| 1. |
- Al-Garawi, A., et al.
(författare)
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Influenza A facilitates sensitization to house dust mite in infant mice leading to an asthma phenotype in adulthood
- 2011
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 4:6, s. 682-694
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Tidskriftsartikel (refereegranskat)abstract
- The origins of allergic asthma, particularly in infancy, remain obscure. Respiratory viral infections and allergen sensitization in early life have been associated with asthma in young children. However, a causal link has not been established. We investigated whether an influenza A infection in early life alters immune responses to house dust mite (HDM) and promotes an asthmatic phenotype later in life. Neonatal (8-day-old) mice were infected with influenza virus and 7 days later, exposed to HDM for 3 weeks. Unlike adults, neonatal mice exposed to HDM exhibited negligible immune responsiveness to HDM, but not to influenza A. HDM responsiveness in adults was associated with distinct Ly6c(+) CD11b(+) inflammatory dendritic cell and CD8 alpha(+) plasmacytoid (pDC) populations that were absent in HDM-exposed infant mice, suggesting an important role in HDM-mediated inflammation. Remarkably, HDM hyporesponsiveness was overcome when exposure occurred concurrently with an acute influenza infection; young mice now displayed robust allergen-specific immunity, allergic inflammation, and lung remodeling. Remodeling persisted into early adulthood, even after prolonged discontinuation of allergen exposure and was associated with marked impairment of lung function. Our data demonstrate that allergen exposure coincident with acute viral infection in early life subverts constitutive allergen hyporesponsiveness and imprints an asthmatic phenotype in adulthood.
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| 2. |
- Ali, Mohamad N., et al.
(författare)
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Osteopontin Expression in Small Airway Epithelium in Copd is Dependent on Differentiation and Confined to Subsets of Cells
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Osteopontin (OPN) plays a role in inflammation via recruitment of neutrophils and tissue remodeling. In this study, we investigated the distribution of OPN-expressing cells in the airway epithelium of normal lung tissue and that from patients with chronic obstructive pulmonary disease (COPD). OPN was detected on the epithelial cell surface of small airways and in scattered cells within the epithelial cell layer. Staining revealed higher OPN concentrations in tissue showing moderate to severe COPD compared to that in controls. In addition, OPN expression was confined to goblet and club cells, and was absent from ciliated and basal cells as detected via immunohistochemistry. However, OPN expression was up-regulated in submerged basal cells cultures exposed to cigarette smoke (CS) extract. Cell fractioning of air-liquid interface cultures revealed increased OPN production from basal compartment cells compared to that in luminal fraction cells. Furthermore, both constitutive and CS-induced expression of OPN decreased during differentiation. In contrast, cultures stimulated with interleukin (IL)-13 to promote goblet cell hyperplasia showed increased OPN production in response to CS exposure. These results indicate that the cellular composition of the airway epithelium plays an important role in OPN expression and that these levels may reflect disease endotypes in COPD.
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| 3. |
- Andersson, Cecilia, et al.
(författare)
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Alveolar mast cells shift to an FcεRI-expressing phenotype in mild atopic asthma: a novel feature in allergic asthma pathology.
- 2011
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 66:12, s. 1590-1597
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Tidskriftsartikel (refereegranskat)abstract
- Background: A unique feature of alveolar mast cells is their low high-affinity IgE receptor (FcεRI) expression. Recent discoveries in uncontrolled asthma suggest that the appearance of FcεRI-expressing alveolar mast cells may be a novel disease-specific feature of allergic asthma. This study investigates whether increased FcεRI-expressing alveolar mast cells are present in patients with mild allergic asthma or even in non-asthmatic allergic rhinitis patients (AR) who have developed bronchial hyperactivity (BHR). Methods: Bronchial and alveolar tissues were obtained from healthy controls, AR patients with or without BHR, and AR patients with concurrent asthma. Samples were processed for immunohistochemical identification of MC(T) and MC(TC) and expression of FcεRI and surface-bound IgE. Results: Bronchial mast cell expression of FcεRI was high in all groups. In contrast, in the alveolar tissue, the expression of FcεRI on mast cells was low in healthy controls and in the AR patient groups, whereas a high expression was present in AR patients with concurrent asthma (P = 0.006 compared to controls). The asthmatics had a 29-fold increase in numbers (P = 0.006) and a 19-fold increase in proportion (P = 0.007) of alveolar mast cells that expressed surface-bound IgE. Conclusions: The present data show that alveolar mast cells in patients with mild atopic asthma, but not atopic patients with AR, have turned into a highly FcεRI- and IgE-expressing phenotype. These data support the hypothesis that increased FcεRI expression on alveolar mast cells is a novel disease-specific feature of allergic asthma that is important for understanding asthma phenotypes and designing new therapeutic strategies.
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| 4. |
- Andersson, Cecilia K, et al.
(författare)
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Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis
- 2011
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 12:139
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Tidskriftsartikel (refereegranskat)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.
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| 5. |
- Andersson, Cecilia K, et al.
(författare)
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Alterations in Lung Mast Cell Populations in Patients with COPD.
