scholarly journals The underlying physiological mechanisms whereby anticholinergics alleviate asthma

2018 ◽  
Vol 96 (5) ◽  
pp. 433-441 ◽  
Author(s):  
Morgan Gazzola ◽  
Samuel Mailhot-Larouche ◽  
Clémentine Beucher ◽  
Ynuk Bossé
Keyword(s):  
Smooth Muscle ◽  
Well Being ◽  
Respiratory Resistance ◽  
Healthy Individuals ◽  
Cholinergic Nerves ◽  
Small Reduction ◽  
Physiological Mechanisms ◽  
Airway Narrowing ◽  
Asthma Outcomes ◽  
Contractile Activation

The mechanisms whereby anticholinergics improve asthma outcomes, such as lung function, symptoms, and rate of exacerbation, can be numerous. The most obvious is by affecting the contraction of airway smooth muscle (ASM). The acetylcholine released from the cholinergic nerves is the most important bronchoconstrictor that sets the baseline degree of contractile activation of ASM in healthy individuals. Although the degree of ASM’s contractile activation can also be fine-tuned by a plethora of other bronchoconstrictors and bronchodilators in asthma, blocking the ceaseless effect of acetylcholine on ASM by anticholinergics reduces, at any given moment, the overall degree of contractile activation. Because the relationships that exist between the degree of contractile activation, ASM force, ASM shortening, airway narrowing, airflow resistance, and respiratory resistance are not linear, small decreases in the contractile activation of ASM can be greatly amplified and thus translate into important benefits to a patient’s well-being. Plus, many inflammatory and remodeling features that are often found in asthmatic lungs synergize with the contractile activation of ASM to increase respiratory resistance. This review recalls that the proven effectiveness of anticholinergics in the treatment of asthma could be merely attributed to a small reduction in the contractile activation of ASM.

scholarly journals Abl activation regulates the dissociation of CAS from cytoskeletal vimentin by modulating CAS phosphorylation in smooth muscle

2010 ◽  
Vol 299 (3) ◽  
pp. C630-C637 ◽  
Author(s):  
Li Jia ◽  
Dale D. Tang
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Actin Polymerization ◽  
Spatial Location ◽  
Smooth Muscle Contraction ◽  
Nonreceptor Tyrosine Kinase ◽  
Force Development ◽  
Muscle Inhibition ◽  
A Cell ◽  
Contractile Activation

Abl is a nonreceptor tyrosine kinase that is required for smooth muscle contraction. However, the mechanism by which Abl regulates smooth muscle contraction is not completely understood. In the present study, Abl underwent phosphorylation at Tyr412 (an index of Abl activation) in smooth muscle in response to contractile activation. Treatment with a cell-permeable decoy peptide, but not the control peptide, attenuated Abl phosphorylation during contractile stimulation. Treatment with the decoy peptide did not affect the association of Abl with the cytoskeletal protein vinculin and the spatial location of vinculin in smooth muscle. Inhibition of Abl phosphorylation by the decoy peptide attenuated the agonist-induced phosphorylation of Crk-associated substrate (CAS), an adapter protein participating in the signaling processes that regulate force development in smooth muscle. Additionally, previous studies have shown that contractile stimulation triggers the dissociation of CAS from the vimentin network, which is important for cytoskeletal signaling and contraction in smooth muscle. In this report, the decrease in the amount of CAS in cytoskeletal vimentin in response to contractile activation was reversed by the Abl inhibition with the decoy peptide. Moreover, force development and the enhancement of F-actin-to-G-actin ratios (an indication of actin polymerization) upon contractile activation were also attenuated by the Abl inhibition. However, myosin phosphorylation induced by contractile activation was not affected by the inhibition of Abl. These results suggest that Abl regulates the dissociation of CAS from the vimentin network, actin polymerization, and contraction by modulating CAS phosphorylation in smooth muscle.

