again would be involved in resolution of inflammation and healing of the diseased airways. A major aspect of resolution is the elimination of inflammatory cells from the diseased airway wall. This is accomplished, it is thought, by activation of a programmed cell death (apoptosis) followed by 'silent' elimination through phagocytosis of the apoptotic cells. Based on their potential to induce apoptosis of eosinophils and lymphocytes, and increase phagocytosis of apoptotic leukocytes, the mainstay airway anti-inflammatory drugs, glucocorticoids, are considered as pro-resolution drugs ([1], and references cited therein). However, it appears that few in vivo data have been publicised during the last two decades in support of a significant role of leukocyte apoptosis in airways diseases, whether steroid treatment has been involved or not. This limited support for a central dogma on resolution may increasingly be realised by authors involved in research on respiratory disorders: Downey et al [2] recently observed that findings of reduced neutrophil apoptosis in resolving exacerbations of cystic fibrosis "seem counter intuitive as it should be expected that neutrophil apoptosis should have increased to aid resolution of infection and inflammation". On a slightly different note Porter [3], examining transepithelial migration of lymphocytes in vitro, stated that it is widely assumed that the clearance of these cells from inflamed airway tissues involves apoptosis thus "ignoring a potentially very important exit across the bronchial epithelial barrier". This exit has been named 'luminal entry'. Analogous to the exit of cells across the venular endothelial barrier it may also be called 'transepithelial egression', 'transepithelial migration', or 'transmigrat
Rhinovirus and dsRNA Induce RIG-I-Like Receptors and Expression of Interferon β and λ1 in Human Bronchial Smooth Muscle Cells
Jenny Calvén, Yuliana Yudina, Lena Uller
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062718
Abstract: Rhinovirus (RV) infections cause exacerbations and development of severe asthma highlighting the importance of antiviral interferon (IFN) defence by airway cells. Little is known about bronchial smooth muscle cell (BSMC) production of IFNs and whether BSMCs have dsRNA-sensing receptors besides TLR3. dsRNA is a rhinoviral replication intermediate and necrotic cell effect mimic that mediates innate immune responses in bronchial epithelial cells. We have explored dsRNA-evoked IFN-β and IFN-λ1 production in human BSMCs and potential involvement of TLR3 and RIG-I-like receptors (RLRs). Primary BSMCs were stimulated with 0.1–10 μg/ml dsRNA, 0.1–1 μg/ml dsRNA in complex with the transfection agent LyoVec (dsRNA/LyoVec; selectively activating cytosolic RLRs) or infected with 0.05–0.5 MOI RV1B. Both dsRNA stimuli evoked early (3 h), concentration-dependent IFN-β and IFN-λ1 mRNA expression, which with dsRNA/LyoVec was much greater, and with dsRNA was much less, after 24 h. The effects were inhibited by dexamethasone. Further, dsRNA and dsRNA/LyoVec concentration-dependently upregulated RIG-I and MDA5 mRNA and protein. dsRNA and particularly dsRNA/LyoVec caused IFN-β and IFN-λ1 protein production (24 h). dsRNA- but not dsRNA/LyoVec-induced IFN expression was partly inhibited by chloroquine that suppresses endosomal TLR3 activation. RV1B dose-dependently increased BSMC expression of RIG-I, MDA5, IFN-β, and IFN-λ1 mRNA. We suggest that BSMCs express functional RLRs and that both RLRs and TLR3 are involved in viral stimulus-induced BSMC expression of IFN-β and IFN-λ1.
A Randomized, Double-Blind, Placebo-Controlled Pilot Clinical Study on ColdZyme® Mouth Spray against Rhinovirus-Induced Common Cold  [PDF]
Mats Clarsund, Marcus Fornbacke, Lena Uller, Sebastian L. Johnston, Cecilia Ahlstr?m Emanuelsson
Open Journal of Respiratory Diseases (OJRD) , 2017, DOI: 10.4236/ojrd.2017.74013
Common colds incur significant costs in terms of sick leave and personal discomfort for affected individuals. This study investigated the performance of ColdZyme Mouth Spray (ColdZyme), a protective barrier against common cold, in rhinovirus-inoculated healthy volunteers. This randomized, doubleblind, placebo-controlled pilot study was conducted on 46 healthy volunteers inoculated with rhinovirus 16 via the nose. Subjects self-administered ColdZyme or placebo 6 times daily for 11 days. Symptoms were recorded daily in a diary. Rhinovirus 16 in nasal and oropharyngeal samples at days 0, 3, 4, 6, 7 and 10 were quantified by RT-qPCR. The primary outcome measure was the reduction in viral load in oropharyngeal samples. Rhinovirus 16 was only detected in 35 out of 46 inoculated subjects. Exploratory analysis measuring the total viral load (i.e., area under the curve (AUC)) for days 3 - 10 in successfully inoculated subjects found that ColdZyme treatment resulted in a lower total viral load in the oropharynx (p = 0.023). In subjects who experienced symptomatic common cold, irrespectively, if virus were detected, treatment with ColdZyme resulted in a reduction in the number of days with common cold symptoms from 6.5 to 3.0 days (p = 0.014) in comparison to placebo. ColdZyme reduced virus infection in the oropharynx and reduced the number of days with common cold symptoms and highlights the possible importance of the oropharynx in common cold infections. Suitable outcome measures for a feasible study on ColdZyme are total viral load in the oropharynx in subjects having detectable virus present in nasal or oropharyngeal samples.