- 2010
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 181:3, s. 206-217
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Mast cells have important roles in innate immunity and tissue remodeling but have remained poorly studied in inflammatory airway diseases like COPD. OBJECTIVES: To perform a detailed histological characterization of human lung mast cell popu-lations at different severities of COPD, comparing with smoking and never-smoking controls. METHODS: Mast cells were analyzed in lung tissues from patients with mild to very severe COPD, GOLD IâIV (n = 25, 10 of whom were treated with corticosteroids). Never-smokers and smokers served as controls. The density, morphology and molecular characteristics of mucosal and connective tissue mast cells (MCT and MCTC, respectively) were analyzed in several lung regions. MEASUREMENTS AND MAIN RESULTS: In all compartments of COPD lungs, especially at severe stages, the MCTC population increased in density while the MCT population decreased. The net result was a reduction in total mast cell density. This phenomenon was paralleled by in-creased numbers of luminal mast cells whereas the numbers of TUNEL(+) apoptotic mast cells remained unchanged. In COPD lungs, the MCT and MCTC populations showed alterations in morphology and expression of CD88 (C5a-R), TGF-beta, and renin. Statistically significant cor-relations were found between several COPD-related mast cell alterations and lung function parameters. CONCLUSIONS: As COPD progresses to its severe stages, the mast cell population in the lung undergoes changes in density, distribution, and molecular expression. In COPD lungs, these novel histopathological features were found to be correlated to lung function and they may thus have clinical consequences.
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| 6. |
- Andersson, Cecilia K, et al.
(författare)
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Distal respiratory tract viral infections in young children trigger a marked increase in alveolar mast cells
- 2018
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Ingår i: ERJ Open Research. - : European Respiratory Society (ERS). - 2312-0541. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- Viral infections predispose to the development of childhood asthma, a disease associated with increased lung mast cells (MCs). This study investigated whether viral lower respiratory tract infections (LRTIs) can already evoke a MC response during childhood. Lung tissue from young children who died following LRTIs were processed for immunohistochemical identification of MCs. Children who died from nonrespiratory causes served as controls. MCs were examined in relation to sensitisation in infant mice exposed to allergen during influenza A infection. Increased numbers of MCs were observed in the alveolar parenchyma of children infected with LRTIs (median (range) 12.5 (0-78) MCs per mm2) compared to controls (0.63 (0-4) MCs per mm2, p=0.0005). The alveolar MC expansion was associated with a higher proportion of CD34+ tryptase+ progenitors (controls: 0% (0-1%); LRTIs: 0.9% (0-3%) CD34+ MCs (p=0.01)) and an increased expression of the vascular cell adhesion molecule (VCAM)-1 (controls: 0.2 (0.07-0.3); LRTIs: 0.3 (0.02-2) VCAM-1 per mm2 (p=0.04)). Similarly, infant mice infected with H1N1 alone or together with house dust mite (HDM) developed an increase in alveolar MCs (saline: 0.4 (0.3-0.5); HDM: 0.6 (0.4-0.9); H1N1: 1.4 (0.4-2.0); HDM+H1N1: 2.2 (1.2-4.4) MCs per mm2 (p<0.0001)). Alveolar MCs continued to increase and remained significantly higher into adulthood when exposed to H1N1+HDM (day 36: 2.2 (1.2-4.4); day 57: 4.6 (1.6-15) MCs per mm2 (p=0.01)) but not when infected with H1N1 alone. Our data demonstrate that distal viral infections in young children evoke a rapid accumulation of alveolar MCs. Apart from revealing a novel immune response to distal infections, our data may have important implications for the link between viral infections during early childhood and subsequent asthma development.
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| 7. |
- Andersson, Cecilia K, et al.
(författare)
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Novel Site-Specific Mast Cell Subpopulations in the Human Lung.
- 2009
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Ingår i: Thorax. - : BMJ. - 1468-3296 .- 0040-6376. ; 64, s. 297-305
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Lung mast cells are stereotypically divided into connective tissue (MCTC) and mucosal (MCT) mast cells. This study tests the hypothesis that each of these subtypes can be divided further into site-specific populations created by the microenvironment within each anatomic lung compartment. METHODS: To study mast cells under non-inflamed conditions surgical resections and bronchial and transbronchial biopsies from non-smoking individuals were obtained to investigate morphometric and molecular characteristics of mast cell populations in multiple lung structures by immunohistochemistry and electron microscopy. RESULTS: MCT and MCTC coexisted at all compartments with MCT being the prevailing type in bronchi, bronchioles and the alveolar parenchyma. MCTC were more abundant in pulmonary vessels and the pleura. Each of the MCTC and MCT phenotypes could be further differentiated into site-specific populations. MCTC was of significantly larger size in pulmonary vessels than in small airway walls (p<0.001) while a reversed pattern was observed for MCT (p<0.001). Within each MCTC and MCT population there was also distinct site-specific expression pattern of the IgE-receptor, IL-9 receptor, renin, histidine decarboxylase, VEGF, FGF, 5-Lipoxygense, and LTC4-synthase; e.g. bronchial MCT consistently expressed more histidine decarboxylase than alveolar MCT (p<0.004). Renin content was high among vascular MCTC but markedly reduced among MCTC in other compartments (p<0.0002). Notably, for both MCTC and MCT IgE-receptor was highly expressed in conducting airways but virtually absent in alveolar parenchyma. CONCLUSION: Our findings demonstrate novel site-specific sub-populations of lung MCTC and MCT. This observation is suggested to have important implications in unravelling the recently proposed role of mast cells in a variety of pulmonary diseases.
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| 8. |
- Andersson, Cecilia, et al.
