Approach For Asthma Research Articles

The effect of biologics in lung function and quality of life of patients with united airways disease: A systematic review

Increasing evidence supports the united airway disease concept for the management of upper and lower respiratory tract diseases, particularly in patients with asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). However, evidence for a combined approach in asthma and CRSwNP is scarce. In this systematic review, we focused on the role of biologics in the lung function and quality of life in patients with severe asthma and CRSwNP. We conducted a systematic search of 3 electronic databases using 2 search strategies to identify studies published from January 2010 to March 2022. Quality assessment was performed with the Critical Appraisal Skills Programme. Of 1030 studies identified, 48 original studies reporting data of benralizumab (12), dupilumab (14), mepolizumab (10), omalizumab (13), and reslizumab (2) were analyzed. Primary diagnosis was mostly asthma or CRSwNP, with only 15 studies, mainly observational, performed in populations with united airway disease. In total, 18 studies reported data on quality of life (mostly 22-item Sino-Nasal Outcome Test score), 8 on lung function (mostly FEV1), and 22 on both outcomes. Significant FEV1 and 22-item Sino-Nasal Outcome Test score improvements were consistently observed after 24-week treatment, and thereafter, mostly in real-world studies that included variable proportions of patients with asthma/CRSwNP. The use of biologics in patients with severe asthma and CRSwNP was overall associated with significant improvements in lung function and quality of life. However, we observed a high heterogeneity of populations and outcome measurements across studies. Notwithstanding the need of larger studies, our results reinforce the joint management of asthma and CRSwNP as united airway disease in clinical practice.

Optimization of Long-Acting Bronchodilator Dose Ratios Using Isolated Guinea Pig Tracheal Rings for Synergistic Combination Therapy in Asthma and COPD

The co-administration of a long-acting β2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), has been shown to be beneficial in the management of non-communicable chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The resulting relaxation of the airways can be synergistically enhanced, reducing symptoms and optimizing lung function. This provides an insight into more effective treatments. In this study, the LABAs formoterol fumarate dihydrate (FOR) and indacaterol maleate (IND) were each associated with tiotropium bromide monohydrate (TIO) to assess their synergistic potential. This was done using an appropriate ex vivo model of isolated perfused guinea pig tracheal rings, and pharmacological models of drug interaction. Among the dose ratios studied for both types of combination, a higher synergistic potential was highlighted for FOR/TIO 2:1 (w/w). This was done through three steps by using multiple additions of drugs to the organ baths based on a non-constant dose ratio and then on a constant dose ratio, and by a single addition to the organ baths of specific amounts of drugs. In this way, the synergistic improvement of the relaxant effect on the airways was confirmed, providing a basis for improving therapeutic approaches in asthma and COPD. The synergy found at this dose ratio should now be confirmed on a preclinical model of asthma and COPD by assessing lung function.

Using Computational Methods to Improve Integrated Disease Management for Asthma and Chronic Obstructive Pulmonary Disease: Protocol for a Secondary Analysis.

BackgroundAsthma and chronic obstructive pulmonary disease (COPD) impose a heavy burden on health care. Approximately one-fourth of patients with asthma and patients with COPD are prone to exacerbations, which can be greatly reduced by preventive care via integrated disease management that has a limited service capacity. To do this well, a predictive model for proneness to exacerbation is required, but no such model exists. It would be suboptimal to build such models using the current model building approach for asthma and COPD, which has 2 gaps due to rarely factoring in temporal features showing early health changes and general directions. First, existing models for other asthma and COPD outcomes rarely use more advanced temporal features, such as the slope of the number of days to albuterol refill, and are inaccurate. Second, existing models seldom show the reason a patient is deemed high risk and the potential interventions to reduce the risk, making already occupied clinicians expend more time on chart review and overlook suitable interventions. Regular automatic explanation methods cannot deal with temporal data and address this issue well.ObjectiveTo enable more patients with asthma and patients with COPD to obtain suitable and timely care to avoid exacerbations, we aim to implement comprehensible computational methods to accurately predict proneness to exacerbation and recommend customized interventions.MethodsWe will use temporal features to accurately predict proneness to exacerbation, automatically find modifiable temporal risk factors for every high-risk patient, and assess the impact of actionable warnings on clinicians’ decisions to use integrated disease management to prevent proneness to exacerbation.ResultsWe have obtained most of the clinical and administrative data of patients with asthma from 3 prominent American health care systems. We are retrieving other clinical and administrative data, mostly of patients with COPD, needed for the study. We intend to complete the study in 6 years.ConclusionsOur results will help make asthma and COPD care more proactive, effective, and efficient, improving outcomes and saving resources.International Registered Report Identifier (IRRID)PRR1-10.2196/27065

