An inflammation-independent contraction mechanophenotype of airway smooth muscle in asthma

An, Steven S.; Mitzner, Wayne; Tang, Wan Yee; Ahn, Kwangmi; Yoon, A-Rum; Huang, Jessie; Kilic, Onur; Yong, Hwan Mee; Fahey, Jed W.; Kumar, Sarvesh; Biswal, Shyam; Holgate, Stephen T.; Panettieri, Reynold A.; Solway, Julian; Liggett, Stephen B.

doi:10.1016/j.jaci.2015.12.1315

Cited by 60 publications

(57 citation statements)

References 11 publications

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“…In this method, we applied forced motions of a functionalized bead tethered to the underlying cytoskeleton through the cell surface integrin receptors. Dynamic changes in the stiffness measured with this single-cell technology are robust indices for contraction and relaxation of isolated ASM cells49. Unlike bitter tastants of diverse structures that caused rapid and substantial decreases in the stiffness of isolated human ASM cells9, none of the SCFAs in the range typically detected in the digestive tract, serum and/or the lung (0.1–10 mM38404142) or in the range of detection of cAMP signaling of OR51E2 (EC 50 = ~2 mM), caused acute changes in the cell stiffness (data not shown), nor did they alter histamine-induced single-cell contraction (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Both mouse and human ASM cells were maintained in serum-free media for 24 h at 37 °C in humidified air containing 5% CO 2 prior to study. These conditions have been optimized for seeding cultured cells on collagen matrix and for assessing their mechanical properties4955.…”

Section: Methodsmentioning

confidence: 99%

“…We then applied forced motions of the functionalized beads using MTC495556 and measured the stiffness of individual ASM cells. In brief, RGD-coated ferrimagnetic beads bound on the surface of the cell were magnetized horizontally with a brief 1,000-Gauss pulse and twisted in a vertically aligned homogeneous magnetic field (20 Gauss) that was varying sinusoidally in time.…”

Section: Methodsmentioning

confidence: 99%

“…The major cause of morbidity and mortality of the disease is airflow obstruction, which is in part due to actively constricted smooth muscle of human bronchi, as well as increased smooth muscle mass234. Therapies for airflow obstruction from airway smooth muscle (ASM) contraction include the use of antagonists to receptors for specific spasmogens that are released locally due to inflammation or other triggers, or β-agonists, which are direct bronchodilators acting on ASM β 2 -adrenergic receptors (β 2 ARs)56.…”

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confidence: 99%

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Defining an olfactory receptor function in airway smooth muscle cells

Aisenberg

Huang

Zhu

et al. 2016

Sci Rep

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Pathways that control, or can be exploited to alter, the increase in airway smooth muscle (ASM) mass and cellular remodeling that occur in asthma are not well defined. Here we report the expression of odorant receptors (ORs) belonging to the superfamily of G-protein coupled receptors (GPCRs), as well as the canonical olfaction machinery (Golf and AC3) in the smooth muscle of human bronchi. In primary cultures of isolated human ASM, we identified mRNA expression for multiple ORs. Strikingly, OR51E2 was the most highly enriched OR transcript mapped to the human olfactome in lung-resident cells. In a heterologous expression system, OR51E2 trafficked readily to the cell surface and showed ligand selectivity and sensitivity to the short chain fatty acids (SCFAs) acetate and propionate. These endogenous metabolic byproducts of the gut microbiota slowed the rate of cytoskeletal remodeling, as well as the proliferation of human ASM cells. These cellular responses in vitro were found in ASM from non-asthmatics and asthmatics, and were absent in OR51E2-deleted primary human ASM. These results demonstrate a novel chemo-mechanical signaling network in the ASM and serve as a proof-of-concept that a specific receptor of the gut-lung axis can be targeted to treat airflow obstruction in asthma.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Defining an olfactory receptor function in airway smooth muscle cells

Aisenberg

Huang

Zhu

et al. 2016

Sci Rep

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“…Another area of uncertainty is the link between OSA and bronchial reactivity . Asthma is characterized by reversible airflow obstruction due to inflammatory changes and smooth muscle contraction in bronchi . Excessive reactivity of bronchi (bronchial hyper‐responsiveness or bronchial hyper‐reactivity (BHR)) can be elicited by a challenge test using inhaled methacholine (MCh) and is associated with asthma .…”