Role of Rho in Ca2+-insensitive contraction and paxillin tyrosine phosphorylation in smooth muscle

2000 ◽  
Vol 279 (2) ◽  
pp. C308-C318 ◽  
Author(s):  
Dolly Mehta ◽  
Dale D. Tang ◽  
Ming-Fang Wu ◽  
Simon Atkinson ◽  
Susan J. Gunst
Keyword(s):  
Smooth Muscle ◽  
Tyrosine Phosphorylation ◽  
Actin Polymerization ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Cytochalasin D ◽  
Cytoskeletal Proteins ◽  
Tracheal Smooth Muscle ◽  
Contractile Activation ◽  
Mlc Phosphorylation

We investigated whether Rho activation is required for Ca2+-insensitive paxillin phosphorylation, myosin light chain (MLC) phosphorylation, and contraction in tracheal muscle. Tyrosine-phosphorylated proteins have been implicated in the Ca2+-insensitive contractile activation of smooth muscle tissues. The contractile activation of tracheal smooth muscle increases tyrosine phosphorylation of the cytoskeletal proteins paxillin and focal adhesion kinase. Paxillin is implicated in integrin-mediated signal transduction pathways that regulate cytoskeletal organization and cell motility. In fibroblasts and other nonmuscle cells, paxillin tyrosine phosphorylation depends on the activation of Rho and is inhibited by cytochalasin, an inhibitor of actin polymerization. In permeabilized muscle strips, we found that ACh induced Ca2+-insensitive contraction, MLC phosphorylation, and paxillin tyrosine phosphorylation. Ca2+-insensitive contraction and MLC phosphorylation induced by ACh were inhibited by C3 transferase, an inhibitor of Rho activation; however, C3 transferase did not inhibit paxillin tyrosine phosphorylation. Ca2+-insensitive paxillin tyrosine phosphorylation was also not inhibited by the Rho kinase inhibitor Y-27632, by cytochalasin D, or by the inhibition of MLC phosphorylation. We conclude that, in tracheal smooth muscle, Rho mediates Ca2+-insensitive contraction and MLC phosphorylation but that Rho is not required for Ca2+-insensitive paxillin tyrosine phosphorylation. Paxillin phosphorylation also does not require actomyosin activation, nor is it inhibited by the actin filament capping agent cytochalasin D.

Physical activity and subjective well-being in healthy individuals: a meta-analytic review

2020 ◽  
pp. 1-19 ◽  
Author(s):  
Susanne Buecker ◽  
Thomas Simacek ◽  
Britta Ingwersen ◽  
Sophia Terwiel ◽  
Bianca A. Simonsmeier
Keyword(s):  
Physical Activity ◽  
Well Being ◽  
Subjective Well Being ◽  
Healthy Individuals ◽  
Analytic Review

scholarly journals Decreased airway narrowing and smooth muscle contraction in hyperresponsive pigs

2002 ◽  
Vol 93 (4) ◽  
pp. 1296-1300 ◽  
Author(s):  
Debra J. Turner ◽  
Peter B. Noble ◽  
Matthew P. Lucas ◽  
Howard W. Mitchell
Keyword(s):  
Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Porcine Model ◽  
Smooth Muscle Contraction ◽  
Airway Wall ◽  
Muscle Contractility ◽  
Smooth Muscle Contractility ◽  
Airway Narrowing

Increased smooth muscle contractility or reduced smooth muscle mechanical loads could account for the excessive airway narrowing and hyperresponsiveness seen in asthma. These mechanisms were investigated by using an allergen-induced porcine model of airway hyperresponsiveness. Airway narrowing to electric field stimulation was measured in isolated bronchial segments, over a range of transmural pressures (0–20 cmH2O). Contractile responses to ACh were measured in bronchial segments and in isolated tracheal smooth muscle strips isolated from control and test (ovalbumin sensitized and challenged) pigs. Test airways narrowed less than controls ( P < 0.0001). Test pigs showed reduced contractility to ACh, both in isolated bronchi ( P < 0.01) and smooth muscle strips ( P < 0.01). Thus isolated airways from pigs exhibiting airway hyperresponsiveness in vivo are hyporesponsive in vitro. The decreased narrowing in bronchi from hyperresponsive pigs may be related to decreased smooth muscle contractility. These data suggest that mechanisms external to the airway wall may be important to the hyperresponsive nature of sensitized lungs.

scholarly journals Sex Differences and Commonalities in the Impact of a Palatable Meal on Thalamic and Insular Connectivity

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1627
Author(s):  
Lisa Kilpatrick ◽  
Teodora Pribic ◽  
Barbara Ciccantelli ◽  
Carolina Malagelada ◽  
Dan M. Livovsky ◽  
...  
Keyword(s):  
Sex Differences ◽  
Well Being ◽  
Neural Mechanisms ◽  
Healthy Individuals ◽  
Resonance Imaging ◽  
Subjective Responses ◽  
Biological Variable ◽  
Before And After ◽  
Meal Ingestion ◽  
The Impact

