PAHs Changed Epigenetics by One Carbon Metabolism in Childhood Asthma

Background: Epigenetic mechanisms may play a role in which PAHs exert its adverse effects in childhood asthma. However, the underlying molecular mechanism remain to be fully elucidated. This study aimed to investigate this process in view of cellular metabolism, especially one carbon metabolism. Methods: Fifty asthmatic children and fifty control subjects were recruited in this study. Serum IgE and IL-17A was detected by ELISA assay. Serum PAHs levels were measured by GC-MS. One carbon-related metabolites were determined by UPLC-Orbitrap-MS. Blood DNA methylation in long interspersed nucleotide element-1 (LINE-1) was analyzed by bisulfite sequencing PCR. ChIP assays were used to examine H3K4me3 modifications on IL-17A gene. Multivariable linear regression was performed to evaluate the associates between PAHs and DNA methylation and histone methylation mediated by one carbon metabolism. Results: The asthmatic group presented significantly higher total serum IgE and IL-17A levels. Serum Fla was associated with childhood asthma. The asthmatic group displayed a significantly decreasing in SAM abundance and a smaller but corresponding decrease in SAH, which indicated the increasing conversion from SAM to SAH and the elevated capacity of methylation reactions. Fla had a great effect on one carbon metabolites, especially SAH, SAM and Ser, which exerted significant mediation effects between the Fla level and asthma. What’s more, Fla had a positive effect on LINE-1 DNA methylation (β=0.395, P=0.000) and H3K4 tri-methylation level in the IL-17A promoter region(β=0.293, P=0.002). We did find significant mediation effect between serum Fla and asthma by LINE-1 DNA methylation and H3K4me3 level in the IL-17A promoter region.Conclusion: PAHs disturbed one carbon metabolism to influence the methyl group refill of DNA methylation and histone methylation, which may elevate serum IL-17A level in asthmatic children.

Network and co-expression analysis of airway smooth muscle cell transcriptome delineates potential gene signatures in asthma

Airway smooth muscle (ASM) is known for its role in asthma exacerbations characterized by acute bronchoconstriction and remodeling. The molecular mechanisms underlying multiple gene interactions regulating gene expression in asthma remain elusive. Herein, we explored the regulatory relationship between ASM genes to uncover the putative mechanism underlying asthma in humans. To this end, the gene expression from human ASM was measured with RNA-Seq in non-asthmatic and asthmatic groups. The gene network for the asthmatic and non-asthmatic group was constructed by prioritizing differentially expressed genes (DEGs) (121) and transcription factors (TFs) (116). Furthermore, we identified differentially connected or co-expressed genes in each group. The asthmatic group showed a loss of gene connectivity due to the rewiring of major regulators. Notably, TFs such as ZNF792, SMAD1, and SMAD7 were differentially correlated in the asthmatic ASM. Additionally, the DEGs, TFs, and differentially connected genes over-represented in the pathways involved with herpes simplex virus infection, Hippo and TGF-β signaling, adherens junctions, gap junctions, and ferroptosis. The rewiring of major regulators unveiled in this study likely modulates the expression of gene-targets as an adaptive response to asthma. These multiple gene interactions pointed out novel targets and pathways for asthma exacerbations.

Cavidine protects against asthma in neonatal asthmatic mice model by attenuating PI3Ks/NF-κB signaling pathway

Purpose: To evaluate the protective effect of cavidine against asthma in neonatal mice. Methods: Neonatal mice were treated with cavidine at doses of 5 and 10 mg/kg, po, 2 h prior to asthma induction with ovalbumin (OVA) on the 1st and 14th days of the treatment protocol. The anti-asthma activity of cavidine was evaluated by determining the number of inflammatory cells and cytokine levels in broncho-alveolar lavage fluid (BALF) and OVA-specific IgE and TGF-β 1 in the serum of OVAsensitized mice. The levels of NF-ƙB and PI3K protein expression were determined in the lung tissues of OVA-sensitized mice. Results: Cavidine attenuated the number of inflammatory cells and cytokines in BALF of OVAsensitized mice. The levels of OVA-specific IgE and TGF-β 1 decreased significantly in cavidine-treated groups, when compared to asthmatic group of mice, while NF-ƙB was significantly downregulated (p < 0.01). The altered expression of PI3K signaling protein was attenuated in the lung tissues of cavidinetreated mice sensitized with OVA. Conclusion: These results reveal that the anti-asthma effect of cavidine in OVA-induced asthmatic neonatal mice occurs via reduction of inflammation and immune responsive cells linked to PI3Ks/ NF-κB signaling pathway in lung tissues. These findings suggest that cavidine may be clinically suitable for the management of asthma.

