Browsing by Author "Kanik, ET"

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    Influence of VEGF and TNF antagonism on zonula occludens proteins in an experimental asthma model
    Yuksel, H; Yilmaz, O; Karaman, M; Firinci, F; Turkeli, A; Kanik, ET; Inan, S
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    Changes in epithelial barrier components E-cadherin, Beta-catenin, EGR with steroid treatment in murine model of asthma
    Yuksel, H; Yilmaz, O; Karaman, M; Firinci, F; Turkeli, A; Kanik, ET; Inan, S
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    Epithelial Barrier Dysfunction Related To Neutrophilic Inflammation In Non-Cystic Fibrosis Bronchiectasis
    Yilmaz, O; Simsek, Y; Aslan, C; Kanik, ET; Ulman, C; Yildiz, R; Ozdogru, E; Yuksel, H
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    Anti-VEGF treatment suppresses remodeling factors and restores epithelial barrier function through the E-cadherin/β-catenin signaling axis in experimental asthma models
    Türkeli, A; Yilmaz, Ö; Karaman, M; Kanik, ET; Firinci, F; Inan, S; Yüksel, H
    Besides maintaining a physical barrier with adherens junctional (AJ) and tight junctional proteins, airway epithelial cells have important roles in modulating the inflammatory processes of allergic asthma. E-cadherin and beta-catenin are the key AJ proteins that are involved in airway remodeling. Various mediators such as transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet derived growth factor (PDGF), insulin-like growth factor (IGF), tumor necrosis factor-alpha (TNF-alpha) and angiogenic factors, such as vascular endothelial growth factor (VEGF), are released by the airway epithelium in allergic asthma. The signaling pathways activated by these growth factors trigger epithelial-mesenchymal transition (EMT), which contributes to fibrosis and subsequent downregulation of E-cadherin. The present study used a mouse asthma model to investigate the effects of anti-VEGF, anti-TNF and corticosteroid therapies on growth factor and E-cadherin/beta-catenin expression. The study used 38 male BALB/c mice, divided into 5 groups. A chronic mouse asthma model was created by treating 4 of the groups with inhaled and intraperitoneal ovalbumin (n= 8 per group). Saline, anti-TNF-alpha (etanercept), anti-VEGF (bevacizumab) or a corticosteroid (dexamethasone) were applied to each group by intraperitoneal injection. No medication was administered to the control group (n=6). Immunohistochemistry for E-cadherin, beta-catenin and growth factors was performed on lung tissues and protein expression levels assessed using H-scores. Statistically significant differences were observed in E-cadherin, beta-catenin, EGF, FG, and PFGF (P<0.001 for all) as well as the IGF H-scores between the five groups (P<0.005). Only anti-VEGF treatment caused E-cadherin and beta-catenin levels to increase to the level of non-asthmatic control groups (P>0.005). All treatment groups had reduced TGF-beta, PDGF and FGF H-scores in comparison with the untreated asthma group (P=0.001). The EGF and IGF levels were not significantly different between the untreated asthmatic and non-asthmatic controls. The results suggested that anti-VEGF and TNF-alpha inhibition treatments are effective in decreasing growth factors, in a similar manner to conventional corticosteroid treatments. Anti-VEGF and TNF inhibition therapy may be an effective treatment for remodeling in asthma while offering an alternative therapeutic option to steroid protective agents. The data suggested that anti-VEGF treatment offered greater restoration of the epithelial barrier than both anti-TNF-alpha and corticosteroid treatment.
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    Sensitization to food allergens is associated with more severe wheezing in children
    Yilmaz, O; Patino, CM; Taneli, F; Kanik, ET; Turkeli, A; Gozukara, C; Irmak, S; Yuksel, H
    Aims: We investigated sensitization to food allergens as a prognostic factor for wheezing in children with recurrent wheezing and compared serum club cell 16 (CC16) and surfactant protein D (SP-D) among these children with and without sensitization to food allergens. Materials and methods: Children with recurrent wheezing were enrolled in this prospective cohort study. Specific IgE to five common food allergens (Fx5) was assessed at baseline, and children were followed-up for 1 year for new-onset wheezing episodes. Baseline wheezing severity score, CC16, and SP-D levels were measured. Results: We enrolled 295 children (44 Fx5(+)). Poisson regression analysis revealed that Fx5 positivity changed the yearly frequency of wheeze by a factor of 1.66 (p = 0.05, 95% CI: (0.99 - 2.75)). Levels of CC16 and SP-D were not significantly different between the groups (p = 0.679 and p = 0.988). Conclusion: Sensitization to food allergens irrespective of food associated clinical allergy findings is associated with worse prognosis of wheezing in children.
