scholarly journals Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED: an exploratory analysis

2018 ◽  
Vol 51 (5) ◽  
pp. 1702173 ◽  
Author(s):  
Kentaro Takahashi ◽  
Stelios Pavlidis ◽  
Francois Ng Kee Kwong ◽  
Uruj Hoda ◽  
Christos Rossios ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Airflow Obstruction ◽  
Bronchial Epithelial Cell ◽  
Smoking History ◽  
Protein Levels ◽  
Cell Counts ◽  
Asthma Patients ◽  
Mucin 2 ◽  
Cystatin Sn ◽  
Cell Transcriptome

Severe asthma patients with a significant smoking history have airflow obstruction with reported neutrophilia. We hypothesise that multi-omic analysis will enable the definition of smoking and ex-smoking severe asthma molecular phenotypes.The U-BIOPRED cohort of severe asthma patients, containing current-smokers (CSA), ex-smokers (ESA), nonsmokers and healthy nonsmokers was examined. Blood and sputum cell counts, fractional exhaled nitric oxide and spirometry were obtained. Exploratory proteomic analysis of sputum supernatants and transcriptomic analysis of bronchial brushings, biopsies and sputum cells was performed.Colony-stimulating factor (CSF)2 protein levels were increased in CSA sputum supernatants, with azurocidin 1, neutrophil elastase and CXCL8 upregulated in ESA. Phagocytosis and innate immune pathways were associated with neutrophilic inflammation in ESA. Gene set variation analysis of bronchial epithelial cell transcriptome from CSA showed enrichment of xenobiotic metabolism, oxidative stress and endoplasmic reticulum stress compared to other groups. CXCL5 and matrix metallopeptidase 12 genes were upregulated in ESA and the epithelial protective genes, mucin 2 and cystatin SN, were downregulated.Despite little difference in clinical characteristics, CSA were distinguishable from ESA subjects at the sputum proteomic level, with CSA patients having increased CSF2 expression and ESA patients showing sustained loss of epithelial barrier processes.

scholarly journals Randomised controlled trials in severe asthma: selection by phenotype or stereotype

2018 ◽  
Vol 52 (6) ◽  
pp. 1801444 ◽  
Author(s):  
Thomas Brown ◽  
Thomas Jones ◽  
Kerry Gove ◽  
Clair Barber ◽  
Scott Elliott ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Randomised Controlled Trials ◽  
Airflow Obstruction ◽  
Phase Iii ◽  
Smoking History ◽  
Trial Participation ◽  
Controlled Trials ◽  
Biological Therapies ◽  
Asthma Patients ◽  
Randomised Controlled

Previous publications have highlighted the disparity between research trial populations and those in clinical practice, but it has not been established how this relates to randomised controlled trials (RCTs) of phenotype-targeted biological therapies in severe asthma.Detailed characterisation data for 342 severe asthma patients within the Wessex Severe Asthma Cohort (WSAC) was compared against comprehensive trial eligibility criteria for published phase IIB and phase III RCTs evaluating biological therapies in severe asthma since 2000.37 RCTs evaluating 20 biological therapies were identified. Only a median of 9.8% (range 3.5–17.5%) of severe asthma patients were found to be eligible for enrolment in the phase III trials. Stipulations for airflow obstruction, bronchodilator reversibility and smoking history excluded significant numbers of patients. A median of 78.9% (range 73.2–86.6%) of patients with severe eosinophilic asthma would have been excluded from participation in the phase III licensing trials of interleukin (IL)-5/IL-5R targeted therapies.Despite including only well characterised and optimally treated severe asthmatics under specialist care within the WSAC study, the vast majority were excluded from trial participation by criteria designed to re-confirm diagnostic labels rather than by biomarker criteria that predict the characteristic addressed by the treatment.

scholarly journals Immunobiology of Steroid-Unresponsive Severe Asthma

2021 ◽  
Vol 2 ◽  
Author(s):  
Courtney Lynn Marshall ◽  
Kosovare Hasani ◽  
Neeloffer Mookherjee
Keyword(s):  
Immune Responses ◽  
Airway Inflammation ◽  
Severe Asthma ◽  
Airflow Obstruction ◽  
Bronchial Hyperresponsiveness ◽  
Disease Process ◽  
Molecular Networks ◽  
Uncontrolled Asthma ◽  
Immune Mediators ◽  
Asthma Patients

Asthma is a heterogeneous respiratory disease characterized by airflow obstruction, bronchial hyperresponsiveness and airway inflammation. Approximately 10% of asthma patients suffer from uncontrolled severe asthma (SA). A major difference between patients with SA from those with mild-to-moderate asthma is the resistance to common glucocorticoid treatments. Thus, steroid-unresponsive uncontrolled asthma is a hallmark of SA. An impediment in the development of new therapies for SA is a limited understanding of the range of immune responses and molecular networks that can contribute to the disease process. Typically SA is thought to be characterized by a Th2-low and Th17-high immunophenotype, accompanied by neutrophilic airway inflammation. However, Th2-mediated eosinophilic inflammation, as well as mixed Th1/Th17-mediated inflammation, is also described in SA. Thus, existing studies indicate that the immunophenotype of SA is diverse. This review attempts to summarize the interplay of different immune mediators and related mechanisms that are associated with airway inflammation and the immunobiology of SA.