Prevalence of asthma and other allergic diseases in pregnant women

Asthma and allergic disorders can affect the outcome of pregnancy. Asthma and allergies are common comorbidities during pregnancy and exacerbations are the major clinical problem. Results are not consistent between studies .Therefore, the aim of this study was to determine the frequency of asthma and allergic disease during pregnancy. This prospective cohort study was carried out at the antenatal clinic of Mobini Hospital in Iran. Overall, 1,603 women were enrolled prior to the 24th week of pregnancy. All participants were interviewed for allergy disease, allergic trigger factors and severity of asthma. Also, asthma control was categorized as per GINA guidelines. The diagnosis of asthma was based on symptoms, pulmonologist diagnosis, and spirometry assessment. The results were analyzed using SPSS version 20 and T-tests and Chi-square test. The prevalence of asthma during pregnancy was 2.1% among the participants. The most common allergens in asthmatic group were pollen, stress, and climate. There was a significant relationship between age, education and place of living in asthmatic and non-asthmatic group, p = 0.003, p=0.05, p=0.008, respectively. There was a significant relationship between asthma symptoms among the two groups (p=0.001). In addition, a significant relationship was found between asthma and other allergic diseases including eczema, allergy, rhinitis, and wheeze in asthmatic women, with a significant relationship between wheeze and coughing and allergy. Exposure of the pregnant women to high levels of allergens, like pollen, and allergic diseases resulted in an increased risk of pregnancy outcomes. Careful management of these diseases should prevent most of the serious complications

Combined score of C-reactive protein level and neutrophil-to-lymphocyte ratio: A novel marker in distinguishing children with exacerbated asthma

Background Both C-reactive protein (CRP) level and neutrophil-to-lymphocyte ratio (NLR) are commonly elevated in patients with asthma. It is necessary to develop a novel marker, the combined score of CRP level and NLR (C-NLR score) based on cutoff points of CRP and NLR, and apply it in asthma diagnosis. The aim of this study was to explore whether C-NLR could distinguish children with exacerbated asthma. Methods Children suffering from exacerbated asthma were regarded as the asthmatic group ( n = 86), which was divided into three groups: mild ( n = 54), moderate ( n = 17), and severe ( n = 15). The control group consisted of children without any allergic disease and infection ( n = 38). To compare CRP level and NLR between the asthmatic group and control group, a receiver-operating characteristic curve was constructed to determine area under the curve (AUC) and optimal cutoff point. Thereafter, the C-NLR score was classified as follows: C-NLR score of 2 with an elevated CRP level and high NLR, a C-NLR score of 1 with one of these abnormalities, and a C-NLR score of 0 with a normal CRP level and low NLR. The C-NLR score was then compared among different asthma groups. Results In the control group, the CRP level and NLR were 1.9 (0.5–2.6) mg/L and 1.01 (0.69–1.31), respectively. In the asthmatic group, the CRP level and NLR were 7.3 (3.2–14.2) mg/L and 3.08 (1.73–5.34), respectively, which were higher than those in the control group ( p < 0.001 for CRP and p < 0.001 for NLR). The AUC of CRP was 0.86, and the optimal cutoff point was 3.6 mg/L. The AUC of NLR was 0.86, and the optimal cutoff point was 1.72. The AUC of the C-NLR score was 0.94, and the optimal cutoff point was 1. Conclusions C-NLR, a novel inflammatory marker, was applied here for the exacerbated asthma for the first time. Our study has shown C-NLR is a promising marker to distinguish children with exacerbated asthma from healthy children.

