Smooth muscle molecular mechanics in airway hyperresponsiveness and asthmaThis paper is one of a selection of papers published in this Special Issue, entitled the Young Investigators' Forum.

2007 ◽  
Vol 85 (1) ◽  
pp. 133-140 ◽  
Author(s):  
Fulvio R. Gil ◽  
Anne-Marie Lauzon
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Airway Remodeling ◽  
Force Production ◽  
Muscle Length ◽  
Protective Role ◽  
Respiratory Disorder ◽  
Airway Narrowing ◽  
Muscle Plasticity

Asthma is a respiratory disorder characterized by airway inflammation and hyperresponsiveness associated with reversible airway obstruction. The relative contributions of airway hyperresponsiveness and inflammation are still debated, but ultimately, airway narrowing mediated by airway smooth muscle contraction is the final pathway to asthma. Considerable effort has been devoted towards identifying the factors that lead to the airway smooth muscle hypercontractility observed in asthma, and this will be the focus of this review. Airway remodeling has been observed in severe and fatal asthma. However, it is unclear whether remodeling plays a protective role or worsens airway responsiveness. Smooth muscle plasticity is a mechanism likely implicated in asthma, whereby contractile filament rearrangements lead to maximal force production, independent of muscle length. Increased smooth muscle rate of shortening via altered signaling pathways or altered contractile protein expression has been demonstrated in asthma and in numerous models of airway hyperresponsiveness. Increased rate of shortening is implicated in counteracting the relaxing effect of tidal breathing and deep inspirations, thereby creating a contracted airway smooth muscle steady-state. Further studies are therefore required to understand the numerous mechanisms leading to the airway hyperresponsiveness observed in asthma as well as their multiple interactions.

Relationship of airway narrowing, compliance, and cartilage in isolated bronchial segments

2002 ◽  
Vol 92 (3) ◽  
pp. 1119-1124 ◽  
Author(s):  
P. B. Noble ◽  
D. J. Turner ◽  
H. W. Mitchell
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Length ◽  
Electrical Field Stimulation ◽  
Cross Sectional ◽  
Intact Control ◽  
Airway Narrowing ◽  
Lumen Narrowing ◽  
Morphometric Assessment ◽  
Relationship Of

Structural components of the airway wall may act to load airway smooth muscle and restrict airway narrowing. In this study, the effect of load on airway narrowing was investigated in pig isolated bronchial segments. In some bronchi, pieces of cartilage were removed by careful dissection. Airway narrowing was produced by maximum electrical field stimulation. An endoscope was used to record lumen narrowing. The compliance of the bronchial segments was determined from the cross-sectional area of the lumen and the transmural pressure. Airway narrowing and the velocity of airway narrowing were increased in cartilage-removed airways compared with intact control bronchi. Morphometric assessment of smooth muscle length showed greater muscle shortening to acetylcholine in cartilage-removed airways than in controls. Airway narrowing was positively correlated with airway compliance. Compliance and area of cartilage were negatively correlated. These results show that airway narrowing is increased in compliant airways and that cartilage significantly loads airway smooth muscle in whole bronchi.

scholarly journals Dynamic equilibration of airway smooth muscle contraction during physiological loading

2002 ◽  
Vol 92 (2) ◽  
pp. 771-779 ◽  
Author(s):  
Jeanne Latourelle ◽  
Ben Fabry ◽  
Jeffrey J. Fredberg
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Experimental Method ◽  
Airway Smooth Muscle ◽  
Muscle Length ◽  
Transpulmonary Pressure ◽  
Smooth Muscle Contraction ◽  
Control Force ◽  
Airway Narrowing

