Increased airway smooth muscle in preschool wheezers who have asthma at school age

O'Reilly, Ruth; Ullmann, Nicola; Irving, Samantha; Bossley, Cara; Sonnappa, Samatha; Zhu, Jie; Oates, Thomas; Banya, Winston; Jeffery, Peter K.; Bush, Andrew; Saglani, Sejal

doi:10.1016/j.jaci.2012.08.044

Cited by 136 publications

(149 citation statements)

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“…Most studies of preschool wheeze have been based on birth cohorts. A small number of studies have focused on severe preschool wheeze [9,30] and they have provided valuable insights into the underlying pathophysiology and natural history of preschool wheeze. In common with the TENOR (The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens) [27] and SARP (Severe Asthma Research Program) [26,28] severe asthma cohorts, U-BIOPRED children with severe asthma were commonly atopic, had high healthcare utilisation and a high treatment burden.…”

Section: Discussionmentioning

confidence: 99%

“…Some but not all preschool children with severe wheeze have evidence of airway remodelling and inflammation from an early age [8], consistent with established asthma, but little is known about the underlying mechanisms, which in many cases appear to be very different from school-age and adult asthma. These early changes do not always predict a progression to asthma [9]. These observations are indicative of considerable heterogeneity amongst children with severe school-aged asthma or severe preschool wheeze.…”

Section: Introductionmentioning

confidence: 91%

See 1 more Smart Citation

The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts

Fleming

Murray

Bansal³

et al. 2015

Eur Respir J

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts

Fleming

Murray

Bansal³

et al. 2015

Eur Respir J

Self Cite

197

145

View full text Add to dashboard Cite

show abstract

“…Pre-school children with severe wheezing that developed asthma only had significantly more ASM in their endobronchial biopsies at pre-school age compared with those wheezers that did not develop asthma, while tissue eosinophilia or RBM thickness were not predictors [36]. In addition, increased ASM was the only change associated with atopy in severe pre-school wheezers [31].…”

Section: Airway Smooth Musclementioning

confidence: 86%

“…However, experimental models using eosinophil knockout mice demonstrate similar allergic airways disease to wild-type mice [34]. Moreover, biopsy studies of infants with severe wheeze [35][36][37] have shown that eosinophils are not necessary for the development of asthma. In addition, targeting eosinophils does not seem to modify disease progression, as development of asthma from pre-school wheeze is not prevented by steroids [38,39], nor is there a maintained disease-modifying effect after anti-IL-5 antibody therapy is stopped [40].…”

Section: Are Eosinophilic Inflammation and Remodelling Linked?mentioning

confidence: 99%

Novel concepts in airway inflammation and remodelling in asthma

2015

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The hallmark pathological features of asthma include airway eosinophilic inflammation and structural changes (remodelling) which are associated with an irreversible loss in lung function that tracks from childhood to adulthood. In parallel with changes in function, pathological abnormalities occur early, during the pre-school years, are established by school age and subsequently remain (even though symptoms may remit for periods during adulthood). Given the equal importance of inflammation and remodelling in asthma pathogenesis, there is a significant disparity in studies undertaken to investigate the contribution of each. The majority focus on the role of inflammation, and although novel therapeutics such as those targeted against T-helper cell type 2 (Th2) mediators have arisen, it is apparent that targeting inflammation alone has not allowed disease modification. Therefore, unless airway remodelling is addressed for future therapeutic strategies, it is unlikely that we will progress towards a cure for asthma. Having acknowledged these limitations, the focus of this review is to highlight the gaps in our current knowledge about the mechanisms underlying airway remodelling, the relationships between remodelling, inflammation and function, remodelling and clinical phenotypes, and the importance of utilising innovative and realistic pre-clinical models to uncover effective, disease-modifying therapeutic strategies. @ERSpublications We discuss mechanisms of airway inflammation and remodelling in asthma to uncover effective therapeutic strategies http://ow.ly/SsXiO

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“…It is therefore noteworthy that, while it was traditionally believed that airway remodeling occurred after years of chronic inflammation, a number of bronchial biopsy studies have now established that several major components of airway remodeling, including increased smooth muscle mass and thickening of the lamina reticularis, are already present in pre-school children, often before the clinical diagnosis of asthma has been made (6)(7)(8). Interestingly, signs of airway remodeling are not detected in infants with wheezing illnesses (9), implying that exposure to some inciting stimuli in early childhood induces remodeling.…”

Section: Introductionmentioning

confidence: 99%

Human Rhinovirus Infection of Epithelial Cells Modulates Airway Smooth Muscle Migration

Shariff

Shelfoon

Holden

et al. 2017

Am J Respir Cell Mol Biol

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Rationale: Airway remodeling, a characteristic feature of asthma, begins in early life. Recurrent human rhinovirus (HRV) infections are a potential inciting stimulus for remodeling. One component of airway remodeling is an increase in airway smooth muscle cell mass with a greater proximity of the airway smooth muscle cells (ASMC) to the airway epithelium. We asked whether human bronchial epithelial cells infected with HRV produced mediators that are chemotactic for ASMC.Methods: ASMC migration was investigated using the modified Boyden Chamber and the xCELLigence Real-Time Cell Analyzer. Multiplex bead analysis was used to measure HRVinduced epithelial chemokine release. The chemotactic effects of CCL5, CXCL8 and CXCL10 were also examined.Results: Supernatants from HRV-infected epithelial cells caused ASMC chemotaxis. Pretreatment of ASMC with pertussis toxin abrogated chemotaxis, as did treatment with formoterol, forskolin, or 8-bromo-cAMP. CCL5, CXCL8, and CXCL10 were most up-regulated chemokines produced by HRV-infected airway epithelial cells. When recombinant CCL5, CXCL8 and CXCL10 were used at levels found in epithelial supernatants they induced ASMC chemotaxis similar to that seen with epithelial cell supernatants. When examined individually, CCL5 was the most effective chemokine in causing ASMC migration and treatment of supernatant from HRVinfected epithelial cells with anti-CCL5 antibodies significantly attenuated ASMC migration. Conclusion:These findings suggest that HRV-induced CCL5 can induce ASMC chemotaxis, and thus may contribute to the pathogenesis of airway remodeling in asthmatic patients.3

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Increased airway smooth muscle in preschool wheezers who have asthma at school age

Cited by 136 publications

References 50 publications

The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts

The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts

Novel concepts in airway inflammation and remodelling in asthma

Human Rhinovirus Infection of Epithelial Cells Modulates Airway Smooth Muscle Migration

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