Evolution of Airway Inflammation in Preschoolers with Asthma—Results of a Two-Year Longitudinal Study

Fractional exhaled nitric oxide (FeNO) is a non-invasive marker for eosinophilic airway inflammation and has been used for monitoring asthma. Here, we assess the characteristics of FeNO from preschool to school age, in parallel with asthma activity. A total of 167 asthmatic children and 66 healthy, age-matched controls were included in the 2-year prospective PreDicta study evaluating wheeze/asthma persistence in preschool-aged children. Information on asthma/rhinitis activity, infections and atopy was recorded at baseline. Follow-up visits were performed at 6-month intervals, as well as upon exacerbation/cold and 4–6 weeks later in the asthmatic group. We obtained 539 FeNO measurements from asthmatics and 42 from controls. At baseline, FeNO values did not differ between the two groups (median: 3.0 ppb vs. 2.0 ppb, respectively). FeNO values at 6, 12, 18 and 24 months (4.0, CI: 0.0–8.6; 6.0, CI: 2.8–12.0; 8.0, CI: 4.0–14.0; 8.5, CI: 4.4–14.5 ppb, respectively) increased with age (correlation p ≤ 0.001) and atopy (p = 0.03). FeNO was non-significantly increased from baseline to the symptomatic visit, while it decreased after convalescence (p = 0.007). Markers of disease activity, such as wheezing episodes and days with asthma were associated with increased FeNO values during the study (p < 0.05 for all). Age, atopy and disease activity were found to be important FeNO determinants in preschool children. Longitudinal and individualized FeNO assessment may be valuable in monitoring asthmatic children with recurrent wheezing or mild asthma.

Nebivolol attenuates oxidative stress and inflammation in a guinea pig model of ovalbumin-induced asthma: a possible mechanism for its favorable respiratory effects

An experimental model of ovalbumin (OVA) induced asthma was used to assess the effects of nebivolol, the third-generation selective β1-adrenergic receptor blocker, on airway reactivity, lung inflammation, and oxidative stress markers. The asthma induction protocol was done by OVA sensitization and challenge. Guinea pigs were classified into control, asthmatic, or asthmatic receiving nebivolol either 7.5 or 15 mg·kg–1·day–1 orally. At the end of the study respiratory, the anti-inflammatory and antioxidative effects of nebivolol were assessed. The asthmatic group exhibited a significant increase in early and late airway resistance, airway hyperreactivity to histamine, total and absolute leucocytic count, tumor necrosis factor-α, and interleukin-6 in bronchoalveolar lavage fluid and lung lipid peroxidation and a significant decrease in superoxide dismutase and glutathione compared to the control group. Additionally, there was a significant decrease in lung endothelial nitric oxide synthase (eNOS) and a significant increase in inducible nitric oxide synthase (iNOS) mRNA expression compared to the control group. The high dose of nebivolol counteracted the increased airway resistance induced by OVA, whereas it had no effect on airway hyperresponsiveness. Moreover, nebivolol exhibited significant anti-inflammatory and antioxidant effects and restored the altered levels of eNOS and iNOS compared to the asthmatic group. Collectively, these results suggest a beneficial effect of nebivolol in asthma.

Exacerbation of Asthma during Pregnancy: Fetomaternal Outcomes

Background Asthma is a common occurrence during pregnancy. Exacerbation during pregnancy represents a important and challenging medical problem and may result in poor fetomaternal outcomes. Until now, there are no studies comparing the fetomaternal outcomes in pregnant women with case (asthma) exacerbation and with control group (non-asthma) women of similar age and period of gestation. Therefore, we analysed selected fetomaternal outcomes retrospectively in these group of women.Material & Methods This is a retrospective observational comparative study. During the study period, total number of deliveries was 5,568. Women who were admitted with the diagnosis of exacerbation of asthma during pregnancy between 1st Jan 2015 to 31st Dec were included in the study. These cases were compared with random selection of controls who were admitted in the same duration of time for the delivery without asthma after matching maternal age and period of gestation. Ethical clearance was obtained before the study. Fetomaternal outcomes were compared between women with exacerbation of asthma and non-asthma.Results One hundred and eight pregnant women from each asthmatic and non- asthmatic group were analysed for selected fetomaternal outcomes. The mean age of asthmatic and nonasthmatic group was 23.2± 4.3 and 24.9±3.2 years respectively. LSCS, UTI and preeclampsia were more common in asthmatic women. Birth weight and APGAR score was lower in babies with asthmatic women. Inpatient care and mortality rate were more common in babies of asthmatic women.Conclusion Exacerbation of asthma during pregnancy may result in poor fetomaternal outcome. Therefore, a more careful monitoring of women with exacerbation of asthma during pregnancy and delivery is required.Journal of Nobel Medical College Vol.5(2) 2016; 32-36

