Airway pathology in severe asthma is related to airflow obstruction but not symptom control

Ferreira, Diogenes S.; Carvalho-Pinto, Regina Maria; Gregório, Marcelo Gervilla; Annoni, Raquel; Teles, Aila Mirtes; Buttignol, Monique; Araújo-Paulino, Bianca Bergamo de; Katayama, Edgard H.; Oliveira, B. L.; Frari, H. S. Del; Cukier, Alberto; Dolhnikoff, Marisa; Stelmach, Rafaël; Rabe, Klaus F.; Mauad, Thaís

doi:10.1111/all.13323

Cited by 37 publications

(35 citation statements)

References 40 publications

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“…Our study is the first to evaluate simultaneously the levels of TGF-ß and of periostin in the sputum of severe asthmatics with a different bronchial obstruction; in this respect, the increased levels of TGF-ß and periostin observed in patients with persistent obstruction suggest a greater degree of airway remodelling in this group. In contrast to our results, severe asthmatics with persistent airflow obstruction displayed a decreased number of periostin and TGF-ß positive muscle cells 7 . The discrepancy with our findings is not surprising if we consider that we measured the secretion rather than the intracellular store of periostin and TGF-ß, and that the concentrations of soluble mediators in sputum samples are influenced by all the inflammatory and resident cells, and not only by the muscle cells.…”

Section: Discussioncontrasting

confidence: 99%

“…Airway remodelling has usually been assessed by histologic evaluation of bronchial wall abnormalities (sub-epithelial fibrosis, smooth muscle cells and mucous gland hypertrophy/hyperplasia), but these measurements can only be obtained with invasive procedures and are only related to large airways 1 , 7 . As an alternative, some authors assessed airway thickness by high-resolution computed tomography scanning 2 .…”

Section: Discussionmentioning

confidence: 99%

“…We used persistent airway obstruction as a marker of functional remodelling. This approach, associated with structural abnormalities in airway smooth muscle and/or submucosal fibrosis in bronchial biopsies, 2 , 4 , 7 has been previously used by other authors to select patients with or without airway remodelling 9 …”

Section: Discussionmentioning

confidence: 99%

“…This cytokine is a potent chemotactic factor and activator for different types of inflammatory cells, and is also involved in epithelial transformation, sub-epithelial fibrosis and airway smooth muscle alteration 6 . In this respect, Ferreira et al 7 . reported that the decreased periostin-TGF-ß pathway in the muscle cells of severe asthmatic biopsies was associated with a more proliferative phenotype of airway smooth muscle cells, suggesting a prominent role of both periostin and TGF-ß in the structural changes in the airways of severe asthmatic patients with persistent bronchial obstruction.…”

Section: Introductionmentioning

confidence: 99%

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Distinct profile of inflammatory and remodelling biomarkers in sputum of severe asthmatic patients with or without persistent airway obstruction

Cianchetti

Cardini

Puxeddu

et al. 2019

World Allergy Organization Journal

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BackgroundBoth inflammatory and remodelling processes are associated with irreversible airway obstruction observed in severe asthma. Our aim was to characterize a group of severe asthmatic patients with or without persistent airway obstruction in relation to specific sputum inflammatory and remodelling biomarkers.MethodsForty-five patients under regular high-dose inhaled corticosteroid/ß-2agonist treatment were studied, after a follow-up period of at least 2 years, with a minimum of 4 visits. Periostin, TGF-ß, RANTES, IL-8, GM-CSF, FGF-2, and cell counts were measured in induced sputum. Serum periostin was also measured.ResultsSputum induction was successfully performed in all but 5 patients. There were no significant differences in demographic and clinical data between patients with non-persistent obstruction (NO: FEV1/VC>88%pred.) and those with persistent obstruction (O: a not completely reversible obstruction with FEV1/VC<88%pred. at each visit before the study visit). Patients with persistent obstruction had significantly higher sputum periostin and TGF-ß concentrations than NO patients and a trend of higher serum periostin levels. GM-CSF and FGF-2 were significantly increased in NO compared to O patients. No differences between groups were found for RANTES, IL-8 and differential cell counts. Sputum periostin inversely correlated with functional parameters (prebronch. FEV1: rho = −0.36, p < 0.05; postbronch. FEV1: rho = −0.33, p = 0.05). Patients with high sputum periostin concentration (>103.3 pg/ml: median value) showed an absolute number of sputum eosinophils significantly higher than patients with low sputum periostin; this behavior was unobserved when serum periostin was considered.ConclusionsOnly periostin and TGF-ß identified a subgroup of severe asthmatic patients with persistent airway obstruction. Sputum periostin was also inversely associated with FEV1 and proved to be a more sensitive biomarker than serum periostin to identify severe asthmatics with higher sputum eosinophilia.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Distinct profile of inflammatory and remodelling biomarkers in sputum of severe asthmatic patients with or without persistent airway obstruction

