Anti-VEGF treatment suppresses remodeling factors and restores epithelial barrier function through the E-cadherin/ß-catenin signaling axis in experimental asthma models.

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 ß-catenin are the key AJ proteins that are involved in airway remodeling. Various mediators such as transforming growth factor-ß (TGF-ß), epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet derived growth factor (PDGF), insulin-like growth factor (IGF), tumor necrosis factor-α (TNF-α) 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/ß-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-α (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, ß-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, ß-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 ß-catenin levels to increase to the level of non-asthmatic control groups (P>0.005). All treatment groups had reduced TGF-ß, 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-α 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-α and corticosteroid treatment.

Optical densitometric measurements of the cornea and lens in children with allergic rhinoconjunctivitis.

BACKGROUND: Our aim was to investigate the impact of allergic rhinoconjunctivitis on corneal and lenticular optical densitometry, pachymetry and anterior chamber depth in children. METHODS: Fifty-four patients who had allergic rhinoconjunctivitis (study group) and 54 age-matched healthy children (control group) were recruited in this cross-sectional and comparative study. Corneal and lenticular optical densitometry, pachymetry, corneal volume and anterior chamber depth measurements were taken with the Scheimpflug imaging system. RESULTS: The lens density and anterior chamber depth were similar between the groups (p > 0.05), while corneal density and thickness were significantly higher in the study group (p < 0.05). Although the corneal volume was higher in children with allergic rhinoconjunctivitis, the difference was not statistically significant (p = 0.07). CONCLUSIONS: The cornea is affected in allergic rhinoconjunctivitis in respect to optical density and thickness, while the anterior chamber and lens are not influenced.

Pediatricians' approach to children with acute urticaria.

BACKGROUND: Acute urticaria is a common condition in childhood that concerns both patients and pediatricians. The aim of this study was to evaluate the general approach of pediatricians to children with acute urticaria. METHODS: A data collection form consisting of 17 questions was created to evaluate pediatricians' general knowledge and practical approaches about urticaria. This form was distributed at the hospitals where pediatricians and pediatric residents work. The data was recorded in SPSS for Windows v.15 (SPSS, Inc., Chicago, IL, USA). The frequency (%) was used for descriptive data, while Pearson χ2 and Fisher's Exact tests were used for comparisons between groups. P<0.05 was considered significant. The study was approved by the local ethics committee. RESULTS: Pediatricians suggest that foods and food additives are the most common etiological factors in the development of urticaria and, therefore, often advise dietary changes. Second-generation antihistamines are preferred for treatment and are administered for about 5-7 days. Pediatric residents were found to prefer parenteral drug administration for the treatment of urticaria. A different generation antihistamine therapy was applied for treatment of patients who did not respond to the initial treatment. It was also determined that patients were referred to allergists when urticaria was accompanied by angioedema or when patients were resistant to conventional treatment. CONCLUSIONS: Pediatricians' knowledge regarding the diagnosis and treatment of urticaria was less extensive than expected. According to the results, there was some confusion among physicians regarding the etiological role of some foods in acute urticaria and the strategies for removal of these foods from the diet during the treatment. Participants' treatment approaches were partially correct and sufficient. In general, there were no differences observed between pediatric residents and pediatricians in terms of the management of patients with urticaria, except the route of administration.

Vascular endothelial growth factor antagonism restores epithelial barrier dysfunction via affecting zonula occludens proteins.

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.

Cross-reactivity syndromes: presentation of two cases and review of the literature.

Cross-reactivity has important consequences in some immune disorders, including allergic and autoimmune diseases, which can affect both diagnostic and therapeutic approaches. One of the most common cross-reactivity syndromes is pollen-food syndrome (PFS). The patient is sensitized with pollen by the airways and exhibits an allergic reaction to food antigen with a structural similarity to the pollen. PFS usually presents with pruritus and swelling of the mouth and throat during or just after ingestion of fresh, uncooked fruits and vegetables. Latex fruit syndrome is another cross-reactivity syndrome. It is the association of latex allergy and allergy to plant foods, which affects up to 50% of latex-allergic patients. Here, we present two cases with crossreactivity syndrome.

Effects of inhaled L-arginine administration in a murine model of acute asthma.