Hubungan antara kadar kalsium dengan serangan asma pada anak

Asthma is a chronic inflammatory disorder of the respiratory tract that can cause an increased response and activity within the airway which is characterized by the recurrent episodes of wheezing, shortness of breath, and cough accompanied by airway obstruction in varying degrees. Vitamin D plays a role in the pathogenesis of asthma. Many studies suggest a relation between vitamin D and calcium, which can be seen as a possible link between calcium levels and asthma. This study aimed to determine the correlation between the level of calcium and asthma attacks in children. This was a case-control study that gathered 21 asthmatic children and 19 non-asthmatic children with acute respiratory infections who did not use corticosteroids for the treatment at outpatient services Prof. Dr. R. D. Kandou Hospital Manado from January to June 2015. Calcium levels of asthmatic patients and non-asthmatic were noted. Statistical analysis using logistic regression with a P value < 0.05 were considered significant. The results of logistic regression analysis showed a significant association between calcium level and asthma attack (P = 0.04 with OR = 2.75). The average level of calcium in the asthmatic group was 9.2 mg/dL (0.81, 95% CI 8.91 to 9.64) and the non-asthmatic group was 8.7 mg/dL (0.72, 95% CI 8.38-9.07). Conclusion: There was a correlation between calcium level and asthma attack in children. The lower the level of calcium, the higher the chance of asthma attack.Keywords: children, asthma, calciumAbstrak: Asma adalah kelainan inflamasi kronis saluran pernapasan yang dapat menyebabkan peningkatan respon dan aktivitas jalan napas, ditandai dengan episode mengi berulang, sesak napas, dan batuk yang disertai obstruksi jalan napas dalam derajat bervariasi. Vitamin D berperan dalam patogenesis asma. Banyak penelitian mengatakan bahwa terdapat hubungan antara vitamin D dan kalsium, sehingga diduga adanya hubungan antara kadar kalsium dan asma. Penelitian ini bertujuan untuk mengetahui hubungan kadar kalsium dengan serangan asma pada anak. Jenis penelitian ialah kasus kontrol dimana dikumpulkan 21 anak dengan asma dan 19 anak non-asma dengan infeksi saluran napas akut dan tidak menggunakan kortikosteroid yang datang berobat di pelayanan rawat jalan RSUP Prof. Dr. R. D. Kandou Manado dari Januari sampai Juni 2015. Kadar kalsium pasien asma dan non-asma dicatat. Analisis statistik menggunakan regresi logistik dengan nilai P < 0,05 dianggap bermakna. Hasil analisis regresi logistik menunjukkan hubungan bermakna antara kadar kalsium dengan serangan asma (P = 0,04 dengan OR = 2,75). Rerata kadar kalsium pada kelompok asma 9,2 mg/dL (0,81, 95% CI 8,91-9,64) dan kelompok non asma 8,7 mg/dL (0,72, 95% CI 8,38-9,07). Simpulan: Terdapat hubungan antara kadar kalsium dan serangan asma pada anak. Makin rendah kadar kalsium, makin tinggi peluang terjadinya serangan asma.Kata kunci: anak, asma, kalsium

Rho-Kinase Inhibition Attenuates Airway Inflammation In An Experimental Asthma Model In Sickle Cell Mice

