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- Padra, Médea, 1986, et al.
(författare)
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Increased MUC1 plus a larger quantity and complex size for MUC5AC in the peripheral airway lumen of long-term tobacco smokers
- 2020
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Ingår i: Clinical Science. - : Portland Press Ltd.. - 0143-5221 .- 1470-8736. ; 134:10, s. 1107-1125
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Tidskriftsartikel (refereegranskat)abstract
- There is little information on mucins versus potential regulatory factors in the peripheral airway lumen of long-term smokers with (LTS+) and without (LTS-) chronic obstructive pulmonary disease (COPD). We explored these matters in bronchoalveolar lavage (BAL) samples from two study materials, both including LTS+ and LTS- with a very similar historic exposure to tobacco smoke, and healthy non-smokers (HNSs; n=4-20/group). Utilizing slot blot and immunodetection of processed (filtered and centrifuged), as well as unprocessed BAL samples from one of the materials, we compared the quantity and fraction of large complexes of mucins. All LTS displayed an enhanced (median) level of MUC5AC compared with HNS. LTS- displayed a higher level of large MUC5AC complexes than HNS while LTS+ displayed a similar trend. In all LTS, total MUC5AC correlated with blood leukocytes, BAL neutrophil elastase and net gelatinase activity. Large mucin complexes accounted for most MUC5B, without clear group differences. In all LTS, total MUC5B correlated with total MUC5AC and local bacteria. In the same groups, large MUC5B complexes correlated with serum cotinine. MUC1 was increased and correlated with BAL leukocytes in all LTS whereas MUC2 was very low and without clear group differences. Thus, the main part of MUC5AC and MUC5B is present as large complexes in the peripheral airway lumen and historic as well as current exposure to tobacco smoke emerge as potential regulatory factors, regardless of COPD per se. Bacteria, leukocytes and proteinases also constitute potential regulatory factors, of interest for future therapeutic strategies.
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- Che, K. F., et al.
(författare)
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Interleukin-26 in Antibacterial Host Defense of Human Lungs Effects on Neutrophil Mobilization
- 2014
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 190:9, s. 1022-1031
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: The role of the presumed Th17 cytokine IL-26 in antibacterial host defense of the lungs is not known. Objectives: To characterize the role of IL-26 in antibacterial host defense of human lungs. Methods: Intrabronchial exposure of healthy volunteers to endotoxin and vehicle was performed during bronchoscopy and bronchoalveolar lavage (BAL) samples were harvested. Intracellular IL-26 was detected using immunocytochemistry and immunocytofluorescence. This IL-26 was also detected using flow cytometry, as was its receptor complex. Cytoldnes and phosphorylated signal transducer and activator of transcription (STAT) 1 plus STAT3 were quantified using ELISA. Gene expression was analyzed by real-time polymerase chain reaction and neutrophil migration was assessed in vitro. Measurements and Main Results: Extracellular IL-26 was detected in BAL samples without prior exposure in vivo and was markedly increased after endotoxin exposure. Alveolar macrophages displayed gene expression for, contained, and released IL-26. Th and cytotoxic T cells also contained IL-26. In the BAL samples, IL-26 concentrations and innate effector cells displayed a correlation. Recombinant IL-26 potentiated neutrophil chemotaxis induced by IL-8 and fMLP but decreased chemokinesis for neutrophils. Myeloperoxidase in conditioned media from neutrophils was decreased. The IL-26 receptor complex was detected in neutrophils and IL-26 decreased phosphorylated STAT3 in these cells. In BAL and bronchial epithelial cells, IL-26 increased gene expression of the IL-26 receptor complex and STAT1 plus STAT3. Finally, IL-26 increased the release of neutrophil-mobilizing cytokines in BAL but not in epithelial cells. Conclusions: This study implies that alveolar macrophages produce IL-26, which stimulates receptors on neutrophils and focuses their mobilization toward bacteria and accumulated immune cells in human lungs.
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| 10. |
- Che, K. F., et al.