Increased arginase activity in the airways decreases L-arginine and causes deficiency of bronchodilating and anti-inflammatory nitric oxide (NO) in asthma. As, it is suggested that L-arginine may have therapeutic potential in asthma treatment, we aimed to investigate the effects of inhaled L-arginine on oxygen saturation (SaO2) and airway histology in a murine model of acute asthma. Twenty eight BALB/c mice were divided into four groups; I, II, III and IV (control). All groups except the control were sensitized and challenged with ovalbumin. After establishement of acute asthma attack by metacholine administration, the mice were treated with inhaled L-arginine (Group I), saline (Group II) and budesonide (Group III), respectively. SaO2was measured by pulse oximeter just before and 5 min after methacholine. A third measurement of SaO2was also obtained 15 min after drug administration in these study groups. Inflammation in the lung tissues of the sacrificed animals were scored to determine the effects of the study drugs. The number of eosinophils in bronchoalveolar lavage (BAL) was determined. The results indicated that inflammatory scores significantly improved in groups receiving study drugs when compared with placebo and L-arginine was similar in decreasing scores when compared with budesonide. SaO2had a tendency to increase after L-arginine administration after acute asthma attack and this increase was statistically significant (p=0.043). Eosinophilia in BAL significantly reduced in group receiving L-arginine when compared with placebo (p<0.05). Thus in this study we demonstrated that L-arginine improved SaO2and inflammatory scores in an acute model of asthma.

The effect of atorvastatin on lung histopathology in a murine model of chronic asthma

INTRODUCTION: Atorvastatin is a statin group medicine that reduces the level of serum cholesterol; thus it is used to treat hypercholesterolaemia. Independent of the cholesterol-lowering property of statins they also have anti-inflammatory and immunomodulating effects. This study aimed to investigate the effect of atorvastatin on histological changes in the lungs in a murine model of chronic asthma. MATERIALS AND METHODS: Twenty-eight BALB/c mice in Group I, II, III and IV were divided into four groups. All the mice except the control group (Group I) were sensitised with ovalbumin. Intraperitoneal injection with saline, atorvastatin (10 mg/kg), dexametazon (1 mg/kg) was administered to Group II, Group III, and Group IV respectively for five consecutive days. Mice were sacrificed 24 h after the last drug administration. All the histological properties of lung tissue samples from all groups were evaluated with light and electron microscopy. In addition, IL-4 and IL-5 levels of the lung tissue were measured. RESULTS: When Group II and Group III (atorvastatin) were compared, thicknesses of basement membrane and subepithelial smooth muscle layer, height of epithelium, number of mast and goblet cells were significantly lower in Group III. In comparing Group III (atorvastatin) and Group IV (dexamethasone), all the improvements in histological parameters were similar. In addition, the IL-4 and IL-5 levels of the lung tissue were significantly lower in atorvastatin group (Group III) compared to placebo-treated group

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The Roberts syndrome: a case report of an infant with valvular aortic stenosis and mutation in ESCO2.

Roberts syndrome, which is inherited as an autosomal recessive group of disorders, is a rare syndrome characterized with symmetrical extremity defects, craniofacial abnormalities, and prenatal and postnatal growth retardation. Here, we present a case of Roberts Syndrome brought to the clinic with diarrhoea and multiple abnormalities, that had tetra phocomelia, growth and developmental retardation, abnormality of complete cleft lip-palate accompanied with Aortic stenosis and PDA, and in which cytogenetic analysis identified premature centromere separation. Mutation analysis of ESCO2 revealed a splice site mutation [c.1131+1G>A] in intron 6 in homozygous status in the patient and heterozygous status in the parents. Our case is the first Robert- Syndrome with valvular aortic stenosis in the literature, to the best of our knowledge.

Assessment of the effect of mesangial hypercellularity in childhood nephropathies to the clinical and laboratory findings.

AIM: To assess the relationship between mesangial hypercellularity in various childhood nephropathies and clinical and laboratory parameters. METHODS AND PATIENTS: The reports of the renal biopsies were evaluated retrospectively. The patients with diagnosis of IgA nephropathy (isolated and Henoch-Schönlein nephritis), IgM nephropathy, or isolated mesangial proliferative glomerulonephritis were included. Each nephropathy group was divided into two subgroups according to the severity of mesangial hypercellularity as mild and severe. The biochemical data and histopathological findings of the patients were recorded. RESULTS: When the groups were compared, it was found that the patients with IgA nephropathy had hematuria (p = 0.043) and the patients with IgM nephropathy had nephrotic syndrome more frequently than the other patients (p = 0.01). No difference was detected between the groups regarding the severity of mesangial hypercellularity. On the other hand, when the groups were evaluated within themselves, no significant association was detected between the severity of mesangial hypercellularity and clinical and laboratory parameters. It was determined that the renal biopsy was performed earlier in patients with Henoch-Schönlein nephritis compared to the other cases (p = 0.004). Compared to the isolated IgA nephropathy group, it was found that the number of cases with severe mesangial hypercellularity was higher and the level of proteinuria was more prominent in patients with Henoch-Schönlein nephritis. Additionally, when the patients with Henoch-Schönlein nephritis were evaluated, the degree of proteinuria was found to be higher in patients with severe mesangial hypercellularity compared to those of showing mild mesangial hypercellularity (p = 0.002). CONCLUSION: It was observed that there is no direct relation between the severity of mesangial hypercellularity and clinical and laboratory findings in various childhood nephropathies. However, when Henoch-Schönlein nephritis is compared with IgA nephropathy, it was found that the severity of mesangial hypercellularity was higher in cases with Henoch-Schönlein nephritis and the level of proteinuria was more prominent in those cases. However, no difference was detected in glomerular filtration rates and biochemical data with regard to the level of mesangial hypercellularity.