Airway smooth muscle contraction is the central event in acute airway narrowing in asthma. Most studies of isolated muscle have focused on statically equilibrated contractile states that arise from isometric or isotonic contractions. It has recently been established, however, that muscle length is determined by a dynamically equilibrated state of the muscle in which small tidal stretches associated with the ongoing action of breathing act to perturb the binding of myosin to actin. To further investigate this phenomenon, we describe in this report an experimental method for subjecting isolated muscle to a dynamic microenvironment designed to closely approximate that experienced in vivo. Unlike previous methods that used either time-varying length control, force control, or time-invariant auxotonic loads, this method uses transpulmonary pressure as the controlled variable, with both muscle force and muscle length free to adjust as they would in vivo. The method was implemented by using a servo-controlled lever arm to load activated airway smooth muscle strips with transpulmonary pressure fluctuations of increasing amplitude, simulating the action of breathing. The results are not consistent with classical ideas of airway narrowing, which rest on the assumption of a statically equilibrated contractile state; they are consistent, however, with the theory of perturbed equilibria of myosin binding. This experimental method will allow for quantitative experimental evaluation of factors that were previously outside of experimental control, including sensitivity of muscle length to changes of tidal volume, changes of lung volume, shape of the load characteristic, loss of parenchymal support and inflammatory thickening of airway wall compartments.

scholarly journals Could an increase in airway smooth muscle shortening velocity cause airway hyperresponsiveness?

2011 ◽  
Vol 300 (1) ◽  
pp. L121-L131 ◽  
Author(s):  
Sharon R. Bullimore ◽  
Sana Siddiqui ◽  
Graham M. Donovan ◽  
James G. Martin ◽  
James Sneyd ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Isometric Force ◽  
Muscle Length ◽  
Shortening Velocity ◽  
Bridge Model ◽  
Generating Capacity ◽  
Cross Bridges

Airway hyperresponsiveness (AHR) is a characteristic feature of asthma. It has been proposed that an increase in the shortening velocity of airway smooth muscle (ASM) could contribute to AHR. To address this possibility, we tested whether an increase in the isotonic shortening velocity of ASM is associated with an increase in the rate and total amount of shortening when ASM is subjected to an oscillating load, as occurs during breathing. Experiments were performed in vitro using 27 rat tracheal ASM strips supramaximally stimulated with methacholine. Isotonic velocity at 20% isometric force (Fiso) was measured, and then the load on the muscle was varied sinusoidally (0.33 ± 0.25 Fiso, 1.2 Hz) for 20 min, while muscle length was measured. A large amplitude oscillation was applied every 4 min to simulate a deep breath. We found that: 1) ASM strips with a higher isotonic velocity shortened more quickly during the force oscillations, both initially ( P < 0.001) and after the simulated deep breaths ( P = 0.002); 2) ASM strips with a higher isotonic velocity exhibited a greater total shortening during the force oscillation protocol ( P < 0.005); and 3) the effect of an increase in isotonic velocity was at least comparable in magnitude to the effect of a proportional increase in ASM force-generating capacity. A cross-bridge model showed that an increase in the total amount of shortening with increased isotonic velocity could be explained by a change in either the cycling rate of phosphorylated cross bridges or the rate of myosin light chain phosphorylation. We conclude that, if asthma involves an increase in ASM velocity, this could be an important factor in the associated AHR.

scholarly journals Exchange protein directly activated by cAMP (Epac) protects against airway inflammation and airway remodeling in asthmatic mice

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Yi-fei Chen ◽  
Ge Huang ◽  
Yi-min Wang ◽  
Ming Cheng ◽  
Fang-fang Zhu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Inflammation ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Inflammatory Cell ◽  
Acute Asthma ◽  
Airway Remodeling ◽  
Chronic Asthma ◽  
Mice Model

