Calcium Channel Blocker Reduces Airway Remodeling in Severe Asthma. A Proof-of-Concept Study

Girodet, Pierre‐Olivier; Dournes, Gaël; Thumerel, Matthieu; Bégueret, Hugues; Santos, Pierre Dos; Ozier, A.; Dupin, Isabelle; Trian, Thomas; Montaudon, Michel; Laurent, François; Marthan, Roger; Berger, Patrick

doi:10.1164/rccm.201410-1874oc

Cited by 75 publications

(62 citation statements)

References 26 publications

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“…Various lines of evidence in previous studies indicated that overexpression of the ADAM33 gene (mRNA and protein) was seen in various types of cells in asthma patients, including airway smooth muscle cells, fibroblasts, mesenchymal cells and endothelial cells (2)(3)(4)(5)(6). Furthermore, data from previous studies have demonstrated that the expression of the ADAM33 gene may regulate the expression of transforming growth factor-β, which is a major cytokine expressed and excreted by bronchial macrophages, epithelial cells and mesenchymal cells for airway remodeling (31). A potential mechanism by which ADAM33 affects asthma may be associated with the regulation of airway inflammation, hyperresponsiveness and remodeling processes; however, the exact molecular mechanism requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

ADAM33 gene polymorphisms identified to be associated with asthma in a Chinese Li population

et al. 2017

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Abstract. A disintegrin and metalloprotease 33 (ADAM33)is an asthma susceptibility gene that has been proven to be present in certain human populations. The Li population is a minority ethnic group, most of whom maintain a distinctive lifestyle on Hainan Island in southern China. To the best of our knowledge, no previous study has established whether ADAM33 polymorphisms are associated with asthma in the Li population. Therefore, the ADAM33 polymorphisms in a Li population were investigated in the present study. A total of 150 asthma patients and 100 healthy subjects were enrolled in the present study, and their DNA samples were evaluated to analyze eight single-nucleotide polymorphisms (SNPs) on the ADAM33 gene. Asthma patients were subcategorized into low and high severity groups, and their SNP data were compared with the data of the control subjects. Single-marker and haplotype association was analyzed to demonstrate the association between ADAM33 SNPs and asthma using multiple genetic statistic tests. The results indicated significant differences in allele frequencies at the SNPs rs44707/T2 (P=0.008), rs2787094/V4 (P=0.028) and rs2280089/T+1 (P=0.021) between asthma patients and control subjects. The SNP rs44707/T2 was also found to be associated with the high severity group (P=0.024), although SNPs rs2787094/V4 were associated with the low severity group (P=0.019). Two haplotypes, GGAGAGT and GAAGGGT, were significantly associated with asthma (P=0.003 and 0.008, respectively). To the best of our knowledge, this is the first time that SNP rs2280089/T+1 has been reported to be associated with asthma in an Asian population. These data confirm that ADAM33 polymorphisms are associated with asthma susceptibility in the Li population and confirm the uniqueness of the Li minority population within China. IntroductionAsthma is a chronic inflammatory disease of the airway. More than 100 million people across the globe suffer from this disorder (Global strategy for asthma management and prevention; http://www.ginasthma.org). Airway inflammation, bronchial hyperresponsiveness (BHR), and reversible airflow obstruction are the primary characteristics of asthma. Among these, airway inflammation is most closely associated with the clinical symptoms. Currently, genetic and environmental factors have been found to be involved in the generation of asthma pathologies. Thus, the potential contribution of genetic factors is considered to be an interesting area of clinical and basic research.The A disintegrin and metalloprotease 33 (ADAM33) gene is an asthma susceptibility gene, which was first reported by Van Eerdewegh et al (1). The ADAM33 gene is mapped to the short arm of chromosome 20p13 in the human genome, and is predominantly expressed in airway smooth-muscle cells and lung fibroblast cells, but not in epithelial cells, T cells or inflammatory leukocytes (2-6). ADAM proteins are involved in cell-cell and cell-matrix interactions (5), cell migration (2,3), cell-cell adhesion and signal transduction (4). The following are c...

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Section: Discussionmentioning

confidence: 99%

ADAM33 gene polymorphisms identified to be associated with asthma in a Chinese Li population

et al. 2017

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“…Loss or overload of mitochondrial Fe or Ca 2+ can lead to mitochondrial dysfunction (77) and is associated with PH (76,78), NSCLC (77), asthma (78,79), and CF (33).…”

Section: +mentioning

confidence: 99%

Mitochondria in lung disease

Cloonan¹,

Choi²

2016

Journal of Clinical Investigation

232

192

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“…Encouragingly, a recent interventional clinical trial was designed with the aim of assessing the impact of a calcium channel blocker on established airway remodelling. Specifically, the primary outcome measure was change in bronchial smooth muscle area after 12 months of treatment with the calcium channel blocker gallopamil in adults with severe asthma [77]. Treatment resulted in a reduction in bronchial smooth muscle area and in exacerbations after the intervention period.…”

Section: Airway Smooth Musclementioning

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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Calcium Channel Blocker Reduces Airway Remodeling in Severe Asthma. A Proof-of-Concept Study

Abstract: Gallopamil treatment for 12 months reduces BSM remodeling and prevents the occurrence of asthma exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT 00896428).

Cited by 75 publications

References 26 publications

ADAM33 gene polymorphisms identified to be associated with asthma in a Chinese Li population

ADAM33 gene polymorphisms identified to be associated with asthma in a Chinese Li population

Mitochondria in lung disease

Novel concepts in airway inflammation and remodelling in asthma

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