The neural mechanisms underlying subjective responses to meal ingestion remain incompletely understood. We previously showed in healthy men an increase in thalamocortical, and a decrease in insular-cortical connectivity in response to a palatable meal. As sex is increasingly recognized as an important biological variable, we aimed to evaluate sex differences and commonalities in the impact of a well-liked meal on thalamic and anterior insular connectivity in healthy individuals. Participants (20 women and 20 age-matched men) underwent resting-state magnetic resonance imaging (rsMRI) before and after ingesting a palatable meal. In general, the insula showed extensive postprandial reductions in connectivity with sensorimotor and prefrontal cortices, while the thalamus showed increases in connectivity with insular, frontal, and occipital cortices, in both women and men. However, reductions in insular connectivity were more prominent in men, and were related to changes in meal-related sensations (satiety and digestive well-being) in men only. In contrast, increases in thalamic connectivity were more prominent in women, and were related to changes in satiety and digestive well-being in women only. These results suggest that brain imaging may provide objective and sex-specific biomarkers of the subjective feelings associated with meal ingestion.

scholarly journals Dynamic airway constriction in rats: heterogeneity and response to deep inspiration

2019 ◽  
Vol 317 (1) ◽  
pp. L39-L48
Author(s):  
Thien-Khoi N. Phung ◽  
Scott E. Sinclair ◽  
Patrudu Makena ◽  
Robert C. Molthen ◽  
Christopher M. Waters
Keyword(s):  
Computational Models ◽  
Small Airways ◽  
Respiratory Resistance ◽  
Dynamic Changes ◽  
Airway Narrowing ◽  
Airway Constriction ◽  
X Ray Imaging ◽  
Model Predictions ◽  
Dose Dependent Increase ◽  
Dose Dependent

Airway narrowing due to hyperresponsiveness severely limits gas exchange in patients with asthma. Imaging studies in humans and animals have shown that bronchoconstriction causes patchy patterns of ventilation defects throughout the lungs, and several computational models have predicted that these regions are due to constriction of smaller airways. However, these imaging approaches are often limited in their ability to capture dynamic changes in small airways, and the patterns of constriction are heterogeneous. To directly investigate regional variations in airway narrowing and the response to deep inspirations (DIs), we utilized tantalum dust and microfocal X-ray imaging of rat lungs to obtain dynamic images of airways in an intact animal model. Airway resistance was simultaneously measured using the flexiVent system. Custom-developed software was used to track changes in airway diameters up to generation 19 (~0.3–3 mm). Changes in diameter during bronchoconstriction were then measured in response to methacholine (MCh) challenge. In contrast with the model predictions, we observed significantly greater percent constriction in larger airways in response to MCh challenge. Although there was a dose-dependent increase in total respiratory resistance with MCh, the percent change in airway diameters was similar for increasing doses. A single DI following MCh caused a significant reduction in resistance but did not cause a significant increase in airway diameters. Multiple DIs did, however, cause significant increases in airway diameters. These measurements allowed us to directly quantify dynamic changes in airways during bronchoconstriction and demonstrated greater constriction in larger airways.

The first three minutes: smooth muscle contraction, cytoskeletal events, and soft glasses

2003 ◽  
Vol 95 (1) ◽  
pp. 413-425 ◽  
Author(s):  
Susan J. Gunst ◽  
Jeffrey J. Fredberg
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Smooth Muscle Contraction ◽  
Mechanical Function ◽  
Thin Filaments ◽  
Cross Bridge ◽  
Contractile Activation ◽  
Contraction Cycle ◽  
Soft Glasses

Smooth muscle exhibits biophysical characteristics and physiological behaviors that are not readily explained by present paradigms of cytoskeletal and cross-bridge mechanics. There is increasing evidence that contractile activation of the smooth muscle cell involves an array of cytoskeletal processes that extend beyond cross-bridge cycling and the sliding of thick and thin filaments. We review here the evidence suggesting that the biophysical and mechanical properties of the smooth muscle cell reflect the integrated interactions of an array of highly dynamic cytoskeletal processes that both react to and transform the dynamics of cross-bridge interactions over the course of the contraction cycle. The activation of the smooth muscle cell is proposed to trigger dynamic remodeling of the actin filament lattice within cellular microdomains in response to local mechanical and pharmacological events, enabling the cell to adapt to its external environment. As the contraction progresses, the cytoskeletal lattice stabilizes, solidifies, and forms a rigid structure well suited for transmission of tension generated by the interaction of myosin and actin. The integrated molecular transitions that occur within the contractile cycle are interpreted in the context of microscale agitation mechanisms and resulting remodeling events within the intracellular microenvironment. Such an interpretation suggests that the cytoskeleton may behave as a glassy substance whose mechanical function is governed by an effective temperature.