Abstract Background β2 receptor agonists induce airway smooth muscle relaxation by increasing intracellular cAMP production. PKA is the traditional downstream signaling pathway of cAMP. Exchange protein directly activated by cAMP (Epac) was identified as another important signaling molecule of cAMP recently. The role of Epac in asthmatic airway inflammation and airway remodeling is unclear. Methods We established OVA-sensitized and -challenged acute and chronic asthma mice models to explore the expression of Epac at first. Then, airway inflammation and airway hyperresponsiveness in acute asthma mice model and airway remodeling in chronic asthma mice model were observed respectively after treatment with Epac-selective cAMP analogue 8-pCPT-2′-O-Me-cAMP (8pCPT) and Epac inhibitor ESI-09. Next, the effects of 8pCPT and ESI-09 on the proliferation and apoptosis of in vitro cultured mouse airway smooth muscle cells (ASMCs) were detected with CCK-8 assays and Annexin-V staining. Lastly, the effects of 8pCPT and ESI-09 on store-operated Ca2+ entry (SOCE) of ASMCs were examined by confocal Ca2+ fluorescence measurement. Results We found that in lung tissues of acute and chronic asthma mice models, both mRNA and protein expression of Epac1 and Epac2, two isoforms of Epac, were lower than that of control mice. In acute asthma mice model, the airway inflammatory cell infiltration, Th2 cytokines secretion and airway hyperresponsiveness were significantly attenuated by 8pCPT and aggravated by ESI-09. In chronic asthma mice model, 8pCPT decreased airway inflammatory cell infiltration and airway remodeling indexes such as collagen deposition and airway smooth muscle cell proliferation, while ESI-09 increased airway inflammation and airway remodeling. In vitro cultured mice ASMCs, 8pCPT dose-dependently inhibited, whereas ESI-09 promoted ASMCs proliferation. Interestingly, 8pCPT promoted the apoptosis of ASMCs, whereas ESI-09 had no effect on ASMCs apoptosis. Lastly, confocal Ca2+ fluorescence examination found that 8pCPT could inhibit SOCE in ASMCs at 100 μM, and ESI-09 promoted SOCE of ASMCs at 10 μM and 100 μM. In addition, the promoting effect of ESI-09 on ASMCs proliferation was inhibited by store-operated Ca2+ channel blocker, SKF-96365. Conclusions Our results suggest that Epac has a protecting effect on asthmatic airway inflammation and airway remodeling, and Epac reduces ASMCs proliferation by inhibiting SOCE in part.

scholarly journals Bnip3 regulates airway smooth muscle cell focal adhesion and proliferation

2019 ◽  
Vol 317 (6) ◽  
pp. L758-L767 ◽  
Author(s):  
Shi Pan ◽  
Sushrut D. Shah ◽  
Reynold A. Panettieri ◽  
Deepak A. Deshpande
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Remodeling ◽  
Airway Smooth Muscle Cell ◽  
Mitochondrial Morphology ◽  
Interacting Protein ◽  
Airway Narrowing ◽  
Healthy Donors ◽  
Adenovirus E1b ◽  
And Function

Increased airway smooth muscle (ASM) mass is a key contributor to airway narrowing and airway hyperresponsiveness in asthma. Besides conventional pathways and regulators of ASM proliferation, recent studies suggest that changes in mitochondrial morphology and function play a role in airway remodeling in asthma. In this study, we aimed at determining the role of mitochondrial Bcl-2 adenovirus E1B 19 kDa-interacting protein, Bnip3, in the regulation of ASM proliferation. Bnip3 is a member of the Bcl-2 family of proteins critical for mitochondrial health, mitophagy, and cell survival/death. We found that Bnip3 expression is upregulated in ASM cells from asthmatic donors compared with that in ASM cells from healthy donors and transient downregulation of Bnip3 expression in primary human ASM cells using an siRNA approach decreased cell adhesion, migration, and proliferation. Furthermore, Bnip3 downregulation altered the structure (electron density) and function (cellular ATP levels, membrane potential, and reacitve oxygen species generation) of mitochondria and decreased expression of cytoskeleton proteins vinculin, paxillin, and actinin. These findings suggest that Bnip3 via regulation of mitochondria functions and expression of adhesion proteins regulates ASM adhesion, migration, and proliferation. This study reveals a novel role for Bnip3 in ASM functions and establishes Bnip3 as a potential target in mitigating ASM remodeling in asthma.

Airway smooth muscle shortening in excised canine lung lobes

1993 ◽  
Vol 74 (4) ◽  
pp. 1613-1621 ◽  
Author(s):  
M. Okazawa ◽  
T. R. Bai ◽  
B. R. Wiggs ◽  
P. D. Pare
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Cross Sections ◽  
Muscle Length ◽  
Elastic Recoil ◽  
Pulmonary Resistance ◽  
Airway Narrowing ◽  
Arterial Perfusion ◽  
Muscle Shortening ◽  
Lung Lobes