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    Clinical correlation of epithelial barrier dysfunction related to neutrophilic inflammation in cystic fibrosis
    Kanik, ET; Yilmaz, O; Ozdogru, E; Alper, H; Ulman, C; Kanik, A; Simsek, Y; Yuksel, H
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    Defective epithelial barrier function related to zonula occludens proteins of nasal mucosa in subjects with atopy
    Yilmaz, O; Inan, S; Pinar, E; Turkeli, A; Turkoz, E; Kanik, ET; Yuksel, H
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    Screening Di George Syndrome with A Single Tube of Blood in Cases with Congenital Cardiopathies
    Aksu, G; Karaca, NE; Koroglu, OA; Karaca, E; Kanik, ET; Levent, E; Ozkinay, F
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    Vascular endothelial growth factor antagonism restores epithelial barrier dysfunction via affecting zonula occludens proteins
    Yuksel, H; Yilmaz, O; Karaman, M; Firinci, F; Turkeli, A; Kanik, ET; Inan, S
    Epithelial barrier dysfunction is important in the pathogenesis of asthma and allergic responses, and is therefore a therapeutic target. The aim of the present study was to investigate the effects of dexamethasone, a classic therapeutic agent, an anti-tumor necrosis factor agent (etanercept), which is used to treat difficult cases of asthma, and an anti-vascular endothelial growth factor (VEGF) agent (bevacizumab), which is an angiogenesis inhibitor, on zonula occludens (ZO) proteins in an experimental asthma model. The experimental model of asthma was developed using intraperitoneal (IP) and inhaled administration of ovalbumin in 38 BALB/c mice, which were divided into four groups. The control group (n=6) did not receive any treatment, while the four remaining groups (n=8 per group) received an IP injection of saline, etanercept, bevacizumab or dexamethasone, respectively. Occludin, claudin and junctional adhesion molecule (JAM) were immunohistochemically stained in the left middle lobe samples using an indirect avidin-peroxidase method, after which the staining was semiquantified with H-scores. Statistically significant differences were observed in the occludin, claudin and JAM H-scores among the four groups (P<0.001). In the untreated asthma, etanercept, bevacizumab and dexamethasone groups, the median H-scores for occludin were 93, 177, 280 and 198, respectively, while the H-scores for claudin were 82, 193.5, 274 and 202.5, respectively, and the median H-scores for JAM were 130, 210, 288 and 210, respectively. Pairwise comparisons revealed that all three ZO protein H-scores were significantly lower in the saline group when compared with each treatment group. However, the H-scores of the ZO proteins were not significantly different between the etanercept and dexamethasone groups. Furthermore, the bevacizumab group exhibited higher H-scores for all the proteins compared with the dexamethasone group. Therefore, antagonism of VEGF with bevacizumab restores the epithelial barrier to a greater extent when compared with dexamethasone treatment. This result may be promising for the development of novel therapeutic agents.
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    Relevance between clinical status and exhaled molecules related to neutrophilic inflammation in pediatric cystic fibrosis
    Kanik, ET; Yilmaz, O; Ozdogru, E; Alper, H; Ulman, C; Kanik, A; Simsek, Y; Yuksel, H
    Introduction:Cystic fibrosis (CF) is characterized with chronic inflammation with neutrophil and related cytokines in airway secretions. We aimed to measure the levels of neutrophil related inflammatory markers as nitric oxide, IL-8, IL-17, leukotriene B4 and neutrophil elastase as well as e-cadherin in exhaled breath condensate (EBC), and to determine their relation with clinical findings.Methods:We consecutively enrolled cystic fibrosis patients into our clinics between the age of six and eighteen years who could cooperate for exhaled breath condensate to this case-control study (n = 30). The age and sex matched control group (n = 26) was enrolled. Spirometry was performed during the stable period and EBC samples were obtained for measurement of the markers.Results:The mean age of the subjects enrolled was 12.1(4.2) years and 40% were positive forP.Aeruginosain sputum. Subjects who hadP.Aeruginosain sputum cultures had significantly lower FEV1, FVC and FEF 25/75 values compared to the ones withoutP.Aeruginosa(p = 0.002, p = 0.002 and p = 0.005 respectively). EBC neutrophil elastase levels were significantly higher in the CF patients compared to non-CF controls (3.11 4.71 versus 0.90 2.68, p = 0.04). Nitric oxide, IL-17, IL-8, e-cadherin, neutrophil elastase or leukotriene B4 levels in EBC of CF patients were not related toP.Aeruginosas infection, FEV1 levels or hospital admission in the last year.Conclusion:In our study, neutrophil elastase levels in EBC are higher in CF patients compared to non-CF controls. This is independent of acute infection and is evidence to the persistence of neutrophilic lung injury. However, EBC NO, IL-8, IL-17, e-cadherin, neutrophil elastase and leukotriene B4 levels as inflammatory markers, are not correlated with disease progression or clinical findings.