(författare)
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The neutrophil-mobilizing cytokine interleukin-26 in the airways of long-term tobacco smokers
- 2018
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Ingår i: Clinical Science. - : Portland Press Ltd.. - 0143-5221 .- 1470-8736. ; 132:9, s. 959-983
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Tidskriftsartikel (refereegranskat)abstract
- Long-term tobacco smokers with chronic obstructive pulmonary disease (COPD) or chronic bronchitis display an excessive accumulation of neutrophils in the airways; an inflammation that responds poorly to established therapy. Thus, there is a need to identify new molecular targets for the development of effective therapy. Here, we hypothesized that the neutrophil-mobilizing cytokine interleukin (IL)-26 (IL-26) is involved in airway inflammation amongst long-term tobacco smokers with or without COPD, chronic bronchitis or colonization by pathogenic bacteria. By analyzing bronchoalveolar lavage (BAL), bronchail wash (BW) and induced sputum (IS) samples, we found increased extracellular IL-26 protein in the airways of long-term smokers in vivo without further increase amongst those with clinically stable COPD. In human alveolar macrophages (AM) in vitro, the exposure to water-soluble tobacco smoke components (WTC) enhanced IL-26 gene and protein. In this cell model, the same exposure increased gene expression of the IL-26 receptor complex (IL10R2 and IL20R1) and nuclear factor kappa B (NF-kappa B); a proven regulator of IL-26 production. In the same cell model, recombinant human IL-26 in vitro caused a concentration-dependent increase in the gene expression of NF-kappa B and several pro-inflammatory cytokines. In the long-term smokers, we also observed that extracellular IL-26 protein in BAL samples correlates with measures of lung function, tobacco load, and several markers of neutrophil accumulation. Extracellular IL-26 was further increased in long-term smokers with exacerbations of COPD (IS samples), with chronic bronchitis (BAL samples) or with colonization by pathogenic bacteria (IS and BW samples). Thus, IL-26 in the airways emerges as a promising target for improving the understanding of the pathogenic mechanisms behind several pulmonary morbidities in long-term tobacco smokers.
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| 14. |
- Harmankaya, Necati, 1983, et al.
(författare)
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Healing of complement activating Ti implants compared with non-activating Ti in rat tibia.
- 2012
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Ingår i: Acta biomaterialia. - : Elsevier BV. - 1878-7568 .- 1742-7061. ; 8:9, s. 3532-40
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have revealed that ozone ultraviolet (UVO) illumination of titanium (Ti) implants improves bone-implant anchorage by altering the physico-chemical and immune activating properties of the titanium dioxide (TiO(2)) layer. In the present rat tibia model, the authors compared the early events of inflammation and bone formation around UVO-treated Ti and complement activating immunoglobin g (IgG)-coated Ti. Machined Ti and machined Ti coated with a physical vapour-deposited Ti layer were used as references. Screw-shaped test and reference implants were implanted into rat tibia and harvested after 1, 7 and 28 days. Messenger RNA expression of implant adhered cells and peri-implant tissue ~250 μm from the surface were subsequently analysed with regard to IL-1β, TNF-α, osteocalcin, cathepsin K, BMP-2 and PDGF. Separate implants were retrieved after 7 and 28 days for removal torque measurements, and histological staining and histomorphometric analysis of bone area and bone-to-implant contact. While enhanced expression of inflammatory markers, TNF-α and IL-1β, was observed on IgG-coated surfaces throughout the observation time, UVO-treated surfaces indicated a significantly lower early inflammatory response. In the early phases (1 and 7 days), the UVO-treated surfaces displayed a significantly higher expression of osteoblast markers BMP-2 and osteocalcin. In summary, complement activating Ti implants elicited a stronger inflammatory response than UVO-treated Ti, with low complement activation during the first week of healing. In spite of this, the UVO-treated Ti induced only marginally more bone growth outside the implants.
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| 15. |
- Harmankaya, Necati, 1983, et al.
(författare)
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Raloxifene and alendronate containing thin mesoporous titanium oxide films improve implant fixation to bone.