To estimate the importance of lung parenchymal airway interdependence in attenuating airway narrowing, airway smooth muscle shortening in response to nebulized carbachol was measured in excised canine lung lobes and compared with the calculated load applied by lung elastic recoil. Pulmonary resistance of matched right and left upper lobes of five dogs was measured in a pressure-compensated volume plethysmograph by forced oscillation (6 Hz) before and after administration of an aerosol of carbachol (250 mg/ml) or saline. Matched lobes were studied at transpulmonary pressures (PL) of 5, 7, 10, 12, and 15 cmH2O. The lungs were then fixed at that PL by pulmonary arterial perfusion with formaldehyde, and cross sections of multiple airways from each lobe (n = 275) were examined by use of morphometric techniques to measure luminal area and smooth muscle length. By use of the saline lobe as a control, percentage of muscle shortening and decrease in airway lumen area caused by carbachol could be calculated. Passive and active smooth muscle stresses in each airway were calculated from PL and the calculated change in peribronchial pressure for a given change in airway diameter. The increase in pulmonary resistance and average smooth muscle shortening after administration of carbachol was greater in lobes held at lower PL. There was marked variation in narrowing between airways within a lobe: smooth muscle shortening ranged between 0 and 65% but averaged < 45% at all levels of PL.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals STIM1 is a core trigger of airway smooth muscle remodeling and hyperresponsiveness in asthma

2021 ◽  
Vol 119 (1) ◽  
pp. e2114557118
Author(s):  
Martin T. Johnson ◽  
Ping Xin ◽  
J. Cory Benson ◽  
Trayambak Pathak ◽  
Vonn Walter ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Airway Remodeling ◽  
Asthma Severity ◽  
Glycolytic Flux ◽  
Activated T Cells ◽  
Surface Receptors ◽  
Transcriptional Reprogramming ◽  
Associated Proteins

Airway remodeling and airway hyperresponsiveness are central drivers of asthma severity. Airway remodeling is a structural change involving the dedifferentiation of airway smooth muscle (ASM) cells from a quiescent to a proliferative and secretory phenotype. Here, we show up-regulation of the endoplasmic reticulum Ca2+ sensor stromal-interacting molecule 1 (STIM1) in ASM of asthmatic mice. STIM1 is required for metabolic and transcriptional reprogramming that supports airway remodeling, including ASM proliferation, migration, secretion of cytokines and extracellular matrix, enhanced mitochondrial mass, and increased oxidative phosphorylation and glycolytic flux. Mechanistically, STIM1-mediated Ca2+ influx is critical for the activation of nuclear factor of activated T cells 4 and subsequent interleukin-6 secretion and transcription of pro-remodeling transcription factors, growth factors, surface receptors, and asthma-associated proteins. STIM1 drives airway hyperresponsiveness in asthmatic mice through enhanced frequency and amplitude of ASM cytosolic Ca2+ oscillations. Our data advocates for ASM STIM1 as a target for asthma therapy.

scholarly journals Biophysical basis for airway hyperresponsivenessThis article is one of a selection of papers published in the Special Issue on Recent Advances in Asthma Research.

2007 ◽  
Vol 85 (7) ◽  
pp. 700-714 ◽  
Author(s):  
Steven S. An ◽  
Jeffrey J. Fredberg
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Airway Smooth Muscle ◽  
Muscle Cell ◽  
Muscle Length ◽  
Airway Smooth Muscle Cell ◽  
Airway Narrowing ◽  
Dynamic Setting ◽  
Airway Mechanics ◽  
Myosin Motors

Airway hyperresponsiveness is the excessive narrowing of the airway lumen caused by stimuli that would cause little or no narrowing in the normal individual. It is one of the cardinal features of asthma, but its mechanisms remain unexplained. In asthma, the key end-effector of acute airway narrowing is contraction of the airway smooth muscle cell that is driven by myosin motors exerting their mechanical effects within an integrated cytoskeletal scaffolding. In just the past few years, however, our understanding of the rules that govern muscle biophysics has dramatically changed, as has their classical relationship to airway mechanics. It has become well established, for example, that muscle length is equilibrated dynamically rather than statically, and that in a dynamic setting nonclassical features of muscle biophysics come to the forefront, including unanticipated interactions between the muscle and its time-varying load, as well as the ability of the muscle cell to adapt (remodel) its internal microstructure rapidly in response to its ever-changing mechanical environment. Here, we consider some of these emerging concepts and, in particular, focus on structural remodeling of the airway smooth muscle cell as it relates to excessive airway narrowing in asthma.

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