Ca2+ handling and sensitivity in airway smooth muscle: Emerging concepts for mechanistic understanding and therapeutic targeting

Koopmans, Tim; Anaparti, Vidyanand; Castro‐Piedras, Isabel; Yarova, Polina; Irechukwu, N; Nelson, Carl P.; Perez‐Zoghbi, Jose F.; Tan, Xiahui; Ward, Jeremy P. T.; Wright, Donna

doi:10.1016/j.pupt.2014.05.001

Cited by 32 publications

(26 citation statements)

References 197 publications

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“…Owing to its ability to act as a multimodal chemosensor, the potential relevance of CaSR to asthma pathophysiology is manifold, yet there is currently no evidence regarding CaSR expression or function in asthma. In this regard, a fundamental aspect of asthma pathophysiology is elevated intracellular calcium ion concentration ([Ca 2+ ] i ) in airway smooth muscle (ASM) cells that is not only critical to the enhanced bronchoconstriction of nonspecific AHR but also implicated in longer-term, likely genomic effects that result in airway remodeling such as increased ASM cell proliferation (leading to airway wall thickening) and deposition of extracellular matrix components (20, 21). There is currently no information as to whether the CaSR can regulate [Ca 2+ ] i in the asthmatic airways, even though a polycation sensor such as the CaSR, whose activation leads to an increase in [Ca 2+ ] i , seems a likely candidate.…”

Section: Introductionmentioning

confidence: 99%

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

et al. 2015

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Airway hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma that are accompanied by increases in certain polycations, such as eosinophil cationic protein. Levels of these cations in body fluids correlate with asthma severity. We show that polycations and elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cyclic adenosine monophosphate breakdown, and p38 mitogen-activated protein kinase phosphorylation in airway smooth muscle (ASM) cells. These effects can be prevented by CaSR antagonists, termed calcilytics. Moreover, asthmatic patients and allergen-sensitized mice expressed more CaSR in ASMs than did their healthy counterparts. Indeed, polycations induced hyper-reactivity in mouse bronchi, and this effect was prevented by calcilytics and absent in mice with CaSR ablation from ASM. Calcilytics also reduced airway hyperresponsiveness and inflammation in allergen-sensitized mice in vivo. These data show that a functional CaSR is up-regulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Thus, calcilytics may represent effective asthma therapeutics.

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Section: Introductionmentioning

confidence: 99%

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

et al. 2015

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“…Intracellular calcium responses to histamine were examined, given the relevance of calcium regulation to airway contractility (37) and the role of altered ASMC calcium homeostasis in airway hyperreactivity of asthma (8,15,21,28,31) As assessed by the F340/F380 ratio, ASMCs cultured on the gel with E gel of 27 kPa produced greater calcium responses than those adhered to the gel with E gel of 93 kPa (Fig. 3 with E gel of 15 kPa detached following exposure to histamine.…”

Section: Resultsmentioning

confidence: 99%

Matrix stiffness-modulated proliferation and secretory function of the airway smooth muscle cells

Shkumatov

Thompson

Choi

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Multiple pulmonary conditions are characterized by an abnormal misbalance between various tissue components, for example, an increase in the fibrous connective tissue and loss/increase in extracellular matrix proteins (ECM). Such tissue remodeling may adversely impact physiological function of airway smooth muscle cells (ASMCs) responsible for contraction of airways and release of a variety of bioactive molecules. However, few efforts have been made to understand the potentially significant impact of tissue remodeling on ASMCs. Therefore, this study reports how ASMCs respond to a change in mechanical stiffness of a matrix, to which ASMCs adhere because mechanical stiffness of the remodeled airways is often different from the physiological stiffness. Accordingly, using atomic force microscopy (AFM) measurements, we found that the elastic modulus of the mouse bronchus has an arithmetic mean of 23.1 ± 14 kPa (SD) (median 18.6 kPa). By culturing ASMCs on collagen-conjugated polyacrylamide hydrogels with controlled elastic moduli, we found that gels designed to be softer than average airway tissue significantly increased cellular secretion of vascular endothelial growth factor (VEGF). Conversely, gels stiffer than average airways stimulated cell proliferation, while reducing VEGF secretion and agonist-induced calcium responses of ASMCs. These dependencies of cellular activities on elastic modulus of the gel were correlated with changes in the expression of integrin-β1 and integrin-linked kinase (ILK). Overall, the results of this study demonstrate that changes in matrix mechanics alter cell proliferation, calcium signaling, and proangiogenic functions in ASMCs.

