Interleukin-13 inhibits proliferation and enhances contractility of human airway smooth muscle cells without change in contractile phenotype

Risse, Paul-André; Jo, Taisuke; Suárez, Fernando; Hirota, Nobuaki; Tolloczko, Barbara; Ferraro, Pasquale; Grütter, Peter; Martin, James G.

doi:10.1152/ajplung.00247.2010

Cited by 69 publications

(39 citation statements)

References 40 publications

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“…Thus, ROCK inhibitors abrogate contractile responses in tracheal rings stimulated with acetylcholine (57). IL-13 receptors are expressed on airway smooth muscle (58) and IL-13 has been shown to promote AHR via direct effects on airway smooth muscle (59, 60), effects that require ROCK (61). Thus, even though IL-13 itself was unaffected by ROCK insufficiency (Fig.4A), it is possible that ROCKs are part of the signaling cascade initiated by IL-13 acting on its receptors on smooth muscle that promotes OVA-induced AHR.…”

Section: Discussionmentioning

confidence: 99%

Abrogation of airway hyperresponsiveness but not inflammation by rho kinase insufficiency

Kasahara¹,

Ninin²,

Wurmbrand³

et al. 2015

Clin Experimental Allergy

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Background Major features of allergic asthma include airway hyperresponsiveness (AHR), eosinophilic inflammation, and goblet cell metaplasia. Rho kinase (ROCK) is a serine/threonine protein kinase that regulates the actin cytoskeleton. By doing so, it can modulate airway smooth muscle cell contraction and leukocyte migration and proliferation. This study was designed to determine the contributions of the two ROCK isoforms, ROCK1 and ROCK2, to AHR, inflammation and goblet cell metaplasia in a mast-cell dependent model of allergic airways disease. Methods and Results Repeated intranasal challenges with OVA caused AHR, eosinophilic inflammation, and goblet cell hyperplasia in wildtype (WT) mice. OVA-induced AHR was partially or completely abrogated in mice haploinsufficient for ROCK2 (ROCK2+/−) or ROCK1 (ROCK1+/−), respectively. In contrast, there was no effect of ROCK insufficiency on allergic airways inflammation, although both ROCK1 and ROCK2 insufficiency attenuated mast cell degranulation. Goblet cell hyperplasia, as indicated by PAS staining, was not different in ROCK1+/− versus WT mice. However, in ROCK2+/− mice, goblet cell hyperplasia was reduced in medium but not large airways. Maximal acetylcholine-induced force generation was reduced in tracheal rings from ROCK1+/− and ROCK2+/− versus WT mice. The ROCK inhibitor, fasudil, also reduced airway responsiveness in OVA-challenged mice, without affecting inflammatory responses. Conclusion In a mast cell model of allergic airways disease, ROCK1 and ROCK2 both contribute to AHR, likely through direct effects on smooth muscle cell and effects on mast-cell degranulation. In addition, ROCK2 but not ROCK1 plays a role in allergen-induced goblet cell hyperplasia.

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Section: Discussionmentioning

confidence: 99%

Abrogation of airway hyperresponsiveness but not inflammation by rho kinase insufficiency

Kasahara¹,

Ninin²,

Wurmbrand³

et al. 2015

Clin Experimental Allergy

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“…Propidium iodide staining after treating cells with growth factor with or without TAS2R agonists for 24 h was performed as previously described (45). Briefly, human ASM cells were grown in F-12 complete medium supplemented with 10% FBS and antibiotics.…”

Section: Methodsmentioning

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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“…5), including TNF-␣, IL-4, IL-5, IL-13 (but see Ref, 254), TGF-␤, thymic stromal lymphopoietin (TSLP), and those of the Th17 family (11,39,152,190,232,245,246). However, there is also some suggestion that "normal" stimuli such as bronchoconstrictor agonists (114,233,341) and other locally produced factors (5,53,75) could trigger increased proliferation under certain conditions, leading to the asthmatic phenotype.…”

Section: Asm In Airway Remodelingmentioning

confidence: 99%

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Prakash

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

179

154

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Prakash YS. Airway smooth muscle in airway reactivity and remodeling: what have we learned? Am J Physiol Lung Cell Mol Physiol 305: L912-L933, 2013. First published October 18, 2013 doi:10.1152/ajplung.00259.2013.-It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca 2ϩ ]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro-vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis.

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Interleukin-13 inhibits proliferation and enhances contractility of human airway smooth muscle cells without change in contractile phenotype

Cited by 69 publications

References 40 publications

Abrogation of airway hyperresponsiveness but not inflammation by rho kinase insufficiency

Abrogation of airway hyperresponsiveness but not inflammation by rho kinase insufficiency

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

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

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