Section: Introductionmentioning

confidence: 99%

Nocturnal symptoms perceived as asthma are associated with obstructive sleep apnoea risk, but not bronchial hyper‐reactivity

et al. 2019

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Background and objective Obstructive sleep apnoea (OSA) and asthma are associated, and nocturnal breathing difficulty that is usually identified as asthma‐like symptoms can be present in both conditions. We investigated how nocturnal asthma‐like symptoms (NAS) and bronchial hyper‐reactivity (BHR) contribute to the association between OSA risk and current asthma, which is currently unknown but a clinically important question. Methods We used data from 794 middle‐aged participants in a population‐based cohort who provided information on OSA risk (defined by a STOP‐Bang questionnaire score of at least 3), current asthma and NAS, and underwent methacholine bronchial challenge testing. Using regression models, we examined the association between OSA risk and current asthma‐NAS subgroups and investigated any effect modification by BHR. Results The participants were aged 50 years (49.8% male). OSA risk was associated with NAS with or without current asthma (odds ratio (OR): 2.6; 95% CI = 1.3–5.0; OR: 4.2; 95% CI = 1.1–16.1, respectively), but not with current asthma in the absence of NAS. BHR was associated with current asthma with or without NAS (OR: 2.9; 95% CI = 1.4–5.9; OR: 3.4; 95% CI = 2.0–7.0, respectively) but not with NAS in the absence of current asthma. The associations between OSA risk and current asthma were neither modified nor mediated by BHR. Conclusion Our findings suggest that some of the nocturnal symptoms perceived as asthma may be OSA symptoms. Patients with nocturnal asthma symptoms should be considered for possible OSA.

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Stiffness Mediated‐Mechanosensation of Airway Smooth Muscle Cells on Linear Stiffness Gradient Hydrogels

Tan,

Wang,

Chin

et al. 2024

Adv Healthcare Materials

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In obstructive airway diseases such as asthma and chronic obstructive pulmonary disease, the extracellular matrix (ECM) protein amount and composition of the airway smooth muscle (ASM) is often remodelled, likely altering tissue stiffness. The underlying mechanism of how human ASM cell (hASMC) mechanosenses the aberrant microenvironment is not well understood. Physiological stiffnesses of the ASM layer were measured by uniaxial compression tester using porcine ASM layers under 0, 5 and 10% longitudinal stretch above in situ length. Linear stiffness gradient hydrogels (2–30 kPa range) were fabricated and functionalized with ECM proteins, collagen I (ColI), fibronectin (Fn) and laminin (Ln), to recapitulate the above‐measured range of stiffnesses with an Atomic Force Microscope. Overall, hASMC mechanosensation exhibited a clear correlation with the underlying hydrogel stiffness with some specificity to ECM protein type. Cell size, nuclear size and contractile marker alpha‐smooth muscle actin (αSMA) expression showed a strong correlation to substrate stiffness. Mechanosensation, assessed by Lamin‐A intensity and YAP nuclear translocalization, exhibited stiffness‐mediated behaviour only on ColI and Fn‐coated hydrogels. Inhibition studies using blebbistatin or Y27632 attenuated most mechanotransduction‐derived cell morphological responses, αSMA and Lamin‐A expression and YAP nuclear translocalization (blebbistatin only). This study highlights the interplay and complexities between stiffness and ECM protein type on hASMC mechanosensation, relevant to airway remodelling in obstructive airway diseases.This article is protected by copyright. All rights reserved

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An inflammation-independent contraction mechanophenotype of airway smooth muscle in asthma

Cited by 60 publications

References 11 publications

Defining an olfactory receptor function in airway smooth muscle cells

Defining an olfactory receptor function in airway smooth muscle cells

Nocturnal symptoms perceived as asthma are associated with obstructive sleep apnoea risk, but not bronchial hyper‐reactivity

Stiffness Mediated‐Mechanosensation of Airway Smooth Muscle Cells on Linear Stiffness Gradient Hydrogels

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