Targeting Caspase-4 and pyroptosis as a new therapeutic approach for asthma

Targeting Caspase-4 and pyroptosis as a new therapeutic approach for asthma

Ectopic olfactory receptors in the respiratory system

New findings and concepts on a role of so-called “ectopic” chemosensory receptors arise recently. The ectopic receptors are expressed outside their classical localization (nasal cavity) and referred to as extra-nasal olfactory receptors. Functional investigations of the ectopic olfactory receptors in the lungs are also ongoing. To date, it is well-known that molecules of odorous substances (odorants) bind to the G-protein-associated olfactory receptor (Gαolf) that can activate type III adenylate cyclase and increase concentration of a secondary messenger, cyclic adenosine monophosphate (cAMP). In turn, this induces the opening of cAMP-dependent cationic channels including calcium channels. Olfactory receptor activation in neuroendocrine cells of the lungs affected serotonin release which decreased after the stimulation of those cells by an odorant. Amyl butyrate and burgenal, agonists of OR2AG1 and OR1D2 olfactory receptors, respectively, affect smooth muscle contractibility in human bronchi. Amyl butyrate inhibits histamine-induces muscle contractibility, whereas burgenal increases the smooth muscle contractibility. Both the processes are mediated by cAMP-dependent increase in the intracellular calcium concentration. Data have been published about the receptor expression on immune cells such as monocytes, natural killers, T- and B-lymphocites, and polymorphonuclears. Ectopic olfactory receptors are thought to participate in modulation (controlling) of intrinsic cell functions which provide a special role of inflammatory cells in asthma. In future, the olfactory receptor modulation could be probably used as a novel therapeutic approach in asthma and other chronic inflammatory lung diseases.

Recent advances in relationship between interferon and asthma

Interferons(IFN)have antiviral, immunomodulation and other biological functions.Viruses are the major causes of asthma exacerbations, which may be related to deficiencies of interferons in asthmatic patients in response to viral infection and impaired antiviral immune response.Adjuvant interferons treatment would be beneficial to some asthma phenotypes, which provide a new approach for asthma treatments.This review mainly focuses on the biological functions, relationships with asthma and the potential adjuvant treatment significance of interferons. Key words: Interferon; Rhinovirus; Asthma; Treatment

Complementary therapeutic approaches in asthma

Asthma is defined by The Initiative for Asthma (GINA 2018) as a heterogeneous disease, which include chronic airway inflammation and a history of respiratory symptoms. In the last decades asthma had a rise in prevalence, becoming one of the most frequent diagnosed diseases in the world. The main goals of asthma management are to achieve good symptom control, minimize the risks of exacerbations, decrease rescue medication intake, improve the quality of life by decreasing respiratory system inflammation and ameliorating the patient’s lung function. Beside effective medications, asthma continues to impair quality of life for most patients. Due to the difficulty of controlling symptoms and exacerbations, the need of developing complementary options of treatment is increasing in order to achieve an optimum control and a lower risk of acute episodes or fatal events. Pulmonary rehabilitation is suggested for asthma patients when adequate medical therapy poorly control the symptoms and mental, physical or social consequences of illness persist during the daily life. The following non-drug therapy components are included in the rehabilitation program: physical training, comprehensive smoking cessation program, comprehensive patient education, respiratory physiotherapy, psychosocial support and comprehensive nutritional counseling. These complementary therapies have been proven to improve muscle strength, exercise capacity and symptomatology. Also, it has been associated to fewer exacerbations and a lower use of rescue medication, leading to a better quality of life. Key words: asthma, quality of life, symptomatology, rehabilitation, physiotherapy,

Troglitazone, a PPAR-γ agonist, decreases LTC4 concentration in mononuclear cells in patients with asthma.

