House Dust Mites Induce Proliferation of Severe Asthmatic Smooth Muscle Cells via an Epithelium-Dependent Pathway

Trian, Thomas; Allard, Benoît; Dupin, Isabelle; Carvalho, Gabrielle; Ousova, Olga; Maurat, Élise; Bataille, J.; Thumerel, Matthieu; Bégueret, Hugues; Girodet, Pierre‐Olivier; Marthan, Roger; Berger, Patrick

doi:10.1164/rccm.201409-1582oc

Cited by 56 publications

(59 citation statements)

References 42 publications

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“…One study has suggested leukotriene receptor antagonists possess growth inhibitory effects in animal models (23), yet no human studies have provided evidence for an antiremodeling effect of leukotriene receptor antagonists (21,28). Interestingly, a recent in vitro study by Trian et al, using a human bronchial epithelial and smooth muscle cell (obtained from severe persistent asthmatic subjects) coculture model, demonstrated that epithelium-generated paracrine factors, including leukotrienes, regulate ASM proliferation that could be inhibited by pretreating cells with the leukotriene receptor antagonist montelukast (53). Additional in vivo studies are needed to further ascertain the effect of leukotriene receptor antagonists on airway remodeling in asthmatic subjects.…”

Section: Discussionmentioning

confidence: 99%

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Sharma

Panebra

Pera

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediateconductance calcium-activated K ϩ channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as bronchoconstriction in obstructive airway disease. asthma; airway remodeling; G protein-coupled receptor; type 2 taste receptors G PROTEIN-COUPLED RECEPTOR (GPCR) signaling plays a vital role in the regulation of airway smooth muscle (ASM) contraction, relaxation, and proliferation (4, 12). Exaggerated presentation of procontractile GPCR agonists in the airways during allergic inflammation contributes to bronchoconstriction in obstructive airway disease such as asthma. Another salient feature of inflammatory airway diseases is airway remodeling that is characterized by excessive proliferation and accumulation of resident cells, including ASM cells. Animal models demonstrate ASM mass is increased by allergic airway inflammation, while human studies demonstrate a progressive increase in ASM mass in asthmatic subjects that increases both dynamic and fixed airway resistance, limiting the effectiveness of current rescue bronchodilators (11,21,22,26). Current antiasthma therapies, including ␤-agonists and corticosteroids, aim at alleviating bronchoconstriction and infl...

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Section: Discussionmentioning

confidence: 99%

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Sharma

Panebra

Pera

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…BSMCs were further isolated from bronchial specimens as described previously 15. Patient characteristics are presented in online supplementary table S1.…”

Section: Methodsmentioning

confidence: 99%

Microfibrillar-associated protein 4 modulates airway smooth muscle cell phenotype in experimental asthma

Pilecki

Schlosser

Wulf-Johansson

et al. 2015

Thorax

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“…The use of single allergen immunotherapy is often the concern regarding oral immunotherapy; however, the targeting of treatment with dust mite allergen makes sense given that this is known to be the most frequent indoor allergen associated with asthma worldwide. In fact, recent laboratory data demonstrated that house dust mite exposure selectively increased the proliferation of bronchial smooth muscle in patients with severe asthma [40]. It is expected that future research will continue to develop oral immunotherapy with a particular focus on dust mites.…”

Section: New Treatments To Disrupt the Allergen–asthma Associationmentioning

confidence: 99%

Indoor allergen exposure and asthma outcomes

Sheehan

Phipatanakul

2016

Current Opinion in Pediatrics

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Purpose of review The aim of the present review is to discuss updates on research regarding the relationship between indoor allergen exposure and childhood asthma with a focus on clinical effects, locations of exposure, and novel treatments. Recent findings Recent data continue to demonstrate that early life sensitization to indoor allergens is a predictor of asthma development later in life. Furthermore, avoidance of exposure to these allergens continues to be important especially given that the vast majority of children with asthma are sensitized to at least one indoor allergen. New research suggests that mouse allergen, more so than cockroach allergen, may be the most relevant urban allergen. Recent evidence reminds us that children are exposed to clinically important levels of indoor allergens in locations away from their home, such as schools and daycare centers. Exposure to increased levels of indoor mold in childhood has been associated with asthma development and exacerbation of current asthma; however, emerging evidence suggests that early exposure to higher fungal diversity may actually be protective for asthma development. Novel treatments have been developed that target TH2 pathways thus decreasing asthmatic responses to allergens. These therapies show promise for the treatment of severe allergic asthma refractory to avoidance strategies and standard therapies. Summary Understanding the relationship between indoor allergens and asthma outcomes is a constantly evolving study of timing, location, and amount of exposure.

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House Dust Mites Induce Proliferation of Severe Asthmatic Smooth Muscle Cells via an Epithelium-Dependent Pathway

Abstract: This work demonstrates the selective role of HDM on BSM remodeling in patients with severe asthma and points out different therapeutic targets at epithelial and smooth muscle levels.

Cited by 56 publications

References 42 publications

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Microfibrillar-associated protein 4 modulates airway smooth muscle cell phenotype in experimental asthma

Indoor allergen exposure and asthma outcomes

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