Expectoration of a foreign body at the late period: A case report.

Foreign body (FB) aspiration is a relatively common problem in children, particularly during the first 3 years of life. It is an emergency condition and the removal of the FB by bronchoscopy is the primary treatment. Children with undiagnosed retained foreign bodies may present with respiratory symptoms including recurrent or persistent wheezing, with or without respiratory failure. Spontaneous expectoration of a FB is a rare occurrence. Herein, we present a case that was diagnosed with FB aspiration during investigation for persistent wheezing and who expectorated part of a sunflower seed 2 months after aspiration.

The effect of atorvastatin on lung histopathology in a murine model of chronic asthma.

INTRODUCTION: Atorvastatin is a statin group medicine that reduces the level of serum cholesterol; thus it is used to treat hypercholesterolaemia. Independent of the cholesterol-lowering property of statins they also have anti-inflammatory and immunomodulating effects. This study aimed to investigate the effect of atorvastatin on histological changes in the lungs in a murine model of chronic asthma. MATERIALS AND METHODS: Twenty-eight BALB/c mice in Group I, II, III and IV were divided into four groups. All the mice except the control group (Group I) were sensitised with ovalbumin. Intraperitoneal injection with saline, atorvastatin (10mg/kg), dexametazon (1mg/kg) was administered to Group II, Group III, and Group IV respectively for five consecutive days. Mice were sacrificed 24h after the last drug administration. All the histological properties of lung tissue samples from all groups were evaluated with light and electron microscopy. In addition, IL-4 and IL-5 levels of the lung tissue were measured. RESULTS: When Group II and Group III (atorvastatin) were compared, thicknesses of basement membrane and subepithelial smooth muscle layer, height of epithelium, number of mast and goblet cells were significantly lower in Group III. In comparing Group III (atorvastatin) and Group IV (dexamethasone), all the improvements in histological parameters were similar. In addition, the IL-4 and IL-5 levels of the lung tissue were significantly lower in atorvastatin group (Group III) compared to placebo-treated group. CONCLUSION: Atorvastatin had a beneficial effect on histological changes in a chronic murine model of asthma.

Hyperbilirubinemia and urinary tract infection: the effect of indirect hyperbilirubinemia on the in vitro growth of uropathogen Escherichia coli in newborn urine.

High serum bilirubin is antioxidant and cytoprotective. We evaluated if urine samples of hyperbilirubinemic newborns impede uropathogenic Escherichia coli growth. Bag-urine samples of hyperbilirubinemic newborns (study group) were cultured at presentation and during remission. Urine sample were obtained only once from healthy newborns (control group). Escherichia coli [2 × 104 colony-forming unit (cfu)/mL] was inoculated into the sterile urine samples and colony counts were determined after 24 h. Bilirubin levels at presentation and remission were also recorded. Escherichia coli colony counts of the control versus study groups and of the presentation versus remission samples in the study group were compared. There were 13 study and 17 control cases. Escherichia coli colony counts were not different in the study group at presentation versus remission (5.4 ± 0.7 vs. 5.5 ± 0.8 log10, respectively; p = 0.659). Escherichia coli colony count of the control group (5.2 ± 0.6 log10) was also not different from the study group. In conclusion, the urine of hyperbilirubinemic newborns did not affect the growth rate of uropathogenic E. coli.

Comparison of TNF antagonism by etanercept and dexamethasone on airway epithelium and remodeling in an experimental model of asthma.

BACKGROUND: The aim of the study was to compare the influence of TNF antagonism and corticosteroid treatment on epithelial, smooth muscle and basement membrane component of airway remodeling in an experimental murine model of chronic asthma. METHODS: We used 30 BALB/c mice. Group 1 not exposed to ovalbumin or any medication was designated as control group. Chronic asthma model was achieved in the other three groups with intraperitoneal (IP) and inhaled ovalbumin. Then, Group 2 received IP saline, Group 3 received IP dexamethasone and Group 4 received IP etanercept. Epithelial, subepithelial smooth muscle and basement membrane thickness as well as goblet cells and mast cells were examined on samples isolated from left lung. RESULTS: Etanercept treatment led to thinner epithelial and basement membrane layer and lower goblet and mast cell number than untreated asthmatic mice (p<0.001, p=0.001, p=0.005 and p=0.03 respectively). Neither epithelial and basement membrane thickness nor mast cell number was different among mice treated with etanercept and dexamethasone (p=0.38, p=0.79 and p=0.51 respectively). However, etanercept group was associated with thicker subepithelial muscle layer but lower goblet cell number (p<0.001 and p=0.04 respectively) than dexamethasone group. CONCLUSIONS: Corticosteroids are more effective in decreasing smooth muscle mass while TNF antagonists in reducing goblet cell number in animal model of asthma. Therefore, further research is needed to assess the synergistic use of TNF antagonism and dexamethasone for more rational remodeling control.