Asthma is an inflammatory disorder with multiple mediators involved in the inflammatory response. Despite several attempts, no new anti-inflammatory drugs have been registered for asthma treatment for several years. However, thiazolidinediones, peroxisome proliferator-activated receptor agonists, have demonstrated some anti-inflammatory properties in various experimental settings. The aim of this study was to assess the influence of troglitazone on LTC4 and 15-HETE concentrations. It also evaluates TNF-induced eotaxin synthesis in peripheral blood mononuclear cells from 14 patients with mild asthma and 13 healthy controls. PBMCs were isolated from the whole blood of the asthmatics and healthy subjects and pretreated with 0.1, 1 or 10μM of Troglitazone. The cells were then exposed to 10-6M calcium jonophore or 10ng/ml TNF. The production and release of LTC4, 15-HETE and eotaxin were then assessed. Troglitazone caused a dose-dependent inhibition in LTC4 synthesis in both asthmatics and healthy subjects. Troglitazone did not influence 15-HETE or eotaxin production in either asthmatic patients or in healthy individuals. Due to its inhibition of LTC4 synthesis, troglitazone therapy is an interesting potential therapeutic approach in asthma and other LTC4 related inflammatory disorders.

Spleen tyrosine kinase inhibition blocks airway constriction and protects from Th2-induced airway inflammation and remodeling.

Spleen tyrosine kinase (Syk) is an intracellular nonreceptor tyrosine kinase, which has been implicated as central immune modulator promoting allergic airway inflammation. Syk inhibition has been proposed as a new therapeutic approach in asthma. However, the direct effects of Syk inhibition on airway constriction independent of allergen sensitization remain elusive. Spectral confocal microscopy of human and murine lung tissue was performed to localize Syk expression. The effects of prophylactic or therapeutic Syk inhibition on allergic airway inflammation, hyperresponsiveness, and airway remodeling were analyzed in allergen-sensitized and airway-challenged mice. The effects of Syk inhibitors BAY 61-3606 or BI 1002494 on airway function were investigated in isolated lungs of wild-type, PKCα-deficient, mast cell-deficient, or eNOS-deficient mice. Spleen tyrosine kinase expression was found in human and murine airway smooth muscle cells. Syk inhibition reduced allergic airway inflammation, airway hyperresponsiveness, and pulmonary collagen deposition. In naïve mice, Syk inhibition diminished airway responsiveness independently of mast cells, or PKCα or eNOS expression and rapidly reversed established bronchoconstriction independently of NO. Simultaneous inhibition of Syk and PKC revealed additive dilatory effects, whereas combined inhibition of Syk and rho kinase or Syk and p38 MAPK did not cause additive bronchodilation. Spleen tyrosine kinase inhibition directly attenuates airway smooth muscle cell contraction independent of its protective immunomodulatory effects on allergic airway inflammation, hyperresponsiveness, and airway remodeling. Syk mediates bronchoconstriction in a NO-independent manner, presumably via rho kinase and p38 MAPK, and Syk inhibition might present a promising therapeutic approach in chronic asthma as well as acute asthma attacks.

Fuzzy model to estimate the number of hospitalizations for asthma and pneumonia under the effects of air pollution.

ABSTRACTOBJECTIVE Predict the number of hospitalizations for asthma and pneumonia associated with exposure to air pollutants in the city of São José dos Campos, São Paulo State.METHODS This is a computational model using fuzzy logic based on Mamdani’s inference method. For the fuzzification of the input variables of particulate matter, ozone, sulfur dioxide and apparent temperature, we considered two relevancy functions for each variable with the linguistic approach: good and bad. For the output variable number of hospitalizations for asthma and pneumonia, we considered five relevancy functions: very low, low, medium, high and very high. DATASUS was our source for the number of hospitalizations in the year 2007 and the result provided by the model was correlated with the actual data of hospitalization with lag from zero to two days. The accuracy of the model was estimated by the ROC curve for each pollutant and in those lags.RESULTS In the year of 2007, 1,710 hospitalizations by pneumonia and asthma were recorded in São José dos Campos, State of São Paulo, with a daily average of 4.9 hospitalizations (SD = 2.9). The model output data showed positive and significant correlation (r = 0.38) with the actual data; the accuracies evaluated for the model were higher for sulfur dioxide in lag 0 and 2 and for particulate matter in lag 1.CONCLUSIONS Fuzzy modeling proved accurate for the pollutant exposure effects and hospitalization for pneumonia and asthma approach.

