scholarly journals Variability in airway inflammation, symptoms, lung function and reliever use in asthma: anti-inflammatory reliever hypothesis and STIFLE study design

2020 ◽  
Vol 6 (2) ◽  
pp. 00333-2019
Author(s):  
Tim Harrison ◽  
Ian D. Pavord ◽  
James D. Chalmers ◽  
Glenn Whelan ◽  
Malin Fagerås ◽  
...  
Keyword(s):  
Lung Function ◽  
Maintenance Therapy ◽  
Airway Inflammation ◽  
Temporal Dynamics ◽  
Inhaled Corticosteroids ◽  
Dry Powder Inhaler ◽  
Airway Disease ◽  
Open Label ◽  
Asthma Symptoms ◽  
Anti Inflammatory

Asthma is a chronic inflammatory airway disease. Increase in airway inflammation is hypothesised to contribute to worsening of asthma symptoms and deterioration in lung function, resulting in the use of reliever medication. Short-acting β2-agonists only treat the symptoms, whereas an anti-inflammatory reliever is believed to treat both symptoms and the underlying inflammation, thereby arresting the progression to an exacerbation. As-needed budesonide/formoterol as an anti-inflammatory reliever reduces the risk of severe exacerbations. However, supporting mechanistic evidence has not yet been described, specifically the temporal dynamics of parameters including airway inflammation, over time and during asthma worsening.The STIFLE study aims to characterise daily variability in airway inflammation, symptoms, lung function and reliever use in people with asthma. This phase IV, open-label, parallel-group, multicentre, exploratory study will enrol 60–80 adult patients with asthma receiving low- or medium-dose inhaled corticosteroids/long-acting β2-agonists (EudraCT identifier number 2018-003467-64). Participants will be randomised 1:1 to either as-needed budesonide/formoterol dry-powder inhaler or salbutamol reliever for 24 weeks, in addition to their maintenance therapy. Daily data will be captured for fractional exhaled nitric oxide, spirometry, asthma symptoms and medication use using devices connected to a smartphone via the STIFLE application. STIFLE will thereby enable not only characterisation of the variability of airway inflammation and clinical outcomes in relation to asthma worsening, but also elucidate the effect of as-needed budesonide/formoterol on airway inflammation against a background of daily maintenance therapy.

scholarly journals Effects of personal air pollution exposure on asthma symptoms, lung function and airway inflammation

2018 ◽  
Vol 48 (7) ◽  
pp. 798-805 ◽  
Author(s):  
L. Chambers ◽  
J. Finch ◽  
K. Edwards ◽  
A. Jeanjean ◽  
R. Leigh ◽  
...  
Keyword(s):  
Air Pollution ◽  
Lung Function ◽  
Airway Inflammation ◽  
Asthma Symptoms ◽  
Air Pollution Exposure ◽  
Pollution Exposure

scholarly journals Regulation of Interaction between the Upper and Lower Airways in United Airway Disease

2019 ◽  
Vol 7 (2) ◽  
pp. 27 ◽  
Author(s):  
Akira Kanda ◽  
Yoshiki Kobayashi ◽  
Mikiya Asako ◽  
Koichi Tomoda ◽  
Hideyuki Kawauchi ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Inhaled Corticosteroids ◽  
Upper Airway ◽  
Airway Disease ◽  
Comprehensive Approach ◽  
Lower Airway ◽  
T Helper 2 ◽  
Neural Modulation ◽  
Lower Airways ◽  
Novel Therapeutic

The concept of united airway disease comprises allergic rhinitis (AR) with asthma, and eosinophilic chronic rhinosinusitis (ECRS) with asthma. It embodies a comprehensive approach to the treatment of upper and lower airway inflammation. The treatment of upper airway inflammation reduces asthma symptoms and decreases the dose of inhaled corticosteroids (ICS) necessary to treat asthma. However, little is known about the mechanisms of interaction between upper and lower airway inflammation. Here we review these mechanisms, focusing on neural modulation and introduce a novel therapeutic approach to united airway disease using a fine-particle ICS. Our understanding of the relationship between the upper and lower airways and its contribution to T helper 2 (Th2)-skewed disease, such as AR and/or ECRS with asthma, has led us to this novel therapeutic strategy for a comprehensive approach to the treatment of upper airway inflammation with asthma.