(författare)
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Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma
- 2011
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 127:4, s. 123-905
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Tidskriftsartikel (refereegranskat)abstract
- Background: A significant proportion of patients with asthma have persistent symptoms despite treatment with inhaled glucocorticosteroids. Objective: We hypothesized that in these patients, the alveolar parenchyma is subjected to mast cell-associated alterations. Methods: Bronchial and transbronchial biopsies from healthy controls (n = 8), patients with allergic rhinitis (n = 8), and patients with atopic uncontrolled asthma (symptoms despite treatment with inhaled glucocorticosteroids; mean dose, 743 mu g/d; n = 14) were processed for immunohistochemical identification of mast cell subtypes and mast cell expression of Fc epsilon RI and surface-bound IgE. Results: Whereas no difference in density of total bronchial mast cells was observed between patients with asthma and healthy controls, the total alveolar mast cell density was increased in the patients with asthma (P < .01). Division into mast cell subtypes revealed that in bronchi of patients with asthma, tryptase positive mast cells (MCT) numbers decreased compared with controls (P <= .05), whereas tryptase and chymase positive mast cells (MCTC) increased (P <= .05). In the alveolar parenchyma from patients with asthma, an increased density was found for both MCT (P <= .05) and MCTC (P <= .05). The increased alveolar mast cell densities were paralleled by an increased mast cell expression of FceRI (P < .001) compared with the controls. The patients with asthma also had increased numbers (P < .001) and proportions (P < .001) of alveolar mast cells with surface-bound IgE. Similar increases in densities, FceRI expression, and surface-bound IgE were not seen in separate explorations of alveolar mast cells in patients with allergic rhinitis. Conclusion: Our data suggest that patients with atopic uncontrolled asthma have an increased parenchymal infiltration of MCT and MCTC populations with increased expression of FceRI and surface-bound IgE compared with atopic and nonatopic controls. (J Allergy Clin Immunol 2011;127:905-12.)
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| 9. |
- Backer, Vibeke, et al.
(författare)
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Clinical characteristics of the BREATHE cohort–a real-life study on patients with asthma and COPD
- 2020
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Ingår i: European clinical respiratory journal. - : Informa UK Limited. - 2001-8525. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The BREATHE study is a cross-sectional study of real-life patients with asthma and/or COPD in Denmark and Sweden aiming to increase the knowledge across severities and combinations of obstructive airway disease. Design: Patients with suspicion of asthma and/or COPD and healthy controls were invited to participate in the study and had a standard evaluation performed consisting of questionnaires, physical examination, FeNO and lung function, mannitol provocation test, allergy test, and collection of sputum and blood samples. A subgroup of patients and healthy controls had a bronchoscopy performed with a collection of airway samples. Results: The study population consisted of 1403 patients with obstructive airway disease (859 with asthma, 271 with COPD, 126 with concurrent asthma and COPD, 147 with other), and 89 healthy controls (smokers and non-smokers). Of patients with asthma, 54% had moderate-to-severe disease and 46% had mild disease. In patients with COPD, 82% had groups A and B, whereas 18% had groups C and D classified disease. Patients with asthma more frequently had childhood asthma, atopic dermatitis, and allergic rhinitis, compared to patients with COPD, asthma + COPD and Other, whereas FeNO levels were higher in patients with asthma and asthma + COPD compared to COPD and Other (18 ppb and 16 ppb vs 12.5 ppb and 14 ppb, p < 0.001). Patients with asthma, asthma + COPD and Other had higher sputum eosinophilia (1.5%, 1.5%, 1.2% vs 0.75%, respectively, p < 0.001) but lower sputum neutrophilia (39.3, 43.5%, 40.8% vs 66.8%, p < 0.001) compared to patients with COPD. Conclusions: The BREATHE study provides a unique database and biobank with clinical information and samples from 1403 real-life patients with asthma, COPD, and overlap representing different severities of the diseases. This research platform is highly relevant for disease phenotype- and biomarker studies aiming to describe a broad spectrum of obstructive airway diseases.
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| 10. |
- Bergqvist, Anders, et al.
(författare)
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Alveolar T-helper type-2 immunity in atopic asthma is associated with poor clinical control
- 2015
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Ingår i: Clinical Science. - 1470-8736. ; 128:1, s. 47-56
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Tidskriftsartikel (refereegranskat)abstract
- Real-world evaluation studies have shown that many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICSs). As conventional ICSs have poor access to the peripheral airways, the aim of the present paper was to study the relationship between peripheral airway inflammation and clinical control in allergic asthma. Consequently, bronchial and transbronchial biopsies were obtained from patients with poorly controlled asthma [n=12, asthma control test (ACT) score < 20], patients with well-controlled asthma (n= 12, ACT score >= 20) and healthy controls (n= 8). Tissue sections were immunostained to assess multiple leucocyte populations. To determine the degree of T-helper type-2 (Th2) immunity, the logarithmic value of the ratio between Th2 cells/mm(2) and Th1 cells/mm(2) was used as a surrogate score for Th2-skewed immunity. In the bronchi, the leucocyte infiltration pattern and the Th2-score were similar between patients with well-controlled asthma and those with poorly controlled asthma. In contrast, in the alveolar parenchyma, the expression of T-helper cells was significantly higher in patients with poorly controlled asthma than in patients with well-controlled asthma (P < 0.01). Furthermore, the alveolar Th2-score was significantly higher in patients with poorly controlled asthma (median 0.4) than in the controlled patients (median -0.10, P < 0.05). In addition, in contrast with bronchial Th2-score, the alveolar Th2-score correlated significantly with ACT score (r(s)=-0.62, P < 0.01) in the pooled asthma group. Collectively, our data reveal an alveolar Th2-skewed inflammation, specifically in asthmatic patients who are poorly controlled with ICSs, and suggest that pharmacological targeting of the peripheral airways may be beneficial in this large patient category.
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| 11. |
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| 12. |
- Briend, Emmanuel, et al.