Cianchetti

Cardini

Puxeddu

et al. 2019

World Allergy Organization Journal

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“…Repeated epithelial injury and repair contributed to histological changes and functional abnormalities in the airway mucosal epithelium [ 4 ]. Airway remodeling involves airflow obstruction which results from mucus hyper-secretion and impaired mucus transport [ 5 , 6 ], subsequently becoming important pathological features of severe asthma and even fetal asthma [ 7 ]. Goblet cells are the major secretory cells involved in airway epithelium [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

TGF-β3 Promotes MUC5AC Hyper-Expression by Modulating Autophagy Pathway in Airway Epithelium

et al. 2018

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Mucus secretion accumulation in the airways may act as a contributing factor for the development of airflow limitation in severe fetal asthma patients. Accumulated evidences showed that transforming growth factor beta (TGF-β) plays a regulatory role in airway remodeling including mucus hyper-secretion in asthma. However, the detailed molecular mechanisms of TGF-β3 induced MUC5AC hyper-expression in airway epithelium remains unclear. Here, we demonstrated the pivotal roles of autophagy in regulation of MUC5AC hyper-production induced by TGF-β3 in airway epithelium. Our experimental data showed that inhibiting autophagy pathway in repeated ovalbumin (OVA) exposed mice exhibited decreased airway hyper-response and airway inflammation, diminishing the expression of Muc5ac and TGF-β3. Furthermore, our studies demonstrated that autophagy was induced upon exposure to TGF-β3 and then mediated MUC5AC hyper-expression by activating the activator protein-1 (AP-1) in human bronchial epithelial cells. Finally, Smad2/3 pathway was involved in TGF-β3-induced MUC5AC hyper-expressions by promoting autophagy. These data indicated that autophagy was required for TGF-β3 induced airway mucous hyper-production, and that inhibition of autophagy exerted therapeutic benefits for TGF-β3 induced airway mucus secretion.

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Normalisation of airflow limitation in asthma: Post‐hoc analyses of TRIMARAN and TRIGGER

Papi

Singh

Virchow³

et al. 2022

Clinical & Translational All

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Background In asthma, persistent airflow limitation (PAL) is associated with poorer control, lung function decline and exacerbations. Using post‐hoc analyses we evaluated: the relationship between post‐salbutamol PAL at screening, airflow limitation (AL) during 52 weeks treatment with extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) versus BDP/FF and the risk of moderate/severe asthma exacerbations. Methods TRIMARAN and TRIGGER were double‐blind studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium‐dose ICS; TRIGGER high‐dose) in adults with uncontrolled asthma. Patients were subgrouped according to post‐salbutamol PAL status at screening, and AL over the 52‐week treatment period. Results Most patients with post‐salbutamol PAL at screening had AL at all on‐treatment visits (TRIMARAN 62.8%; TRIGGER 66.8%). A significantly higher proportion of patients had normalised airflow on ≥1 follow‐up visit when receiving BDP/FF/G than BDP/FF (TRIMARAN 44.1 vs. 33.1% [p = 0.003]; TRIGGER 40.1 vs. 26.0% [p < 0.001]). In patients with post‐salbutamol PAL at screening and normalised AL at ≥1 follow‐up visit, exacerbation rates were 15% (p = 0.105) and 19% (p = 0.039) lower in TRIMARAN and TRIGGER versus those with AL on all visits. There was a trend to lower exacerbation rates in patients receiving BDP/FF/G than BDP/FF, particularly in patients in whom AL was normalised. Conclusion In these analyses, AL in asthma was associated with an increased exacerbation incidence. Inhaled triple therapy with extrafine BDP/FF/G was more likely to normalise airflow, and was associated with a trend to a lower exacerbation rate than BDP/FF, particularly in the subgroup of patients in whom treatment was associated with airflow normalisation. ClinicalTrials.gov: TRIMARAN, NCT02676076; TRIGGER, NCT02676089.

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Airway pathology in severe asthma is related to airflow obstruction but not symptom control

Abstract: Symptom control in severe asthmatics was not associated with airway tissue inflammation and remodeling, although persistent airflow obstruction in these patients was associated with bronchial inflammation and airway structural changes.

Cited by 37 publications

References 40 publications

Distinct profile of inflammatory and remodelling biomarkers in sputum of severe asthmatic patients with or without persistent airway obstruction

Distinct profile of inflammatory and remodelling biomarkers in sputum of severe asthmatic patients with or without persistent airway obstruction

TGF-β3 Promotes MUC5AC Hyper-Expression by Modulating Autophagy Pathway in Airway Epithelium

Normalisation of airflow limitation in asthma: Post‐hoc analyses of TRIMARAN and TRIGGER

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