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    Food Allergen Sensitivity As A Prognostic Factor For Wheezing In Children
    Yilmaz, O; Taneli, F; Kanik, ET; Turkeli, A; Gozukara, C; Yuksel, H
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    A case of propionic acidemia presenting with choreoathetoid movements
    Kanik, ET; Agin, H; Ünalp, A; Isgüder, R; Küçük, M; Kayserili, E
    Propionic acidemia is a disorder of branch-chain aminoacid metabolism. The defect is in the propionyl-CoA carboxylase enzyme with a resultant accumulation of toxic organic acid metabolites. This disorder most commonly is characterized by episodic decompansations with dehydration, lethargy, nause and vomiting. Patients with propionic acidemia usually present in the neonatal period with life-threatining ketoacidosis, often complicated by hyperammonemia. Neurological findings and mental retardation could accompanied clinical manifestations. We report a six-month-old child who had been investigated for choreoathetoid movements and pancytopenia in our clinic with unusual manifestations with a diagnosis of propionic acidemia.
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    E-cadherin as an epithelial barrier protein in exhaled breath condensate
    Yuksel, H; Turkeli, A; Taneli, F; Horasan, GD; Kanik, ET; Kizilkaya, M; Gozukara, C; Yilmaz, O
    Airway epithelium plays an important role as a physical barrier and a modulator of allergic response. Junctions between cells provide epithelial integrity and barrier function. The aim of this study was to investigate the influence of atopy on airway epithelial integrity in asthma and to measure E-cadherin levels in exhaled breath condensate as an indicator epithelial damage. A total of 74 patients with asthma (35 atopic and 39 non-atopic) and 39 healthy children were enrolled in this case-control study. Sociodemographic characteristics and asthma severity parameters in the last three-month period were recorded and pulmonary function tests were performed. Blood samples were obtained to measure serum immunoglobulin E (IgE) levels and peripheral blood eosinophil count, and exhaled breath condensate (EBC) was obtained to measure E-cadherin. EBC E-cadherin levels were significantly lower in the asthmatics when compared to non-atopic controls (0.109 (0.076) versus 0.191 (0.184) ng mL(-1) respectively, p = 0.01). Atopic and non-atopic asthmatic groups had lower EBC E-cadherin levels compared to the control group. (0.112 (0.060) ng ml(-1), 0.106 (0.089) ng ml(-1) and 0.191 (0.184) ng ml(-1), p = 0.02 and p < 0.01 respectively). However, EBC E-cadherin levels were not different between atopic and nonatopic asthmatics. The results of our study support the role of E-cadherin in the pathogenesis of asthma. However, the absence of difference in E-cadherin levels between atopic and non-atopic asthmatics suggests that allergic sensitization is not the primary factor for development of epithelial barrier dysfunction in asthma.