(författare)
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IL-18 associated with lung lymphoid aggregates drives IFNγ production in severe COPD
- 2017
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Increased interferon gamma (IFNγ) release occurs in Chronic Obstructive Pulmonary Disease (COPD) lungs. IFNγ supports optimal viral clearance, but if dysregulated could increase lung tissue destruction. Methods: The present study investigates which mediators most closely correlate with IFNγ in sputum in stable and exacerbating disease, and seeks to shed light on the spatial requirements for innate production of IFNγ, as reported in mouse lymph nodes, to observe whether such microenvironmental cellular organisation is relevant to IFNγ production in COPD lung. Results: We show tertiary follicle formation in severe disease alters the dominant mechanistic drivers of IFNγ production, because cells producing interleukin-18, a key regulator of IFNγ, are highly associated with such structures. Interleukin-1 family cytokines correlated with IFNγ in COPD sputum. We observed that the primary source of IL-18 in COPD lungs was myeloid cells within lymphoid aggregates and IL-18 was increased in severe disease. IL-18 released from infected epithelium or from activated myeloid cells, was more dominant in driving IFNγ when IL-18-producing and responder cells were in close proximity. Conclusions: Unlike tight regulation to control infection spread in lymphoid organs, this local interface between IL-18-expressing and responder cell is increasingly supported in lung as disease progresses, increasing its potential to increase tissue damage via IFNγ.
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| 13. |
- Forkel, Marianne, et al.
(författare)
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Composition and functionality of the intrahepatic innate lymphoid cell-compartment in human nonfibrotic and fibrotic livers
- 2017
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 47:8, s. 1280-1294
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Tidskriftsartikel (refereegranskat)abstract
- Human innate lymphoid cells have been described to exist in different organs, with functional deregulation of these cells contributing to several disease states. Here, we performed the first detailed characterization of the phenotype, tissue-residency properties, and functionality of ILC1s, ILC2s, and ILC3s in the human adult and fetal liver. In addition, we investigated changes in the ILC compartment in liver fibrosis. A unique composition of tissue-resident ILCs was observed in nonfibrotic livers as compared with that in mucosal tissues, with NKp44− ILC3s accounting for the majority of total intrahepatic ILCs. The frequency of ILC2s, representing a small fraction of ILCs in nonfibrotic livers, increased in liver fibrosis and correlated directly with the severity of the disease. Notably, intrahepatic ILC2s secreted the profibrotic cytokine IL-13 when exposed to IL-33 and thymic stromal lymphopoetin (TSLP); these cytokines were produced by hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells in response to TLR-3 stimulation. In summary, the present results provide the first detailed characterization of intrahepatic ILCs in human adult and fetal liver. The results indicate a role for ILC2s in human liver fibrosis, implying that targeting ILC2s might be a novel therapeutic strategy for its treatment.
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| 14. |
- Gela, Anele, et al.
(författare)
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Osteopontin That Is Elevated in the Airways during COPD Impairs the Antibacterial Activity of Common Innate Antibiotics.
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial infections of the respiratory tract contribute to exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). There is also an increased risk of invasive pneumococcal disease in COPD. The underlying mechanisms are not fully understood but include impaired mucociliary clearance and structural remodeling of the airways. In addition, antimicrobial proteins that are constitutively expressed or induced during inflammatory conditions are an important part of the airway innate host defense. In the present study, we show that osteopontin (OPN), a multifunctional glycoprotein that is highly upregulated in the airways of COPD patients co-localizes with several antimicrobial proteins expressed in the airways. In vitro, OPN bound lactoferrin, secretory leukocyte peptidase inhibitor (SLPI), midkine, human beta defensin-3 (hBD-3), and thymic stromal lymphopoietin (TSLP) but showed low or no affinity for lysozyme and LL-37. Binding of OPN impaired the antibacterial activity against the important bacterial pathogens Streptococcus pneumoniae and Pseudomonas aeruginosa. Interestingly, OPN reduced lysozyme-induced killing of S. pneumoniae, a finding that could be explained by binding of OPN to the bacterial surface, thereby shielding the bacteria. A fragment of OPN generated by elastase of P. aeruginosa retained some inhibitory effect. Some antimicrobial proteins have additional functions. However, the muramidase-activity of lysozyme and the protease inhibitory function of SLPI were not affected by OPN. Taken together, OPN can contribute to the impairment of innate host defense by interfering with the function of antimicrobial proteins, thus increasing the vulnerability to acquire infections during COPD.
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| 15. |
- Hvidtfeldt, Morten, et al.
(författare)
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Bronchoscopic mucosal cryobiopsies as a method for studying airway disease
- 2019
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 49:1, s. 27-34
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Tidskriftsartikel (refereegranskat)abstract
- Background: Investigating disease mechanisms and treatment responses in obstructive airway diseases with invasive sampling are hampered by the small size and mechanical artefacts that conventional forceps biopsies suffer from. Endoscopic cryobiopsies are larger and more intact and are being increasingly used. However, the technique has not yet been explored for obtaining mucosa biopsies. Objective: To investigate differences in size and quality of endobronchial mucosal biopsies obtained with cryotechnique and forceps. Further, to check for eligibility of cryobiopsies to be evaluated with immunohistochemistry and in situ hybridization and to investigate tolerability and safety of the technique. Methods: Endobronchial mucosal biopsies were obtained with cryotechnique and forceps from patients with haemoptysis undergoing bronchoscopy and evaluated by quantitative morphometry, automated immunohistochemistry and in situ hybridization. Results: A total of 40 biopsies were obtained from 10 patients. Cross-sectional areas were threefold larger in cryobiopsies (median: 3.08 mm2 (IQR: 1.79) vs 1.03 mm2 (IQR: 1.10), P < 0.001). Stretches of intact epithelium were 8-fold longer (median: 4.61 mm (IQR: 4.50) vs 0.55 mm (IQR: 1.23), P = 0.001). Content of glands (median: 0.095 mm2 (IQR: 0.30) vs 0.00 mm2 (IQR: 0.01), P = 0.002) and airway smooth muscle (median: 0.25 mm2 (IQR: 0.30) vs 0.060 mm2 (IQR: 0.11), P = 0.02) was higher in the cryobiopsies compared with forceps biopsies. Further, the cryobiopsies had well-preserved protein antigens and mRNA. Mild to moderate bleeding was the only complication observed. Conclusion and clinical relevance: By yielding significantly larger and more intact biopsies, the cryotechnique represents a valuable new research tool to explore the bronchi in airway disease. Ultimately with the potential to create better understanding of underlying disease mechanisms and improvement of treatments.