Remodeling of extra-bronchial lung vasculature following allergic airway inflammation
Kristina Rydell-T?rm?nen, Lena Uller, Jonas S Erjef?lt
Respiratory Research , 2008, DOI: 10.1186/1465-9921-9-18
Abstract: 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 α-smooth muscle actin, procollagen I, Ki67 and von Willebrand-factor. Myofibroblasts were defined as and visualized by double staining for α-smooth muscle actin and procollagen I. For quantification the blood vessels were divided, based on length of basement membrane, into groups; small (≤250 μm) and mid-sized (250–500 μm).We discovered marked remodeling in solitary small and mid-sized blood vessels. Smooth muscle mass increased significantly as did the number of proliferating smooth muscle and endothelial cells. The changes were similar to those previously seen in large bronchial-associated vessels. Additionally, normally poorly muscularized blood vessels changed phenotype to a more muscularized type and the number of myofibroblasts around the small and mid-sized vessels increased following allergen challenge.We demonstrate that allergic airway inflammation in mice is accompanied by remodeling of small and mid-sized pulmonary blood vessels some distance away (at least 150 μm) from the allergen-exposed bronchi. The present findings suggest the possibility that allergic airway inflammation may cause such vascular remodeling as previously associated with lung inflammatory conditions involving a risk for development of pulmonary hypertension.Allergic airway inflammation is known to be associated with persistent inflammation and tissue remodeling, such as subepithelial fibrosis, smooth muscle thickening and increased vascularity in the bronchial circulation [1-3]. Most of our knowledge of remodeling in asthma emanates from studies of bronchial biopsies involving the large airways. However, asthma is not only a large airway disease, but also affects other parts of the lung, notably the small airways and possibly the bronchial-associated bloo
Anti-Fas mAb-induced apoptosis and cytolysis of airway tissue eosinophils aggravates rather than resolves established inflammation
Lena Uller, Kristina Rydell-T?rm?nen, Carl GA Persson, Jonas S Erjef?lt
Respiratory Research , 2005, DOI: 10.1186/1465-9921-6-90
Abstract: Weeklong daily allergen challenges of sensitized mice were followed by airway administration of anti-Fas mAb. BAL was performed and airway-pulmonary tissues were examined using light and electron microscopy. Lung tissue analysis for CC-chemokines, apoptosis, mucus production and plasma exudation (fibrinogen) were performed.Anti-Fas mAb evoked apoptosis of 28% and cytolysis of 4% of eosinophils present in allergen-challenged airway tissues. Furthermore, a majority of the apoptotic eosinophils remained unengulfed and eventually exhibited secondary necrosis. A striking histopathology far beyond the allergic inflammation developed and included degranulated eosinophils, neutrophilia, epithelial derangement, plasma exudation, mucus-plasma plugs, and inducement of 6 CC-chemokines. In animals without eosinophilia anti-Fas evoked no inflammatory response.An efficient inducer of eosinophil apoptosis in airway tissues in vivo, anti-Fas mAb evoked unprecedented asthma-like inflammation in mouse allergic airways. This outcome may partly reflect the ability of anti-Fas to evoke direct cytolysis of non-apoptotic eosinophils in airway tissues. Additionally, since most apoptotic tissue eosinophils progressed into the pro-inflammatory cellular fate of secondary necrosis this may also explain the aggravated inflammation. Our data indicate that Fas receptor mediated eosinophil apoptosis in airway tissues in vivo may cause severe disease exacerbation due to direct cytolysis and secondary necrosis of eosinophils.Apoptosis of inflammatory cells followed by their swift removal through phagocytosis is considered a major mechanism of resolution of inflammatory conditions [1,2]. The most common chronic inflammatory disease, asthma is characterized by eosinophilia, epithelial derangement, plasma exudation, and hypersecretion [3,4]. The role of the eosinophil in this disease is currently under intense investigation [5] and much interest has been devoted to apoptosis of eosinophil granulocytes [
Neutrophil cannibalism – a back up when the macrophage clearance system is insufficient
Kristina Rydell-T?rm?nen, Lena Uller, Jonas S Erjef?lt
Respiratory Research , 2006, DOI: 10.1186/1465-9921-7-143
Abstract: 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.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.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.Neutrophils are short lived immune cells who invade tissues in response to a variety of stimuli, for example viral and bacterial infections [1,2]. They are professional phagocytes and contribute to resolution of inflammation by removing infectious and inflammatory stimuli [1,2]. Apart from being present during acute infections, neutrophils are also found to a variable degree during airway diseases such as COPD, asthma and ARDS/ALI [3,4]. Neutrophils have a high turnover and are normally rapidly cleared by apoptosis, followed by macrophage phagocytosis [2,5]. During infection a large number of neutrophils are present in order to efficiently clear the infection, and studies have shown that ingestion of bacteria may delay neutrophil apoptosis [2], thereby causing very large number of cells accumulating in the same area. In such cases, the normally rapid clearance