Expression Level of MiRNA-126 in Serum Exosomes of Allergic Asthma Patients and Lung Tissues of Asthmatic Mice

2019 ◽  
Vol 20 (10) ◽  
pp. 799-803 ◽  
Author(s):  
Meizhen Zhao ◽  
Yu-Pei Li ◽  
Xiao-Rui Geng ◽  
Miao Zhao ◽  
Shi-Bo Ma ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Real Time ◽  
Real Time Pcr ◽  
Lavage Fluid ◽  
Asthmatic Patients ◽  
Protein Levels ◽  
Sige Level ◽  
Bronchial Lumen ◽  
Asthma Patients ◽  
Serum Exosomes

Background: To investigate MiRNA-126 amounts in serum exosomes from allergic asthma patients as well as lung tissues of asthmatic mice, evaluating the expression of its target gene DNMT1 in mouse specimens. Methods: MiRNA-126 amounts in serum exosomes from asthmatic patients were detected by real-time PCR. The mouse model of allergic asthma was established by OVA-sensitization, and allergic symptoms were recorded; serum IL-4 and sIgE level evaluation (ELISA), broncho alveolar lavage fluid (BALF) cell count and H&E staining were performed to assess airway inflammation. MiRNA-126 and DNMT1 levels in the lung of asthmatic and control mice were detected by real-time PCR; DNMT1 protein levels were detected by immunoblot. Results: MiRNA-126 amounts in peripheral blood exosomes from patients with allergic asthma were significantly higher than that of healthy volunteers (P<0.05). The frequencies of scratching of both sides of the nose and sneezing were elevated within 10 min of excitation in asthmatic rats compared with controls. Meanwhile, OVA-sIgE and IL-4 levels were significantly higher in asthmatic animals than controls (P<0.05). In the asthma group, narrowed bronchial lumen and thickened wall were observed, and bronchial and peripheral vessels showed overt inflammatory cell infiltration. Eosinophil, neutrophil and mast cell amounts in the BALF of asthmatic mice were significantly higher than control values. Furthermore, lung miRNA-126 expression in asthmatic mice was significantly higher than that of controls. Finally, DNMT1 mRNA and protein levels were significantly lower in asthmatic animals compared with controls (P < 0.01). Conclusion: MiRNA-126 is highly expressed in serum exosomes from allergic asthma patients and lung tissues of asthmatic mice, suggesting that it may be involved in the pathogenesis of bronchial asthma.

scholarly journals Comparing Patient Characteristics, Clinical Outcomes, and Biomarkers of Severe Asthma Patients in Taiwan

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 764
Author(s):  
Shih-Lung Cheng ◽  
Kuo-Chin Chiu ◽  
Hsin-Kuo Ko ◽  
Diahn-Warng Perng ◽  
Hao-Chien Wang ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Clinical Characteristics ◽  
Linear Models ◽  
Patient Characteristics ◽  
Emergency Department Visits ◽  
Receiver Operating Characteristic Curves ◽  
Increased Risk ◽  
Significant Difference ◽  
Asthma Patients ◽  
Patients At Risk

Purpose: To understand the association between biomarkers and exacerbations of severe asthma in adult patients in Taiwan. Materials and Methods: Demographic, clinical characteristics and biomarkers were retrospectively collected from the medical charts of severe asthma patients in six hospitals in Taiwan. Exacerbations were defined as those requiring asthma-specific emergency department visits/hospitalizations, or systemic steroids. Enrolled patients were divided into: (1) those with no exacerbations (non-exacerbators) and (2) those with one or more exacerbations (exacerbators). Receiver operating characteristic curves were used to determine the optimal cut-off value for biomarkers. Generalized linear models evaluated the association between exacerbation and biomarkers. Results: 132 patients were enrolled in the study with 80 non-exacerbators and 52 exacerbators. There was no significant difference in demographic and clinical characteristics between the two groups. Exacerbators had significantly higher eosinophils (EOS) counts (367.8 ± 357.18 vs. 210.05 ± 175.24, p = 0.0043) compared to non-exacerbators. The optimal cut-off values were 292 for EOS counts and 19 for the Fractional exhaled Nitric Oxide (FeNO) measure. Patients with an EOS count ≥ 300 (RR = 1.88; 95% CI, 1.26–2.81; p = 0.002) or FeNO measure ≥ 20 (RR = 2.10; 95% CI, 1.05–4.18; p = 0.0356) had a significantly higher risk of exacerbation. Moreover, patients with both an EOS count ≥ 300 and FeNO measure ≥ 20 had a significantly higher risk of exacerbation than those with lower EOS count or lower FeNO measure (RR = 2.16; 95% CI, 1.47–3.18; p = < 0.0001). Conclusions: Higher EOS counts and FeNO measures were associated with increased risk of exacerbation. These biomarkers may help physicians identify patients at risk of exacerbations and personalize treatment for asthma patients.