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| 16. |
- Jogdand, Prajakta, et al.
(författare)
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Eosinophils, basophils, and type 2 immune microenvironments in COPD-affected lung tissue
- 2020
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 55:4
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Tidskriftsartikel (refereegranskat)abstract
- Although elevated blood or sputum eosinophils are present in many patients with chronic obstructive pulmonary disease (COPD), uncertainties remain regarding the anatomical distribution pattern of lung-infiltrating eosinophils. Basophils have remained virtually unexplored in COPD. This study mapped tissue-infiltrating eosinophils, basophils, and eosinophil-promoting immune mechanisms in COPD-affected lungs. Surgical lung tissue and biopsies from major anatomical compartments were obtained from COPD patients with severity grades GOLD I-IV; never-smokers/smokers served as controls. Automated immunohistochemistry and in-situ hybridization identified immune cells, the type 2 immunity marker GATA3, and eotaxins (CCL11, CCL24). Eosinophils and basophils were present in all anatomical compartments of COPD-affected lungs and increased significantly in very severe COPD. The eosinophilia was strikingly patchy, and focal eosinophil-rich microenvironments were spatially linked with GATA3+ cells, including Th2 lymphocytes and type 2 innate lymphoid cells. A similarly localised and IL-33/ST2-dependent eosinophilia was demonstrated in influenza-infected mice. Both mice and patients displayed spatially confined eotaxin signatures with CCL11+ fibroblasts and CCL24+ macrophages. In addition to identifying tissue basophilia as a novel feature of advanced COPD, the identification of spatially confined eosinophil-rich type 2 microenvironments represents a novel type of heterogeneity in the immunopathology of COPD that will likely have implications for personalised treatment.
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| 17. |
- Kasetty, Gopinath, et al.
(författare)
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Osteopontin protects against lung injury caused by extracellular histones
- 2019
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219 .- 1935-3456. ; 12:1, s. 39-50
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular histones are present in the airways because of cell death occurring during inflammation. They promote inflammation and cause tissue damage due to their cationic nature. The anionic phosphoglycoprotein osteopontin (OPN) is expressed at high levels during airway inflammation and has been ascribed both pro- and anti-inflammatory roles. In this study, it was hypothesized that OPN may neutralize the harmful activities of extracellular histones at the airway mucosal surface. In a model of histone-induced acute lung injury, OPN−/− mice showed increased inflammation and tissue injury, and succumbed within 24 h, whereas wild-type mice showed lower degrees of inflammation and no mortality. In lipopolysaccharide-induced acute lung injury, wild-type mice showed less inflammation and tissue injury than OPN−/− mice. In bronchoalveolar lavage fluid from ARDS patients, high levels of OPN and also histone–OPN complexes were detected. In addition, OPN bound to histones with high affinity in vitro, resulting in less cytotoxicity and reduced formation of tissue-damaging neutrophil extracellular traps (NETs). The interaction between OPN and histones was dependent on posttranslational modification of OPN, i.e., phosphorylation. The findings demonstrate a novel role for OPN, modulating the pro-inflammatory and cytotoxic properties of free histones.
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| 18. |
- Kearley, Jennifer, et al.
(författare)
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Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection.
- 2015
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Ingår i: Immunity. - : Elsevier BV. - 1074-7613. ; 42:3, s. 566-579
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Tidskriftsartikel (refereegranskat)abstract
- Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL-33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection, exacerbating disease.
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| 19. |
- Mori, Michiko, et al.
(författare)
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Appearance of remodelled and dendritic cell-rich alveolar-lymphoid interfaces provides a structural basis for increased alveolar antigen uptake in chronic obstructive pulmonary disease
- 2013
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Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 68:6, s. 521-531
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Tidskriftsartikel (refereegranskat)abstract
- Rationale The alveolar pathology in chronic obstructive pulmonary disease (COPD) involves antigen-driven immune events. However, the induction sites of alveolar adaptive immune responses have remained poorly investigated. Objectives To explore the hypothesis that interfaces between the alveolar lumen and lymphoid aggregates (LAs) provide a structural basis for increased alveolar antigen uptake in COPD lungs. Methods Lung samples from patients with mild (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I), moderate–severe (GOLD II–III), and very severe (GOLD IV) COPD were subjected to detailed histological assessments of adaptive immune system components. Never smokers and smokers without COPD served as controls. Results Quantitative histology, involving computerised three-dimensional reconstructions, confirmed a rich occurrence of alveolar-restricted LAs and revealed, for the first time, that the vast majority of vascular or bronchiolar associated LAs had alveolar interfaces but also an intricate network of lymphatic vessels. Uniquely to COPD lungs, the interface epithelium had transformed into a columnar phenotype. Accumulation of langerin (CD207)+ dendritic cells occurred in the interface epithelium in patients with COPD but not controls. The antigen-capturing capacity of langerin+ dendritic cells was confirmed by increased alveolar protrusions and physical T cell contact. Several of these immune remodelling parameters correlated with lung function parameters. Conclusions Severe stages of COPD are associated with an emergence of remodelled and dendritic cell-rich alveolar–lymphoid interfaces. This novel type of immune remodelling, which predicts an increased capacity to respond to alveolar antigens, is suggested to contribute to aggravated inflammation in COPD.
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| 20. |
- Mori, Michiko, et al.
(författare)
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Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD
- 2013
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 14
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Tidskriftsartikel (refereegranskat)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.