Early phase resolution of mucosal eosinophilic inflammation in allergic rhinitis
Lena Uller, Cecilia Emanuelsson, Morgan Andersson, Jonas S Erjef?lt, Lennart Greiff, Carl G Persson
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-54
Abstract: 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.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.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.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.Airway tissue signs of established inflammation in asthma and allergic rhinitis include increased mucosal tissue cell turnover, eosinophilia, and increased chemokine production. Institution of steroid treatment eventually reduces both symptoms and eosinophilic inflammation in allergic airways diseases [1]. However, early resolution effects in vivo of this mainstay class of airway drugs are incompletely understood.In recent years, based largely on observations in vitro, the view that est
Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation
Lena Uller, Jesper Mathiesen, Lisa Alenmyr, Magnus Korsgren, Trond Ulven, Thomas H?gberg, Gunnar Andersson, Carl GA Persson, Evi Kostenis
Respiratory Research , 2007, DOI: 10.1186/1465-9921-8-16
Abstract: Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A2 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.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.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.The small lipid mediator prostaglandin D2 (PGD2) is the major cyclooxygenase metabolite of arachidonic acid and is released by activated mast cells in response to allergen exposure [1]. PGD2 has long been considered a potentially important mediator in several diseases such as asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis [2-5]. PGD2 elicits biological responses by interaction with three specific seven-transmembrane receptors, referred to as DP/DP1, DP2/CRTH2, and TP (DP, D prostanoid receptor; CRTH2, chemoattractant receptor homologous molecule expressed on T helper type 2 cells; TP, thromboxane A2 receptor) [6-8]. Via interaction with one (or a combination) of its three specific receptors PGD2 may contribute to bronchoconstriction, eosinophilia and mucus production in allergic asthma. H
The Impact of CBSE’s Activities on E-Commerce Applications  [PDF]
Lena Khaled
iBusiness (IB) , 2013, DOI: 10.4236/ib.2013.51A005

Component based technology is widely used for both academicians and business. There are numbers of benefits for using this type of technology. First, it helps to increase the efficiency and maintainability of software. Second, it improves quality and helps to enhance productivity. Third, the reuse approach that supports component based technology decreases the time to market. Component based e-commerce can be used to solve e-commerce difficulties at application level as well as at system level. This paper introduces how component based activities have effect mainly on building the framework of the e-commerce. It also discusses how the architectural design of the application can be synthesized.

The Price Equation and Extended Inheritance
Heikki Helanter?,Tobias Uller
Philosophy & Theory in Biology , 2010,
Abstract: The presence of various mechanisms of non-genetic inheritance is one of the main problems for current evolutionary theory according to several critics. Sufficient empirical and conceptual reasons exist to take this claim seriously, but there is little consensus on the implications of multiple inheritance systems for evolutionary processes. Here we use the Price Equation as a starting point for a discussion of the differences between four recently proposed categories of inheritance systems; genetic, epigenetic, behavioral and symbolic. Specifically, we address how the components of the Price Equation encompass different non-genetic systems of inheritance in an attempt to clarify how the different systems are conceptually related. We conclude that the four classes of inheritance systems do not form distinct clusters with respect to their effect on the rate and direction of phenotypic change from one generation to the next in the absence or presence of selection. Instead, our analyses suggest that different inheritance systems can share features that are conceptually very similar, but that their implications for adaptive evolution nevertheless differ substantially as a result of differences in their ability to couple selection and inheritance.
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