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    Low Mononuclear Cell IL-18 and IL-27 Response in Children: Susceptibility to Tuberculosis Infection after Contact
    Karabacak, HA; Yilmaz, O; Tuglu, I; Taneli, F; Surucuoglu, S; Kanik, ET; Ozkutuk, N; Gozukara, C; Ozkut, MM; Turkeli, A; Yuksel, H
    Background Identification of the immune response against tuberculosis is vital to develop new diagnostic and therapeutic modalities. The objective of this study was to determine IL (interleukin)-18 and IL-27 responses of peripheral blood mononuclear cells to early secreted antigen (ESAT-6) and culture filtrate protein-10 (CFP-10) stimulation in children with a (+) or (-) tuberculin skin test (TST) with in-house tuberculosis contact. Methods We enrolled 40 children aged 1 to 5 years who had an in-house contact with a tuberculous adult. Blood samples were obtained from all children for QuantiFERON tuberculosis (TB) gold in tube (QFT-GIT), and peripheral blood mononuclear blood cell culture tests. The subjects were grouped as TST (-) QFT-GIT (-), TST (+) QFT-GIT (-), and TST (+) QFT-GIT (+). Supernatant of peripheral blood mononuclear cell culture was separated with and without stimulation of ESAT-6 and CFP-10, and IL-18 and IL-27 levels were measured with enzyme linked immunoassay (ELISA) test. Results The study group included 22 boys and 18 girls with mean age 4.25 +/- 0.9 years. IL-18 and IL-27 levels were statistically significant in ESAT-6/CFP-10-stimulated supernatants of peripheral blood mononuclear cell (PBMC) samples among the three groups (p = 0.000,p = 0.007, respectively). IL-18 levels between the TST (-) QFT-GIT (-) and TST (+) QFT-GIT (+) groups were significantly different (p = 0.026). Both IL-18 and IL-27 levels were significantly different between ESAT-6/CFP-10 stimulated PBMC supernatants of TST (-) QFT-GIT (-) and TST (+) QFT-GIT (-) groups (p = 0.000,p = 0.003, respectively). Conclusion Low IL-18 and IL-27 responses of peripheral blood mononuclear cells in children with Bacillus Calmette-Guerin (BCG) vaccine may play a role inMycobacterium tuberculosisinfection after in-house contact.
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    Atopy may result in more severe airway damage independent of the inflammatory cell type in pediatric asthma
    Turkeli, A; Yilmaz, O; Taneli, F; Horasan, GD; Kanik, ET; Kizilkaya, M; Gozukara, C; Yuksel, H
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    E-cadherin as an epithelial barrier protein: relation to atopy in children with asthma
    Turkeli, A; Yilmaz, O; Taneli, F; Horasan, GD; Kanik, ET; Kizilkaya, MH; Gozukara, C; Yuksel, H
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    IL-5, IL-8 and MMP-9 levels in exhaled breath condensate of atopic and nonatopic asthmatic children
    Turkeli, A; Yilmaz, O; Taneli, F; Horasan, GD; Kanik, ET; Kizilkaya, M; Gozukara, C; Yuksel, H
    Rationale: Asthma is a heterogeneous disease, and a great majority of pediatric patients with asthma demonstrate atopic characteristics and develop a Th2 type cytokine response. Nonatopic asthma, on the other hand, is seen more rarely. Methods: In this study, levels of IL-5, IL-8 and MMP-9 were measured in exhaled breath condensate (EBC) of the subjects to demonstrate the extent of tissue damage as well as eosinophilic and neutrophilic inflammation in children with atopic and nonatopic asthma. A total of 37 children with atopic asthma and 37 children with nonatopic asthma were enrolled in the study. Patients who exhibited protease positive aeroallergen (House dust mite, mould mix, olea, grass mix) sensitivity in allergen skin prick test were included in the atopic asthma group. To evaluate the EBC, the fluid content of the breath was collected by having the patients exhale into an EBC device, after which the IL-5, IL-8 and MMP-9 levels were assayed using the ELISA method. Results: The atopic asthmatics exhibited significantly higher IL-5 levels in their EBC samples than the nonatopic asthmatics (0.271 [0.198-0.489] pg/ml and 0.198 [0.125-0.344] pg/ml, respectively, p = 0.04), while no significant differences were observed in the levels of IL-8 and MMP-9 in the EBC samples of the atopic and nonatopic asthmatics. Conclusions: IL-5 levels, as a marker of eosinophilic inflammation, were demonstrated to be higher in the children with atopic asthma when compared to those with nonatopic asthma in EBC. The fact that no significant difference was apparent in the IL-8 levels between the groups suggests that it is the severity of the disease rather than the atopic state that plays an important role in IL-8 levels. Since no difference was recorded between the groups in terms of MMP-9 levels, lung damage in asthma sufferers seems to develop independent of atopia. (C) 2015 Elsevier Ltd. All rights reserved.