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| 21. |
- Mori, Michiko
(författare)
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New Aspects of Alveolar Adaptive Immune Responses in COPD
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic obstructive pulmonary disease (COPD) is characterised by a chronic inflammation in conducting airways and the alveolar parenchyma. The inflammation, which is a consequence of inhalation of noxious gases like tobacco smoke, has traditionally been thought to be driven by innate immune responses. However, more recent studies have revealed an increase in lymphocyte-rich lymphoid aggregates (LAs) and antigen presenting dendritic cells (DCs) in peripheral airways of patients with COPD. These findings suggest that peripheral adaptive immune responses and antigen-driven immune events may contribute to the immunopathology of COPD. However, the involvement of the alveolar compartment has remained unexplored. The aim of this thesis work was to provide new insights into the structural as well as the immunological basis for alveolar antigen uptake and peripheral adaptive immune responses in COPD. To investigate this, detailed immunohistochemical assessments of adaptive immune system components were performed in surgical specimens obtained from patients with different severities of COPD (GOLD stage I-IV), smokers and never-smoking control subjects. Immunohistochemistry and 3D reconstructions of serial sections were used to demonstrate a rich occurrence of alveolar-restricted LAs and reveal that also the vast majority of the bronchiolar- and vascular-associated LAs have alveolar interfaces. Importantly, in COPD patients but not in controls a selective accumulation of langerin+ DCs was observed along the alveolar-lymphoid interfaces. Moreover, these alveolar interface DCs had increased luminal protrusions and more physical contact with lymphoid T cells than the corresponding mucosal DCs. A further investigation of multiple DC subsets in different peripheral lung compartments found that in COPD the most marked increase in DC subsets, including BDCA-2+, CD1a+langerin- and CD11c+CD68-CD163- DCs, was observed in the alveolar tissue. Notably, the DCs in LA interfaces and alveolar tissue differed from airway DCs by a distinct marker expression profile. The 3D analysis revealed an intricate connection between LAs and lymphatic vessels. Further, a marked increase in the number of alveolar lymphatic vessels was detected in patients with advanced COPD. Importantly, in COPD lymphatic vessels had an activated phenotype as revealed by increased lymphatic expression of CCL21 and D6, both of which are involved in DC transport to lymphoid tissues. In conclusion, the studies in this thesis have discovered that the alveolar parenchyma in COPD lungs contain a novel type of DC-rich alveolar-lymphoid epithelium, elevated levels of multiple DC subsets as well as activated lymphatic vessels. Taken together these findings forward the alveolar parenchyma as an important arena for antigen uptake in COPD. This insight calls for future investigations to find out to what extent the resulting adaptive immune responses contribute to the COPD pathogenesis and how they can be pharmacologically targeted.
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| 22. |
- Mori, Michiko, et al.
(författare)
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Pulmonary and pleural lymphatic endothelial cells from pediatric, but not adult, patients with Gorham-Stout disease and generalized lymphatic anomaly, show a high proliferation rate
- 2016
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gorham-Stout disease (OMIM 123880) and generalized lymphatic anomaly are two rare disorders of lymphendothelial growth in which thoracic involvement with chylothorax is a feared complication. Currently it is believed that both disorders are prenatal malformations that progress slowly after birth. Several pharmaceuticals with antiproliferative properties, including interferon-α-2b, rapamycin and propranolol, have however been shown to affect the disease course in some patients. Deeper knowledge of the growth characteristics of these malformations are therefore needed to guide the clinical approach. Methods: Lymphatic vessels in lung and pleural tissue from both children and adult patients with generalized lymphatic anomaly or Gorham-Stout disease were studied using an immunohistochemical approach, targeting lymphendothelial markers (D2-40/Prox-1) and a proliferation marker (Ki-67). Results: We found significant proliferation and growth in these lesions in pediatric patients but not in adults. Furthermore, the data may suggest that the disease process is at least partly reversible. Conclusions: These malformations of the lymphatic system proliferate at a significant rate long after birth, which could suggest that the clinical approach for children should be different from adults.
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| 23. |
- Mori, Michiko, et al.
(författare)
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Small airway epithelial-C/EBPβ is increased in patients with advanced COPD.
- 2015
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- The expression of CCAAT/enhancer-binding protein (C/EBP)β in the small airway epithelium of COPD is unknown. C/EBPβ was assessed in peripheral lung tissue of non-smoking/smoking controls and patients with GOLD I-IV COPD by quantitative immunohistochemistry. The expression of C/EBPβ was decreased in smokers compared to never smokers. Furthermore, C/EBPβ was significantly elevated in advanced COPD vs. asymptomatic smokers, and the expression correlated to lung function decline. As C/EBPβ exerts pro-inflammatory effects in the context of cigarette smoke, the elevated C/EBPβ in advanced COPD may be an indication of a breakdown of regulatory mechanisms and excessive inflammation.
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| 24. |
- Påhlman, Lisa, et al.
(författare)
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Hypoxia down-regulates expression of secretory leukocyte protease inhibitor in bronchial epithelial cells via TGF-β1.
- 2015
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Ingår i: BMC Pulmonary Medicine. - : Springer Science and Business Media LLC. - 1471-2466. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Secretory leukocyte protease inhibitor (SLPI) is a protein with anti-protease and antimicrobial properties that is constitutively secreted from the airway epithelium. The importance of maintaining a balance between proteases and anti-proteases, and robust innate defence mechanisms in the airways, is exemplified by inflammatory lung conditions such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Both conditions present with a high protease burden in the airways which leads to tissue destruction. These patients also have an impaired innate immune system in the lungs with bacterial colonization and frequent airway infections. Moreover, both diseases are associated with airway hypoxia due to inflammation and mucus plugs. The aim of the present study was to investigate the role of hypoxia on SLPI production from the airway epithelium.