- 2013
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Ingår i: Acta biomaterialia. - : Elsevier BV. - 1878-7568 .- 1742-7061. ; 9:6, s. 7064-73
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Tidskriftsartikel (refereegranskat)abstract
- This study tested the hypothesis that osteoporosis drug-loaded mesoporous TiO2 implant coatings can be used to improve bone-implant integration. Two osteoporosis drugs, Alendronate (ALN) and Raloxifene (RLX), were immobilized in nanoporous oxide films prepared on Ti screws and evaluated in vivo in rat tibia. The drug release kinetics were monitored in vitro by quartz crystal microbalance with dissipation and showed sustained release of both drugs. The osteogenic response after 28days of implantation was evaluated by quantitative polymerase chain reaction (qPCR), removal torque, histomorphometry and ultrastructural interface analysis. The drug-loaded implants showed significantly improved bone fixation. In the case of RLX, stronger bone-remodelling activity was observed compared with controls and ALN-loaded implants. The ultrastructural interface analysis revealed enhanced apatite formation inside the RLX coating and increased bone density outside the ALN coating. Thus, this novel combination of a thin mesoporous TiO2 carrier matrix and appropriate drugs can be used to accelerate implant fixation in trabecular bone.
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| 18. |
- Lestelius, Magnus, et al.
(författare)
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Order/disorder gradients of n-alkanethiols on gold
- 1999
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Ingår i: Colloids and Surfaces B. - : Elsevier. - 0927-7765 .- 1873-4367. ; 15:1, s. 57-70
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Tidskriftsartikel (refereegranskat)abstract
- This paper explores the interfacial properties of one-dimensional molecular gradients of alkanethiols (HS-(CH2)(n)- X) on gold. The kinetics and thermodynamics of monolayer formation are important issues for these types of mixed molecular assemblies. The influence of chain length difference on the contact angles with hexadecane (HD), theta(a) and theta(r), and the hysteresis, has been studied by employing alkanethiols HS-(CH2)(n)-CH3, with n = 9, 11, 13, 15 and 17, in the preparation of the self-assembled monolayers (SAM) gradients. The contact angles with hexadecane, at the very extreme ends of the gradients, show characteristic values of a highly ordered CH3-like assembly: theta(a) = 45-50 degrees. In the middle of the gradients theta(a) drops noticeably and exhibits values representative for CH2-like polymethylenes, theta(a) = 20-30 degrees, indicating a substantial disordering of the protruding chains of the longer component in the gradient assembly. As expected, the exposure of CH2-groups to the probing liquid increases with increasing differential chain length of the two n-alkanethiol used, in this case eight methylene units. However, the contact angles always display a non-zero value which means that even at a chain length difference of eight methylene units there is a substantial exposure of methyl (CH3) groups to the probing liquid. With infrared reflection-absorption spectroscopy (IRAS) we have monitored the structural behavior of the polymethylene chains along the gradient. We find complementary evidence for disordered chains in the gradient region, and the IRAS results correlate well with the contact angle measurements. (C) 1999 Elsevier Science B.V. All rights reserved.
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| 19. |
- Lingaas, Frode, et al.
(författare)
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Bayesian mixed model analysis uncovered 21 risk loci for chronic kidney disease in boxer dogs
- 2023
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Author summaryChronic kidney disease (CKD) is described as a set of heterogeneous disorders affecting kidney structure and function. CKD is common in dogs and has been diagnosed in nearly all breeds. In this study, we identified 21 genetic regions associated with CKD in a boxer population and investigated the relevant genes and putative regulatory variants in these regions. Studies of canine CKD may help to better understand the pathology of kidney disease in both dogs and humans, and shows an important potential for early identification of high-risk individuals. Chronic kidney disease (CKD) affects 10% of the human population, with only a small fraction genetically defined. CKD is also common in dogs and has been diagnosed in nearly all breeds, but its genetic basis remains unclear. Here, we performed a Bayesian mixed model genome-wide association analysis for canine CKD in a boxer population of 117 canine cases and 137 controls, and identified 21 genetic regions associated with the disease. At the top markers from each CKD region, the cases carried an average of 20.2 risk alleles, significantly higher than controls (15.6 risk alleles). An ANOVA test showed that the 21 CKD regions together explained 57% of CKD phenotypic variation in the population. Based on whole genome sequencing data of 20 boxers, we identified 5,206 variants in LD with the top 50 BayesR markers. Following comparative analysis with human regulatory data, 17 putative regulatory variants were identified and tested with electrophoretic mobility shift assays. In total four variants, three intronic variants from the MAGI2 and GALNT18 genes, and one variant in an intergenic region on chr28, showed alternative binding ability for the risk and protective alleles in kidney cell lines. Many genes from the 21 CKD regions, RELN, MAGI2, FGFR2 and others, have been implicated in human kidney development or disease. The results from this study provide new information that may enlighten the etiology of CKD in both dogs and humans.