Harsh parent–child conflict is associated with decreased anti-inflammatory gene expression and increased symptom severity in children with asthma

2015 ◽  
Vol 27 (4pt2) ◽  
pp. 1547-1554 ◽  
Author(s):  
Katherine B. Ehrlich ◽  
Gregory E. Miller ◽  
Edith Chen
Keyword(s):  
Gene Expression ◽  
Airway Inflammation ◽  
Parental Support ◽  
The United States ◽  
Signaling Molecules ◽  
Asthma Symptoms ◽  
Supportive Behaviors ◽  
Children With Asthma ◽  
Anti Inflammatory ◽  
Parent Child

AbstractAsthma is a chronic respiratory disorder that affects over 7 million children in the United States. Evidence indicates that family stressors are associated with worsening of asthma symptoms, and some research suggests that these stressful experiences engender changes in children's immune systems in ways that exacerbate airway inflammation and contribute to both acute and chronic asthma symptoms. We examined the association between observed experiences of parent–child conflict and the expression of signaling molecules involved in the transduction of anti-inflammatory signals that regulate airway inflammation and obstruction. Fifty-seven children and their parents participated in a conflict task, and coders rated interactions for evidence of harsh and supportive behaviors. Children reported on their perceptions of parental support and reported on their daily asthma symptoms for 2 weeks. We collected peripheral blood in children to measure leukocyte expression of messenger RNA for the glucocorticoid receptor and the β2-adrenergic receptor. Analyses revealed that harsh conflict behaviors were associated with decreased expression of both messenger RNAs and more severe asthma symptoms. Neither supportive behaviors nor perceived parental support was associated with gene expression or asthma symptoms. These findings suggest that harsh interactions with parents are associated with downregulation of key anti-inflammatory signaling molecules and difficulties breathing in children with asthma. Children with asthma who are also victims of maltreatment may be particularly susceptible to transcriptional changes in immune cells that could worsen asthma over time.

scholarly journals Neuroimmune Pathophysiology in Asthma

2021 ◽  
Vol 9 ◽  
Author(s):  
Gandhi F. Pavón-Romero ◽  
Nancy Haydée Serrano-Pérez ◽  
Lizbeth García-Sánchez ◽  
Fernando Ramírez-Jiménez ◽  
Luis M. Terán
Keyword(s):  
Inhaled Corticosteroids ◽  
Bronchial Hyperresponsiveness ◽  
Airway Disease ◽  
Neuroendocrine Cells ◽  
Lower Airway ◽  
Neurokinin A ◽  
Type I ◽  
Matrix Deposition ◽  
Novel Approach ◽  
Anti Inflammatory

Asthma is a chronic inflammation of lower airway disease, characterized by bronchial hyperresponsiveness. Type I hypersensitivity underlies all atopic diseases including allergic asthma. However, the role of neurotransmitters (NT) and neuropeptides (NP) in this disease has been less explored in comparison with inflammatory mechanisms. Indeed, the airway epithelium contains pulmonary neuroendocrine cells filled with neurotransmitters (serotonin and GABA) and neuropeptides (substance P[SP], neurokinin A [NKA], vasoactive intestinal peptide [VIP], Calcitonin-gene related peptide [CGRP], and orphanins-[N/OFQ]), which are released after allergen exposure. Likewise, the autonomic airway fibers produce acetylcholine (ACh) and the neuropeptide Y(NPY). These NT/NP differ in their effects; SP, NKA, and serotonin exert pro-inflammatory effects, whereas VIP, N/OFQ, and GABA show anti-inflammatory activity. However, CGPR and ACh have dual effects. For example, the ACh-M3 axis induces goblet cell metaplasia, extracellular matrix deposition, and bronchoconstriction; the CGRP-RAMP1 axis enhances Th2 and Th9 responses; and the SP-NK1R axis promotes the synthesis of chemokines in eosinophils, mast cells, and neutrophils. In contrast, the ACh-α7nAChR axis in ILC2 diminishes the synthesis of TNF-α, IL-1, and IL-6, attenuating lung inflammation whereas, VIP-VPAC1, N/OFQ-NOP axes cause bronchodilation and anti-inflammatory effects. Some NT/NP as 5-HT and NKA could be used as biomarkers to monitor asthma patients. In fact, the asthma treatment based on inhaled corticosteroids and anticholinergics blocks M3 and TRPV1 receptors. Moreover, the administration of experimental agents such as NK1R/NK2R antagonists and exogenous VIP decrease inflammatory mediators, suggesting that regulating the effects of NT/NP represents a potential novel approach for the treatment of asthma.