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| 25. |
- Ravanetti, Lara, et al.
(författare)
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IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral immunity
- 2019
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749. ; 143:4, s. 16-1370
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Tidskriftsartikel (refereegranskat)abstract
- Background: Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immunopathogenesis of exacerbations has remained elusive. Objective: We hypothesized that IL-33 is necessary to drive asthma exacerbations. We intervened with the IL-33 cascade and sought to dissect its role, also in synergy with thymic stromal lymphopoietin (TSLP), in airway inflammation, antiviral activity, and lung function. We aimed to unveil the major source of IL-33 in the airways and IL-33–dependent mechanisms that underlie severe asthma exacerbations. Methods: Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti–IL-33 receptor ST2, anti–TSLP, or both. Results: We identified bronchial ciliated cells and type II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in human subjects and mice, respectively. By blocking ST2, we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced airway hyperresponsiveness and airway inflammation by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite–sensitized mice to dampen IFN-β expression and prevent the TH1-promoting dendritic cell phenotype. IL-33 also boosted luminal NETosis and halted cytolytic antiviral activities but did not affect the TH2 response. Conclusion: Interventions targeting the IL-33/ST2 axis could prove an effective acute short-term therapy for virus-induced asthma exacerbations.
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| 26. |
- Roos, Abraham B., et al.
(författare)
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Increased IL-17RA and IL-17RC in End-Stage COPD and the Contribution to Mast Cell Secretion of FGF-2 and VEGF
- 2017
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells are accumulated in advanced chronic obstructive pulmonary disease (COPD), and interleukin (IL)-17 signaling plays a role in disease progression. The expression, localization and functional relevance of IL-17 receptor (R)A and IL-17RC was explored in COPD by immunodetection, and functional assays. IL-17RA and IL-17RC was increased in very severe COPD, and expressed by mast cells. Increased secretion of the pro-angiogenic basic fibroblast growth factor and vascular endothelial growth factor was observed in vitro-maintained mast cells stimulated with IL-17A. Expression of these mediators was confirmed in end-stage COPD. Thus, accumulation of mast cells in COPD may contribute to vascular remodeling.
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| 27. |
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| 28. |
- Roos, Abraham, et al.
(författare)
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IL-17A is Elevated in End-stage COPD and Contributes to Cigarette Smoke-induced Lymphoid Neogenesis.
- 2015
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 191:11, s. 1232-1241
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Tidskriftsartikel (refereegranskat)abstract
- End-stage chronic obstructive pulmonary disease (COPD) is associated with an accumulation of pulmonary lymphoid follicles. Interleukin (IL)-17A is implicated in COPD and pulmonary lymphoid neogenesis in response to microbial stimuli. We hypothesized that IL-17A is increased in peripheral lung tissue during end-stage COPD and also directly contributes to cigarette smoke-induced lymphoid neogenesis.
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| 29. |
- Sadegh, Mardjaneh Karbalaei, et al.
(författare)
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Biomechanical properties and innervation of the female caveolin-1-deficient detrusor.
- 2011
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; Dec, s. 1156-1170
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Caveolin-1-deficiency is associated with substantial urogenital alterations. Here, a mechanical, histological and biochemical characterization of female detrusors from wild-type (WT) and caveolin-1-deficient (KO) mice was made to increase the understanding of detrusor changes caused by lack of caveolae. Experimental approach: Length-tension relationships were generated, and we recorded responses to electrical field stimulation (EFS), the muscarinic receptor agonist carbachol, and the purinoceptor agonist ATP. Tyrosine nitration and the contents of caveolin-1, cavin-1, muscarinic M(3) receptors, phospholipase C(β1) (PLC(β1) ), muscle-specific kinase (MuSK), and L-type Ca(2+) -channels were determined by immunoblotting. Innervation was assessed by immunohistochemistry. Key results: Bladder to body weight ratio was not changed, nor was there any change in the optimum circumference for force development. Depolarization- and ATP-induced stress was reduced, as was carbachol-induced stress between 0.1 and 3 µM, but the supramaximal relative (% K(+) ) response to carbachol was increased, as was M(3) expression. The scopolamine-sensitive component of the EFS-response was impaired, and yet bladder nerves contained little caveolin-1. The density of cholinergic nerves was unchanged, whereas CART- and CGRP-positive nerves were reduced. Immunoblotting revealed loss of MuSK. Conclusions and implications: Ablation of caveolae in the female detrusor leads to generalised impairment of contractility, ruling out prostate hypertrophy as a contributing factor. Cholinergic neuroeffector transmission is impaired without conspicuous changes in the density of cholinergic nerves or morphology of their terminals, but correlating with reduced expression of MuSK.
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| 30. |
- Sanden, Caroline, et al.
(författare)
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Broad Th2 neutralization and anti-inflammatory action of pentosan polysulfate sodium in experimental allergic rhinitis
- 2017
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Ingår i: Immunity, Inflammation and Disease. - : Wiley. - 2050-4527. ; 5:3, s. 300-309
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Tidskriftsartikel (refereegranskat)abstract
- Th2 cytokines like interleukin-4, -5, and -13 are regarded as important drivers of the immunopathology underlying allergic rhinitis (AR) and asthma. The present study explores the capacity of pentosan polysulfate sodium (PPS), a semi-synthetic heparin-like macromolecular carbohydrate, to bind Th2 cytokines and exert biological neutralization in vitro, as well as anti-inflammatory actions in vivo.
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| 31. |
- Shakirova, Yulia, et al.
(författare)
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Human urinary bladder smooth muscle is dependent on membrane cholesterol for cholinergic activation.