Long-term oropharyngeal colonization by C. albicans in children with cystic fibrosis.

This longitudinal prospective study aimed to determine the prevalence of oropharyngeal colonization by C. albicans in children with cystic fibrosis (CF), and observe the continuity of candidal colonization and the changes in production of virulence factors, susceptibility to antifungal agents and RAPD patterns of the isolates. Thirty-seven children with CF were followed-up for oropharyngeal C. albicans colonization for 18 months. The colonization rate was detected in 54%. All isolates were susceptible to amphotericin B, but those isolated from one patient were resistant to fluconazole. Biofilm production, secretory acid proteinase, phospholipase and esterase activity rates were 30%, 60%, 75% and 80%, respectively. RAPD analysis with the primers OPE-03 and OPE-18 was performed for genotyping. RAPD patterns of the strains isolated from the same patient were related to each other, whereas they were not related with other strains isolated from different patients. Two C. albicans strains isolated from the same patient were found to be unrelated to one another. As a result, long-lasting colonization of the oropharyngeal mucosa of children with CF by endogenous C. albicans isolates having the same RAPD pattern was demonstrated. Colonization prevalance and development of resistance to antifungal agents and the increased production of virulence factors were not correlated.

Role of vascular endothelial growth factor antagonism on airway remodeling in asthma.

BACKGROUND: Vascular endothelial growth factor (VEGF) is an important mediator of the neoangiogenesis component of remodeling in asthma. OBJECTIVE: To evaluate the influence of VEGF blockage on airway remodeling, specifically epithelium thickness, subepithelial smooth muscle thickness, number of mast and goblet cells, and basement membrane thickness, in a mouse model of chronic asthma. METHODS: We used 30 BALB/c mice. The control group was not exposed to ovalbumin or any medication (group 1). Other groups were exposed to intraperitoneal and inhaled ovalbumin to achieve chronic asthma. Each of these groups received intraperitoneal saline (group 2), intraperitoneal dexamethasone (group 3), or intraperitoneal bevacizumab (group 4). Histomorphologic examination for epithelium thickness, subepithelial smooth muscle thickness, number of mast and goblet cells, and basement membrane thickness was performed from the middle zone of the left lung. RESULTS: Treatment with anti-VEGF caused significant reduction in epithelial, subepithelial muscle, and basement membrane thickness compared with untreated asthmatic mice (P = .001, P = .03, and P = .009, respectively). Goblet and mast cell numbers were significantly lower in mice treated with anti-VEGF than in untreated mice (P = .02 and P = .007, respectively). Dexamethasone treatment resulted in improvement of all histomorphologic markers, except goblet cell number. Influences of dexamethasone and anti-VEGF on epithelial and basement membrane thickness and mast and goblet cell numbers did not differ (P > .05), but subepithelial muscle layer was thinner in the former (P = .003). CONCLUSION: VEGF blockage may provide adjunctive therapeutic options as steroid-sparing agents for more effective treatment of remodeling in asthma.

The effect of rupatadine on lung histopathology in a murine model of chronic asthma.

INTRODUCTION: Rupatadine is a new second-generation antihistamine with H(1) receptor antagonist activity and platelet-activating factor antagonist properties. This study aimed to investigate the effect of rupatadine on histologic changes in the lungs in a murine model of chronic asthma. MATERIALS AND METHODS: Thirty-five BALB/c mice were divided into five groups of seven mice each: group I (control), group II (placebo [saline]), group III (dexamethasone 1 mg · kg(-1)·d(-1)), group IV (rupatadine 3 mg·kg(-1) d(-1)), and group V (rupatadine 30 mg·kg(-1)·d(-1)). Groups II through V were sensitized and challenged with ovalbumin and treated once per day via the oral route (gavage). Animals were sacrificed 24 h after the last treatment was administered. Airway histopathology was evaluated using light and electron microscopy in all groups. RESULTS: There were no significant differences observed in any of the histologic parameters between groups II and IV. There were significantly thinner basement membrane, subepithelial smooth muscle layer, and epithelia were significantly thinner in group V than in group II (p < .05). There were no statistically significant differences in the thicknesses of the basement membrane, subepithelial smooth muscle layer and epithelia between groups III and V. CONCLUSION: Rupatadine had a beneficial effect on histologic changes in a chronic murine model of asthma.