scholarly journals Airway inflammation in COPD after long-term withdrawal of inhaled corticosteroids

2016 ◽  
Vol 49 (1) ◽  
pp. 1600839 ◽  
Author(s):  
Lisette I.Z. Kunz ◽  
Nick H.T. ten Hacken ◽  
Thérèse S. Lapperre ◽  
Wim Timens ◽  
Huib A.M. Kerstjens ◽  
...  
Keyword(s):  
Lung Function ◽  
Airway Inflammation ◽  
Inhaled Corticosteroids ◽  
Term Treatment ◽  
Chronic Obstructive ◽  
Lung Function Decline ◽  
Cell Counts ◽  
Long Term Treatment ◽  
Severe Copd

Long-term treatment with inhaled corticosteroids (ICS) might attenuate lung function decline and decrease airway inflammation in a subset of patients with chronic obstructive pulmonary disease (COPD), and discontinuing ICS treatment could result in further lung function decline. We hypothesised that airway inflammation increases after ICS withdrawal following long-term ICS treatment in COPD.In the GLUCOLD-1 study (GL1), 114 patients with moderate-severe COPD were randomised to 6-month or 30-month treatment with fluticasone propionate (500 µg twice daily), 30-month treatment with fluticasone/salmeterol (500/50 µg twice daily) or placebo. During the 5-year follow-up study (GL2), patients were followed prospectively while being treated by their physician. Bronchial biopsies and induced sputum were collected at baseline, at 30 months (end of GL1) and at 7.5 years (end of GL2) to assess inflammatory cell counts. Data were analysed using linear mixed-effects models.In patients using ICS during GL1 and using ICS 0–50% of the time during GL2 (n=61/85), there were significant increases in GL2 bronchial CD3+ (fold change per year calculated as GL2 minus GL1 2.68, 95% CI 1.87–3.84), CD4+ (1.91, 95% CI 1.33–2.75) and CD8+ cells (1.71, 95% CI 1.15–2.53), and mast cells (1.91, 95% CI 1.36–2.68). The sputum total cell counts increased significantly in GL2 (1.90, 95% CI 1.42–2.54), as did counts of macrophages (2.10, 95% CI 1.55–2.86), neutrophils (1.92, 95% CI 1.39–2.65) and lymphocytes (2.01, 95% CI 1.46–2.78).ICS discontinuation increases airway inflammation in patients with moderate-severe COPD, suggesting that the anti-inflammatory effects of ICS in COPD are not maintained after ICS discontinuation.

scholarly journals The use of the mannitol test as an outcome measure in asthma intervention studies: a review and practical recommendations

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Asger Sverrild ◽  
Joanna Leadbetter ◽  
Celeste Porsbjerg
Keyword(s):  
Clinical Trials ◽  
Airway Inflammation ◽  
Intervention Studies ◽  
Outcome Measure ◽  
Inhaled Corticosteroids ◽  
Challenge Test ◽  
Worked Examples ◽  
Pubmed Database ◽  
Anti Inflammatory ◽  
Intervention Trials