scholarly journals K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tatiana Zyrianova ◽  
Benjamin Lopez ◽  
Riccardo Olcese ◽  
John Belperio ◽  
Christopher M. Waters ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lung Compliance ◽  
Alveolar Epithelial Cells ◽  
Pharmacological Intervention ◽  
Alveolar Epithelial ◽  
Protein Levels ◽  
Cell Counts ◽  
Novel Approach ◽  
Intracellular Ca ◽  
Cell Depolarization

AbstractNo targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K2P2.1 (TREK-1) K+ channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmacological intervention. Therefore, we hypothesized that TREK-1 activation protects against HALI. We treated HO-exposed mice and primary alveolar epithelial cells (AECs) with the novel TREK-1 activators ML335 and BL1249, and quantified physiological, histological, and biochemical lung injury markers. We determined the effects of these drugs on epithelial TREK-1 currents, plasma membrane potential (Em), and intracellular Ca2+ (iCa) concentrations using fluorometric assays, and blocked voltage-gated Ca2+ channels (CaV) as a downstream mechanism of cytokine secretion. Once-daily, intra-tracheal injections of HO-exposed mice with ML335 or BL1249 improved lung compliance, histological lung injury scores, broncho-alveolar lavage protein levels and cell counts, and IL-6 and IP-10 concentrations. TREK-1 activation also decreased IL-6, IP-10, and CCL-2 secretion from primary AECs. Mechanistically, ML335 and BL1249 induced TREK-1 currents in AECs, counteracted HO-induced cell depolarization, and lowered iCa2+ concentrations. In addition, CCL-2 secretion was decreased after L-type CaV inhibition. Therefore, Em stabilization with TREK-1 activators may represent a novel approach to counteract HALI.

scholarly journals Trends in oral corticosteroids use in severe asthma: a 14-year population-based study

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Mohsen Sadatsafavi ◽  
Amir Khakban ◽  
Hamid Tavakoli ◽  
Solmaz Ehteshami-Afshar ◽  
Larry D. Lynd ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Poisson Regression ◽  
Population Based ◽  
Population Based Study ◽  
Factors Associated ◽  
Asthma Patients ◽  
Oral Corticosteroids ◽  
Administrative Health Databases ◽  
Time Since Diagnosis

Abstract Background Oral corticosteroids are important components of pharmacotherapy in severe asthma. Our objective was to describe the extent, trends, and factors associated with exposure to oral corticosteroids (OCS) in a severe asthma cohort. Methods We used administrative health databases of British Columbia, Canada (2000–2014) and validated algorithms to retrospectively create a cohort of severe asthma patients. Exposure to OCS within each year of follow-up was measured in two ways: maintenance use as receiving on average ≥ 2.5 mg/day (prednisone-equivalent) OCS, and episodic use as the number of distinct episodes of OCS exposure for up to 14 days. Trends and factors associated with exposure on three time axes (calendar year, age, and time since diagnosis) were evaluated using Poisson regression. Results 21,144 patients (55.4% female; mean entry age 28.7) contributed 40,803 follow-up years, in 8.2% of which OCS was used as maintenance therapy. Maintenance OCS use declined by 3.8%/calendar year (p < 0.001). The average number of episodes of OCS use was 0.89/year, which increased by 1.1%/calendar year (p < 0.001). Trends remained significant for both exposure types in adjusted analyses. Both maintenance and episodic use increased by age and time since diagnosis. Conclusions This population-based study documented a secular downward trend in maintenance OCS use in a period before widespread use of biologics. This might have been responsible for a higher rate of exacerbations that required episodic OCS therapy. Such trends in OCS use might be due to changes in the epidemiology of severe asthma, or changes in patient and provider preferences over time.

scholarly journals Changes of Hematocrit, Hemoglobin, Serum Protein Levels and Red Blood Cell Counts Before and After Stroke

1976 ◽  
Vol 13 (4) ◽  
pp. 207-214
Author(s):  
Hiroshi Yamanouchi ◽  
Hideo Tohgi ◽  
Masakuni Kameyama ◽  
Mototaka Murakami ◽  
Tamotsu Matsuda
Keyword(s):  
Blood Cell ◽  
Serum Protein ◽  
Red Blood Cell ◽  
Protein Levels ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
Before And After
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