Introduction Asthma in sickle cell disease is known to be associated with increased morbidity and an elevated rate of sickle cell complications, such as acute chest syndrome, stroke, vaso-occlusive episodes and early mortality. Experimental asthma increases eosinophil and collagen deposition in the lungs of SCD mice, induces profound increases in pulmonary inflammation, shifts in TH1 and TH2 cytokine production, and airway resistance. A small GTPase, Rho, and its target molecule, Rho-kinase (ROCK), play an important role in cell functions, including contractility, chemotaxis, adhesion, and migration, where the Rho/ROCK-mediated pathway facilitates infiltration of inflammatory cells both in vitro and in vivo. This study was designed to determine whether the Rho/Rho-kinase pathways are involved in eosinophil recruitment and inflammation. To investigate the role of Rho/ROCK in the pathogenesis of SCD asthma, we investigated the effect of fasudil, a specific inhibitor of Rho-kinase, on acute allergic inflammation in SCD mice model. Methods Berkeley SCD mouse bone marrow was transplanted into lethally-irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Female SCD mice were sensitized and challenged with ovalbumin (OVA). OVA-challenge mice were treated intraperitoneally with fasudil (10 mg/kg), 1 h before each OVA-challenge. At 48 h after OVA challenged total cell counts, differential cell counts, cytokines, and chemokine levels were measured by ELISA in bronchoalveolar lavage fluid (BALF), and the mRNA expressions of ROCK-1, ROCK-2, IL-6, MMP-8, MMP-9, MMP-12, TIMP-1, TIMP-2 were measured in lungs by RT-PCR. Results Intranasal challenge of OVA in SCD mice induced airway inflammation after 48h, characterized by increases in total leukocytes numbers (WBC) that were almost exclusively accounted for by eosinophils, when compared with non-sensitized mice (WBC: 12.8 ±1.5 vs 5.5 ± 0.68; eosinophils: 6.67 ± 1.2 vs 0.01 ± 0.01, p<0.05, respectively). When fasudil was administer to OVA-challenged SC mice, increased numbers of total cells and eosinophils in the BALF were significantly attenuated (WBC: 6.8 ± 0.6; eosinophils: 1.14 ± 0.33, p<0.05). The numbers of neutrophils were also reduced in animals treated with fasudil (0.84 ± 0.13 vs 2.32 ± 0.34, p<0.05). However, mononuclear cells were not affected by fasudil treatment. ROCK-1 and ROCK-2 mRNA expressions in mice of the asthmatic group (1.2 ± 0.18 and 0.84 ± 0.10, respectively) were similar than those of the non-sensitized group (1.1±0.05 and 0.97±0.04, respectively). When fasudil was administered, the expressions of ROCK-1 and ROCK-2 mRNA did not alter in the asthmatic group (0.96 ± 0.12 and 0.98 ± 0.15, respectively). MMP-2, MMP-8, MMP-9, MMP-12 and TIMP-1 gene expressions were not significantly different between SCD asthmatic mice and SCD non-sensitized mice. Increased IL-6 mRNA levels were detected in the lungs at 48h after OVA challenge (0.83 ± 0.09 vs 0.4 ± 0.1, p<0.05). Lung mRNA expressions of MMPs, TIMP-1 and cytokines were not significantly reduced in SCD mice treated with fasudil. OVA challenge in sensitized SCD mice induced IL-4, IL-5, IL-6, eotaxin, RANTES, MCP-1, TIMP-1 release into BALF (OVA-sensitized: 11.1 ± 3.2, 31.8 ± 7.7, 20.4 ± 4.0, 8.8 ± 2.2, 11.7 ± 1.8, 46.6 ± 7.1, 2239 ± 424.7, respectively vs OVA-nonsensitized:1.1 ± 0.6; 1.4 ± 0.6, 4.1 ± 2.0, 2.3 ± 1.5; 6.9 ± 1.9; 4.6 ± 0.97; 294.3 ± 45.6 pg/ml, p<0.05). Fasudil reduced levels of IL-5, L-6, RANTES, MCP-1, proMMP-9 and TIMP-1 in BALF of SCD mice after OVA challenges (-46.4 fold, -62.5 fold, -41.4 fold, -48.6 fold, -53.6 fold, p<0.05, respectively). Conclusion Administration of fasudil inhibits eosinophil recruitment in response to allergen challenge. The effects of this agent may be mediated by suppressing the production of chemokine and cytokines related to the pathophysiology of bronchial asthma, such as IL-5, RANTES and MCP-1. In addition, the Rho-kinase inhibitor reduced levels of proteins involved in the degraded the extracelular matrix, such as MMP-9, which directly or indirectly promoted the progression of pulmonary inflammatory responses. Our findings provide evidence that inhibition of the Rho/Rho-kinase pathway may be beneficial for pulmonary complications in sickle cell disease. Financial Support FAPESP/CNPq/INCTS Disclosures: No relevant conflicts of interest to declare.