The Current Genomic Approaches for Common Respiratory Diseases

Common respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and lung cancer are increasing worldwide. Genomic approaches for the diseases provided new insights of the mechanisms and revealed the new therapeutic targets. Genome-wide association studies (GWAS), epigenetic studies, transcriptional profiling, RNA sequencing, chromatin immune precipitation (ChIP) sequencing and microbiota investigation make personalized medicine for common respiratory diseases possible in the near future. In this review, we summarize the current progress of genomic approaches for asthma, COPD and lung cancer and also discuss the future directions of the research of the diseases.

Simvastatin alleviates airway inflammation and remodelling through up-regulation of autophagy in mouse models of asthma.

Statins have been widely used in inflammatory diseases including asthma, because of their anti-inflammatory and immunomodulatory properties. It has been shown that simvastatin induces autophagy and cell death in some circumstances. However, the possible cross-talk between simvastatin and autophagic processes in lung disease is largely unknown. Thus, we investigated the impact of simvastatin on airway inflammation and airway remodelling and the possible relationship of these processes to a simvastatin-induced autophagic pathway in mouse models of asthma. Ovalbumin (OVA)-sensitized and challenged mice were treated with simvastatin and sacrificed. The autophagy-related proteins Atg5, LC3B and Beclin1 were quantified, as well as the autophagy flux in bronchial smooth muscle cells (BSMCs). The relationship between airway inflammation and the autophagic process was investigated. We show that simvastatin treatment mediates activation of autophagy in BSMCs, which is correlated with airway inflammation and airway remodelling in mouse models of asthma. Simvastatin increases autophagy-related protein Atg5, LC3B and Beclin1 expression and autophagosome formation in lung tissue. Simvastatin-induced autophagy is associated with increased interferon-gamma (IFN-γ) and decreased IL-4, IL-5 and IL-13 cytokines production in BSMCs, as well as reversed extracellular matrix (ECM) deposition. In contrast, autophagy inhibitor 3-methyladenine (3-MA) eliminates the therapeutic effect of simvastatin. These findings demonstrate that simvastatin inhibits airway inflammation and airway remodelling through an activated autophagic process in BSMCs. We propose a crucial function of autophagy in statin-based therapeutic approaches in asthma.

Potential therapeutic targets from genetic and epigenetic approaches for asthma

Potential therapeutic targets from genetic and epigenetic approaches for asthma

Asthma heterogeneity and severity—why is comprehensive phenotyping important?

Asthma heterogeneity and severity—why is comprehensive phenotyping important?

Associated demographics of persistent exhaled nitric oxide elevation in treated asthmatics

The fraction of exhaled nitric oxide (FENO) is reduced by anti-inflammatory treatment in asthma. However, the FENO level is also regulated by individual demographics and there is considerable variation among clinically stable patients. We hypothesized that some demographics may be responsible for persistent FENO elevation despite inhaled corticosteroids (ICS) therapy in asthma. This was a prospective observational study. We initially screened 250 stable asthmatics and determined the FENO cut-off point for identifying poorly controlled asthma defined by one of the following criteria: Asthma control test <20, or forced expiratory volume in one-second % of predicted <80%, or peak expiratory flow variability <80% (Study 1). After 12-weeks, 229 patients who maintained high or low FENO were selected and the independent factors which might contribute to a high FENO were examined (Study 2). A FENO level >39.5 p.p.b. yielded 67% sensitivity and 76% specificity for identifying the patients with poorly controlled asthma. The persistent high FENO group (≥ 40 p.p.b.) was more likely to be ex-smokers, to show evidence of atopy (positive specific IgE, higher serum IgE and blood eosinophils), and to have allergic comorbidities. Especially, past smoking history, blood eosinophils, and chronic rhinosinusitis were identified to be independent predictors of high FENO. Neither the dose of ICS nor other medication use showed any difference between the groups. These results suggested that past smoking history, blood eosinophilia, and chronic rhinosinusitis are involved in the persistent airway inflammation detected by FENO. Although their relative contributions on FENO values should be further quantified, clarification of the features of the subjects with high FENO might provide clues for adjustment of the treatment approach in asthma.