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| 20. |
- Padra, Médea, 1986, et al.
(författare)
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Mucin Binding to Moraxella catarrhalis During Airway Inflammation is Dependent on Sialic Acid.
- 2021
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Ingår i: American journal of respiratory cell and molecular biology. - 1535-4989. ; 65:6, s. 593-602
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) is associated with colonization by bacterial pathogens and repeated airway infections, leading to exacerbations and impaired lung function. The highly glycosylated mucins in the mucus lining the airways are an important part of the host defense against pathogens. However, mucus accumulation can contribute to COPD pathology. Here, we examined whether inflammation is associated with glycosylation changes that affect interactions between airway mucins and pathogens. We isolated mucins from lower airway samples (LAS, n=4-9) from long-term smokers with and without COPD and from never-smokers. The most abundant terminal glycan moiety was N-acetylneuraminic acid (Neu5Ac) among smokers with and without COPD and N-acetyl-hexoseamine among never-smokers. Moraxella catarrhalis bound to MUC5 mucins from smokers with and without COPD. M. catarrhalis binding correlated with inflammatory parameters and Neu5Ac content. M. catarrhalis binding was abolished by enzymatic removal of Neu5Ac. Furthermore, M. catarrhalis bound to α2-6 sialyl-lactose suggesting that α2-6 sialic acid contributes to M. catarrhalis binding to mucins. Further, we detected more M. catarrhalis binding to mucins from patients with pneumonia than to those from control subjects (n=8-13) and this binding correlated with C-reactive protein and Neu5Ac levels. These results suggest a key role of inflammation induced Neu5Ac in adhesion of M. catarrhalis to airway mucins. Inflammation induced ability of MUC5 mucins to bind M. catarrhalis is likely a host defense mechanism in the healthy lung, although it cannot be excluded that impaired mucociliary clearance limits the effectiveness of this defense in COPD patients.
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- Tengvall, Sara, 1977, et al.
(författare)
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Gene Therapy Induces Antigen-Specific Tolerance in Experimental Collagen-Induced Arthritis
- 2016
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- Here, we investigate induction of immunological tolerance by lentiviral based gene therapy in a mouse model of rheumatoid arthritis, collagen II-induced arthritis (CIA). Targeting the expression of the collagen type II (CII) to antigen presenting cells (APCs) induced antigen-specific tolerance, where only 5% of the mice developed arthritis as compared with 95% of the control mice. In the CII-tolerized mice, the proportion of Tregs as well as mRNA expression of SOCS1 (suppressors of cytokine signaling 1) increased at day 3 after CII immunization. Transfer of B cells or non-B cell APC, as well as T cells, from tolerized to naive mice all mediated a certain degree of tolerance. Thus, sustainable tolerance is established very early during the course of arthritis and is mediated by both B and non-B cells as APCs. This novel approach for inducing tolerance to disease specific antigens can be used for studying tolerance mechanisms, not only in CIA but also in other autoimmune diseases.
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| 23. |
- Tengvall, Sara, 1977, et al.
(författare)
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Interleukin-26: An Emerging Player in Host Defense and Inflammation
- 2016
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 8:1, s. 15-22
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Tidskriftsartikel (refereegranskat)abstract
- The production of interleukin (IL)-26 was initially attributed to T cells, and in particular to Th17 cells. However, more recent findings indicate IL-26 production in natural killer (NK) cells, macrophages and fibroblast-like cells as well. It is known that IL-26 binds to the IL-20R1/IL-10R2 receptor complex on certain target cells, where it causes specific intracellular signaling and the secretion of IL-1 beta, IL-8 and TNF-alpha. In line with this type of proinflammatory role, IL-26 also increases chemotaxis of human neutrophils. Interestingly, high levels of IL-26 are present even in normal human airways, and endotoxin exposure further enhances these levels; this indicates involvement in antibacterial host defense. Studies on acute inflammatory disorders are few but there are studies showing the involvement of IL-26 in rheumatoid arthritis and inflammatory bowel disease. In conclusion, IL-26 is emerging as a potentially important player in host defense and may also be a pathogenic factor in the chronic inflammatory disorders of humans. (C) 2015 S. Karger AG, Basel
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