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“…Elevation of [Ca 2+ ] i in ASM cells can result from increased Ca 2+ influx from the extracellular fluid and Ca 2+ release from intracellular Ca 2+ stores. Ca 2+ influx in ASM cells can occur through voltage‐gated and receptor‐gated channels on the plasma membrane, as well as by store‐operated Ca 2+ channels that are activated by the depletion of Ca 2+ stores . L‐VDCC acts as a voltage‐gated Ca 2+ channel mediating Ca 2+ influx in response to membrane depolarization to thereby increase [Ca 2+ ] i .…”

Section: Discussionmentioning

confidence: 99%

Inflammatory cytokines tumour necrosis factor‐α and interleukin‐8 enhance airway smooth muscle contraction by increasing L‐type Ca²⁺ channel expression

Ding

Zhang

et al. 2018

Clin Exp Pharma Physio

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Inflammation elevates intracellular calcium concentrations ([Ca ] ) in airway smooth muscle (ASM). The L-type Ca channel (L-VDCC) plays an important role in regulating Ca influx in ASM. However, the role of L-VDCC in the inflammatory cytokine-induced pathology of ASM remains unclear. In the present study, we used calcium imaging and isometric tension measurements to assess the role of L-VDCC in agonist-induced [Ca ] rise and the associated contractions in mouse ASM, and we used immunoblotting to identify L-VDCC protein expression levels in mouse ASM after exposure to tumour necrosis factor alpha (TNF-α) or interleukin-8 (IL-8). Our results showed that high-K - or carbachol-induced contractions of mouse ASM were significantly greater after pretreatment with TNF-α or IL-8 for 24 hours. Both verapamil and nifedipine, L-VDCC inhibitors, abolished this increased contraction induced by TNF-α or IL-8 pretreatment. Moreover, TNF-α treatment enhanced carbachol-induced Ca influx in ASM cells, and this effect was abrogated by verapamil. Additionally, immunoblotting results showed that preincubation of mouse ASM with TNF-α or IL-8 also enhanced L-VDCC protein expression. On the basis of these findings, we concluded that proinflammatory cytokines, such as TNF-α and IL-8, increase the expression level of L-VDCC, which in turn contributes to augmented agonist-induced ASM contractions. This effect of inflammation on L-VDCC expression in ASM may be associated with airway hyper-responsiveness and involved in the development of asthma.

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Ca2+ handling and sensitivity in airway smooth muscle: Emerging concepts for mechanistic understanding and therapeutic targeting

Cited by 32 publications

References 197 publications

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

Matrix stiffness-modulated proliferation and secretory function of the airway smooth muscle cells

Inflammatory cytokines tumour necrosis factor‐α and interleukin‐8 enhance airway smooth muscle contraction by increasing L‐type Ca²⁺ channel expression

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Ca2+ handling and sensitivity in airway smooth muscle: Emerging concepts for mechanistic understanding and therapeutic targeting

Cited by 32 publications

References 197 publications

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

Matrix stiffness-modulated proliferation and secretory function of the airway smooth muscle cells

Inflammatory cytokines tumour necrosis factor‐α and interleukin‐8 enhance airway smooth muscle contraction by increasing L‐type Ca2+ channel expression

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Inflammatory cytokines tumour necrosis factor‐α and interleukin‐8 enhance airway smooth muscle contraction by increasing L‐type Ca²⁺ channel expression