Role of CXCL13 in Asthma: Novel Therapeutic Target

B cells play an important role in allergic asthma. However, the mechanisms by which these cells are activated in the airways remain poorly understood. We used a mouse model of ovalbumin (OVA)-induced allergic inflammation to study CXCL13 and to investigate the concentration of this chemokine in the BAL fluid derived from asthmatic and normal control subjects. We found that OVA-challenged mice upregulate the CXCL13/CXCR5 axis, which is associated with several changes in their airways, including recruitment of B and CD4(+) cells, development of bronchial-associated lymphoid tissue, and airway inflammation. Treating sensitized mice with an anti-CXCL13 antibody reduced cell recruitment, bronchial-associated lymphoid tissue formation, and airways inflammation. Interestingly, measurements of CXCL13 using enzyme-linked immunosorbent assay showed that levels of this cytokine were significantly elevated in BAL fluid from subjects with asthma compared with control subjects (median, 162 [range, 120-296] vs 31 [range, 120-156] pg/mL; P = .005). All together, these findings suggest that CXCL13 is involved in the allergic airway inflammatory process, and targeting this chemokine may constitute a novel approach in asthma.

Targeting the toll-like receptor 7 pathway in asthma: a potential immunomodulatory approach?

In allergic airways, as in asthma, inflammation and impaired functioning of toll-like receptor 7 (TLR7) has been found. The augmentation of this receptor with agonist compounds resulted in bronchodilation and a switch of the TH2 inflammatory pattern, specific for allergic conditions, to TH1 inflammation, characterised by an increased production of interferon-γ. This was a preclinical study evaluating the effects of two TLR7 agonists, imiquimod and resiquimod, on the isolated guinea pig trachea. The TLR7-related downstream signalling pathways were also assessed. Both TLR7 agonists were shown to reduce serotonin-induced bronchoconstriction, which is possibly exerted via the p38MAPK and NF-κB pathways. Therapeutic targeting of TLR7 with specific agonists might represent a promising immunomodulatory approach in asthma, especially if systemic exposure is minimised with inhaled formulations.

New therapies and management strategies in the treatment of asthma: patient-focused developments.

It is increasingly recognized that large proportions of patients with asthma remain poorly controlled with daily symptoms, limitation in activities, or severe exacerbations despite traditional treatment with inhaled corticosteroids and other agents. This suggests that there is considerable scope for the refinement of traditional guidelines on the use of inhaled therapies in asthma and also a need for the development of novel therapeutic agents, particularly for the treatment of severe asthma. This review aims to discuss a range of emerging treatment approaches in asthma. Firstly, we will set the scene by highlighting the importance of achieving good asthma control in a patient-focused manner and discussing recent work that has furthered our understanding of asthma phenotypes and paved the way for patient-specific treatments. Secondly, we will review new strategies to better use the existing therapies such as inhaled corticosteroids and long-acting β2-agonists that remain the mainstay of treatment for most patients. Finally, we will review the novel therapies that are becoming available, both pharmacological and interventional, and discuss their likely place in the management of this complex disease.

Unifying Candidate Gene and GWAS Approaches in Asthma

The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children. Genotyping data were compared to imputation data derived from Illumina HumanHap300 chip genotyping. Results were combined to analyze 566 SNPs covering all 14 candidate gene loci. Genotyped polymorphisms in ADAM33, GSTP1 and VDR showed effects with p-values <0.0035 (corrected for multiple testing). Combining genotyping and imputation, polymorphisms in DPP10, EDN1, IL12B, IL13, IL4, IL4R and TNF showed associations at a significance level between p = 0.05 and p = 0.0035. These data indicate that (a) GWAS coverage is insufficient for many asthma candidate genes, (b) imputation based on these data is reliable but incomplete, and (c) SNPs in three previously identified asthma candidate genes replicate in our GWAS population with significance after correction for multiple testing in 14 genes.

Current opinion: Pharmacological approaches in asthma and COPD

Educational aimsTo illustrate the similarities and differences in the treatment of asthma and COPD.To explain whether the response to bronchodilators in asthma and COPD predicts prognosis and response to other interventions.To assist in therapeutic choices for asthmatic and COPD patients.SummaryBronchodilators, inhaled corticosteroids and other anti-inflammatory agents form the basis of treatment to control the symptoms and progression of asthma and COPD. However, although the armoury of medications used for the two conditions is largely similar, the goals and targets of therapy are different. In fact, owing to their different mechanisms of development, the two diseases are regarded quite differently. Therefore, the two require different pharmacological treatments. In general, therapy for asthma is targeted at reducing inflammation, whereas for COPD it is directed at relief of symptoms. In this article, the pharmacological treatment of asthma and COPD, based on recently updated guidelines, is described.