- 2010
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 634, s. 142-148
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Tidskriftsartikel (refereegranskat)abstract
- Voiding is mediated by muscarinic receptors in urinary bladder smooth muscle cells. Lipid rafts and caveolae are cholesterol enriched membrane domains that modulate the activity of G protein-coupled receptors and second messenger systems. Conflicting findings regarding sensitivity of muscarinic signalling to cholesterol desorption, which perturbs lipid rafts and caveolae, have been reported, and no study has used human urinary bladder. Here, the dependence of human bladder muscarinic receptor signalling on plasma membrane cholesterol was examined. Nerve-mediated contraction, elicited by electrical field stimulation of human bladder strips, was impaired by desorption of cholesterol using methyl-beta-cyclodextrin, and the concentration-response curve for the muscarinic agonist carbachol was right-shifted. No effect of cholesterol desorption was observed in rat, and in mouse increased maximum contraction was seen. Expression of caveolin-1, PLC(beta1) and M(3) muscarinic receptors did not differ between species in a manner that would explain the differential sensitivity to cholesterol desorption. In human bladder, threshold depolarisation eliminated the difference between cyclodextrin-treated and control preparations. Contraction elicited by depolarisation per se was not affected. M(3) muscarinic receptors appeared clustered along plasma membrane profiles as shown by immunohistochemical staining of human bladder, but no redistribution in association with cholesterol reduction were seen. Thus, muscarinic receptor-induced contraction of the urinary bladder exhibits species-specific differences in its sensitivity to cholesterol desorption suggesting differential roles of lipid rafts/caveolae in muscarinic receptor signalling between species.
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| 32. |
- Shikhagaie, Medya Mara, et al.
(författare)
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Neuropilin-1 Is Expressed on Lymphoid Tissue Residing LTi-like Group 3 Innate Lymphoid Cells and Associated with Ectopic Lymphoid Aggregates
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 18:7, s. 1761-1773
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Tidskriftsartikel (refereegranskat)abstract
- Here, we characterize a subset of ILC3s that express Neuropilin1 (NRP1) and are present in lymphoid tissues, but not in the peripheral blood or skin. NRP1+ group 3 innate lymphoid cells (ILC3s) display in vitro lymphoid tissue inducer (LTi) activity. In agreement with this, NRP1+ ILC3s are mainly located in proximity to high endothelial venules (HEVs) and express cell surface molecules involved in lymphocyte migration in secondary lymphoid tissues via HEVs. NRP1 was also expressed on mouse fetal LTi cells, indicating that NRP1 is a conserved marker for LTi cells. Human NRP1+ ILC3s are primed cells because they express CD45RO and produce higher amounts of cytokines than NRP1− cells, which express CD45RA. The NRP1 ligand vascular endothelial growth factor A (VEGF-A) served as a chemotactic factor for NRP1+ ILC3s. NRP1+ ILC3s are present in lung tissues from smokers and patients with chronic obstructive pulmonary disease, suggesting a role in angiogenesis and/or the initiation of ectopic pulmonary lymphoid aggregates.
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| 33. |
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| 34. |
- Siddhuraj, Premkumar, et al.
(författare)
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Histology-based blood leukocyte profiling reveals parallel Th2 and Th17 signatures in seasonal allergic rhinitis
- 2022
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 142:9-12, s. 696-704
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Allergic rhinitis (AR), a common condition in the westernized world, is suggested to be more immunologically complex than the archetypical 'Th2' inflammation. New approaches are needed to decode this complexity.AIMS/OBJECTIVES: In this study, we explored a novel histology-based analysis for circulating blood leukocyte profiling in 16 patients with seasonal AR outside and during the pollen season.MATERIAL AND METHODS: Leukocytes were purified with minimal ex-vivo artefacts, embedded into agarose-paraffin pellets for immunohistochemistry-based immune cell profiling. Blood leukocyte mapping was performed.RESULTS: Samples collected during the pollen season had statistically increased eosinophils, neutrophils, monocytes, and CD8+ T-lymphocytes compared to the off-season baseline. In contrast, no change was observed for CD20+ B-lymphocytes and CD3+ T-lymphocytes. Subclassification of CD4+ T-helper cells demonstrated a parallel and significant expansion of Th2 and Th17-cells during the pollen season, while Th1-cells remained unchanged. Whereas absolute basophils numbers were unaltered, the basophil markers GATA2 and CPA3 increased during the pollen season.CONCLUSIONS AND SIGNIFICANCE: This study introduces a novel and applicable method for systemic immune cell screening and provides further evidence of complex and parallel Th2 and Th17-immune signatures in seasonal AR. It also forwards GATA2 and CPA3 as potential biomarkers for ongoing allergic inflammation.
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| 35. |
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| 36. |
- Swärd, Karl, et al.
(författare)
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Elevated pulmonary arterial pressure and altered expression of Ddah1 and Arg1 in mice lacking cavin-1/PTRF.
- 2013
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Ingår i: Physiological Reports. - 2051-817X. ; 1:1, s. 00008-00008
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Tidskriftsartikel (refereegranskat)abstract
- Caveolae are invaginations in the plasma membrane that depend on caveolins and cavins for maturation. Here, we investigated the pulmonary phenotype in mice lacking cavin-1. Bright field and electron-microscopy showed that the cavin-1-deficient mice lacked caveolae in the lung, had an increased lung tissue density, and exhibited hypertrophic remodeling of pulmonary arteries. The right ventricle of the heart moreover had an increased mass and the right ventricular pressure was elevated. A microarray analysis revealed upregulation of Arg1 and downregulation of Ddah1, molecules whose altered expression has previously been associated with pulmonary arterial hypertension. Taken together, this work demonstrates vascular remodeling and increased pulmonary blood pressure in cavin-1 deficient mice and associates this phenotype with altered expression of Arg1 and Ddah1.
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