Adaptation to chronic length change in explanted airway smooth muscle

2003 ◽  
Vol 95 (1) ◽  
pp. 448-453 ◽  
Author(s):  
Jahanbakhsh Naghshin ◽  
Lu Wang ◽  
Peter D. Paré ◽  
Chun Y. Seow
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Culture Media ◽  
Length Change ◽  
Functional Change ◽  
Muscle Stiffness ◽  
Airway Narrowing

It has been shown that airway smooth muscle in vitro is able to maintain active force over a large length range by adaptation in the absence of periodic stimulations at 4°C (Wang L, Paré PD, and Seow CY. J Appl Physiol 90: 734–740, 2001). In this study, we show that such adaptation also takes place at body temperature and that long-term adaptation results in irreversible functional change in the muscle that could lead to airway hyperresponsiveness. Rabbit tracheal muscle explants were passively maintained at shortened and in situ length for 3 and 7–8 days in culture media; the length-tension relationship was then examined. The length associated with maximal force generation decreased by 10.5 ± 3.8% (SE) after 3 days and 37.7 ± 8.5% after 7 or 8 days of passive shortening. At day 3, the left shift in the length-tension curve due to adaptation at short lengths was reversible by readapting the muscle at a longer length. The shift was, however, not completely reversible after 7 days. The results suggest that long-term adaptation of airway smooth muscle could lead to increased muscle stiffness and force-generating ability at short lengths. Under in vivo condition, this could translate into resistance to stretch-induced relaxation and excessive airway narrowing.

scholarly journals Comparison of Orthognathic Surgery Outcomes Between Patients With and Without Underlying High-Risk Conditions: A Multidisciplinary Team-Based Approach and Practical Guidelines

2019 ◽  
Vol 8 (11) ◽  
pp. 1760 ◽  
Author(s):  
Chou ◽  
Denadai ◽  
Chen ◽  
Pai ◽  
Hsu ◽  
...  
Keyword(s):  
High Risk ◽  
Blood Loss ◽  
Multidisciplinary Team ◽  
Orthognathic Surgery ◽  
Wide Spectrum ◽  
Well Being ◽  
Intraoperative Blood Loss ◽  
Healthy Individuals ◽  
Patient Reported ◽  
Comorbidity Scores

Orthognathic surgery (OGS) has been successfully adopted for managing a wide spectrum of skeletofacial deformities, but patients with underlying conditions have not been treated using OGS because of the relatively high risk of surgical anesthetic procedure-related complications. This study compared the OGS outcomes of patients with and without underlying high-risk conditions, which were managed using a comprehensive, multidisciplinary team-based OGS approach with condition-specific practical perioperative care guidelines. Data of surgical anesthetic outcomes (intraoperative blood loss, operative duration, need for prolonged intubation, reintubation, admission to an intensive care unit, length of hospital stay, and complications), facial esthetic outcomes (professional panel assessment), and patient-reported outcomes (FACE-Q social function, psychological well-being, and satisfaction with decision scales) of consecutive patients with underlying high-risk conditions (n = 30) treated between 2004 and 2017 were retrospectively collected. Patients without these underlying conditions (n = 30) treated during the same period were randomly selected for comparison. FACE-Q reports of 50 ethnicity-, sex-, and age-matched healthy individuals were obtained. The OGS-treated patients with and without underlying high-risk conditions differed significantly in their American Society of Anesthesiologists Physical Status (ASA-PS) classification (p < 0.05), Charlson comorbidity scores, and Elixhauser comorbidity scores. The two groups presented similar outcomes (all p > 0.05) for all assessed outcome parameters, except for intraoperative blood loss (p < 0.001; 974.3 ± 592.7 mL vs. 657.6 ± 355.0 mL). Comparisons with healthy individuals revealed no significant differences (p > 0.05). The patients with underlying high-risk conditions treated using a multidisciplinary team-based OGS approach and the patients without the conditions had similar OGS-related outcomes.

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