Abstract Background The mannitol test is an indirect bronchial challenge test widely used in diagnosing asthma. Response to the mannitol test correlates with the level of eosinophilic and mast cell airway inflammation, and a positive mannitol test is highly predictive of a response to anti-inflammatory treatment with inhaled corticosteroids. The response to mannitol is a physiological biomarker that may, therefore, be used to assess the response to other anti-inflammatory treatments and may be of particular interest in early phase studies that require surrogate markers to predict a clinical response. The main objectives of this review were to assess the practical aspects of using mannitol as an endpoint in clinical trials and provide the clinical researcher and respiratory physician with recommendations when designing early clinical trials. Methods The aim of this review was to summarise previous uses of the mannitol test as an outcome measure in clinical intervention studies. The PubMed database was searched using a combination of MeSH and keywords. Eligible studies included intervention or repeatability studies using the standard mannitol test, at multiple timepoints, reporting the use of PD15 as a measure, and published in English. Results Of the 193 papers identified, 12 studies met the inclusion criteria and data from these are discussed in detail. Data on the mode of action, correlation with airway inflammation, its diagnostic properties, and repeatability have been summarised, and suggestions for the reporting of test results provided. Worked examples of power calculations for dimensioning study populations are presented for different types of study designs. Finally, interpretation and reporting of the change in the response to the mannitol test are discussed. Conclusions The mechanistic and practical features of the mannitol test make it a useful marker of disease, not only in clinical diagnoses, but also as an outcome measure in intervention trials. Measuring airway hyperresponsiveness to mannitol provides a novel and reproducible test for assessing efficacy in intervention trials, and importantly, utilises a test that links directly to underlying drivers of disease.

scholarly journals Increased Ratio of Matrix Metalloproteinase-9 (MMP-9)/Tissue Inhibitor Metalloproteinase-1 from Alveolar Macrophages in Chronic Asthma with a Fast Decline in FEV1 at 5-Year Follow-up

2019 ◽  
Vol 8 (9) ◽  
pp. 1451 ◽  
Author(s):  
Fu-Tsai Chung ◽  
Hung-Yu Huang ◽  
Chun-Yu Lo ◽  
Yu-Chen Huang ◽  
Chang-Wei Lin ◽  
...  
Keyword(s):  
Lung Function ◽  
Airway Inflammation ◽  
Alveolar Macrophages ◽  
Inhaled Corticosteroids ◽  
Airway Remodeling ◽  
Bronchial Biopsy ◽  
Chronic Asthma ◽  
Tissue Inhibitor ◽  
Fev1 Decline

Chronic asthma is associated with progressive airway remodeling, which may contribute to declining lung function. An increase in matrix metalloproteinases-9 (MMP-9)/tissue inhibitor metalloproteinase-1 (TIMP-1) may indicate airway inflammation and bronchial injury. Bronchial biopsy specimens and alveolar macrophages (AMs) were obtained from patients with asthma under regular treatment with inhaled corticosteroids or combination therapy and normal subjects (n = 10). Asthmatics included those with a slow forced expiratory volume in one second (FEV1) decline (<30 mL/year, n = 13) and those with a fast FEV1 decline (≥30 mL/year, n = 8) in 5-year follow-up. Immunostaining expression of MMP-9 and TIMP-1 was detected in airway tissues. MMP-9 and TIMP-1 was measured from AMs cultured for 24 h. After the 5-year treatment, the methacholine airway hyperresponsiveness of the slow FEV1 decline group was decreased, but that of the fast FEV1 decline group was increased (PC20, provocative concentration causing a 20% decrease in FEV1, 3.12 ± 1.10 to 1.14 ± 0.34 mg/dL, p < 0.05). AMs of asthma with a fast FEV1 decline released a higher level of MMP-9 (8.52 ± 3.53 pg/mL, p < 0.05) than those of a slow FEV1 decline (0.99 ± 0.20 pg/mL). The MMP-9/TIMP ratio in the fast FEV1 decline group (0.089 ± 0.032) was higher than that of the slow FEV1 decline group (0.007 ± 0.001, p < 0.01). The annual FEV1 decline in 5 years was proportional to the level of MMP-9 (r = 57, p < 0.01) and MMP-9/TIMP-1 ratio (r = 0.58, p < 0.01). The airways of asthma with greater yearly decline in FEV1 showed an increased thickness of submucosa and strong expression of MMP-9. An increase in MMP-9 and MMP-9/TIMP-1 in airways or AMs could be indicators of chronic airway inflammation and contribute to a greater decline in lung function of patients with chronic asthma.

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