scholarly journals Transition From Phasic to Tonic Contractility in Airway Smooth Muscle After Birth: An Experimental and Computational Modeling Study

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Kimberley C. W. Wang ◽  
Amy Y. Chang ◽  
J. Jane Pillow ◽  
Béla Suki ◽  
Peter B. Noble
Keyword(s):  
Smooth Muscle ◽  
Computational Model ◽  
Airway Smooth Muscle ◽  
Developmental Model ◽  
Cell Coupling ◽  
Phasic Activity ◽  
Phasic Contraction ◽  
Lumen Narrowing ◽  
Underlying Mechanisms ◽  
Cell Cell

Fetal airway smooth muscle (ASM) exhibits phasic contractile behavior, which transitions to a more sustained “tonic” contraction after birth. The timing and underlying mechanisms of ASM transition from a phasic to a tonic contractile phenotype are yet to be established. We characterized phasic ASM contraction in preterm (128 day gestation), term (∼150 day gestation), 1–4 month, 1 yr, and adult sheep (5yr). Spontaneous phasic activity was measured in bronchial segments as amplitude, frequency, and intensity. The mechanism of phasic ASM contraction was investigated further with a computational model of ASM force development and lumen narrowing. The computational model comprised a two-dimensional cylindrical geometry of a network of contractile units and the activation of neighboring cells was dependent on the strength of coupling between cells. As expected, phasic contractions were most prominent in fetal airways and decreased with advancing age, to a level similar to the level in the 1–4 month lambs. Computational predictions demonstrated phasic contraction through the generation of a wave of activation events, the magnitude of which is determined by the number of active cells and the strength of cell–cell interactions. Decreases in phasic contraction with advancing age were simulated by reducing cell–cell coupling. Results show that phasic activity is suppressed rapidly after birth, then sustained at a lower intensity from the preweaning phase until adulthood in an ovine developmental model. Cell–cell coupling is proposed as a key determinant of phasic ASM contraction and if reduced could explain the observed maturational changes.

Are gap junctions necessary for cell-to-cell coupling of smooth muscle?: an update

1992 ◽  
Vol 70 (4) ◽  
pp. 481-490 ◽  
Author(s):  
R. E. Garfield ◽  
G. Thilander ◽  
M. G. Blennerhassett ◽  
N. Sakai
Keyword(s):  
Smooth Muscle ◽  
Gap Junctions ◽  
Current Knowledge ◽  
Smooth Muscles ◽  
Cell Communication ◽  
Circular Muscle ◽  
Cell Coupling ◽  
And Function ◽  
Longitudinal Layer ◽  
Cell Cell

Earlier, it was questioned whether gap junctions (GJs) were necessary for cell–cell communication in smooth muscle, and GJs were not seen in some smooth muscles. We reexamined this question in the myometrium and in intestinal smooth muscle, in light of current knowledge of the presence and function of GJs. In the uterus, numerous studies show that an increase in GJ number is associated with the onset of delivery and is required for effective parturition. In all cases, this increase in GJ number and the changes in uterine contractility were correlated with increased electrical and metabolic coupling. Evidence for the much smaller, but detectable, degree of electrical coupling in the preterm uterus is explained by the small (but again detectable) number of GJs present. In the intestine, GJs are readily detected in the circular muscle layer but have not been described in the adjacent longitudinal layer. While our immunohistochemical studies failed to detect GJs in the longitudinal layer, this may not be adequate to prove their absence. Therefore, current knowledge of GJ number and function is adequate to explain cell–cell coupling in the uterus. Although it remains uncertain whether GJs are absent from the longitudinal muscle of the intestine, there is no definitive evidence that cell–cell coupling can occur by means other than GJs.Key words: gap junctions, myometrium, connexins, smooth muscle, cell communication.

Does the length dependency of airway smooth muscle force contribute to airway hyperresponsiveness?

2013 ◽  
Vol 115 (9) ◽  
pp. 1304-1315 ◽  
Author(s):  
Audrey Lee-Gosselin ◽  
Chris D. Pascoe ◽  
Christian Couture ◽  
Peter D. Paré ◽  
Ynuk Bossé
Keyword(s):  
Smooth Muscle ◽  
Computational Model ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Muscle Force ◽  
Morphological Data ◽  
Airway Wall ◽  
Airway Walls ◽  
Computational Analyses ◽  
Human Bronchi

Airway wall remodeling and lung hyperinflation are two typical features of asthma that may alter the contractility of airway smooth muscle (ASM) by affecting its operating length. The aims of this study were as follows: 1) to describe in detail the “length dependency of ASM force” in response to different spasmogens; and 2) to predict, based on morphological data and a computational model, the consequence of this length dependency of ASM force on airway responsiveness in asthmatic subjects who have both remodeled airway walls and hyperinflated lungs. Ovine tracheal ASM strips and human bronchial rings were isolated and stimulated to contract in response to increasing concentrations of spasmogens at three different lengths. Ovine tracheal strips were more sensitive and generated greater force at longer lengths in response to acetylcholine (ACh) and K+. Equipotent concentrations of ACh were approximately a log less for ASM stretched by 30% and approximately a log more for ASM shortened by 30%. Similar results were observed in human bronchi in response to methacholine. Morphometric and computational analyses predicted that the ASM of asthmatic subjects may be elongated by 6.6–10.4% (depending on airway generation) due to remodeling and/or hyperinflation, which could increase ACh-induced force by 1.8–117.8% (depending on ASM length and ACh concentration) and enhance the increased resistance to airflow by 0.4–4,432.8%. In conclusion, elongation of ASM imposed by airway wall remodeling and/or hyperinflation may allow ASM to operate at a longer length and to consequently generate more force and respond to lower concentration of spasmogens. This phenomenon could contribute to airway hyperresponsiveness.

Role of STIM1/Orai1-mediated store-operated Ca2+ entry in airway smooth muscle cell proliferation

2011 ◽  
Vol 110 (5) ◽  
pp. 1256-1263 ◽  
Author(s):  
Jin-jing Zou ◽  
Ya-dong Gao ◽  
Shuang Geng ◽  
Jiong Yang
Keyword(s):  
Smooth Muscle ◽  
Mrna Expression ◽  
Airway Smooth Muscle ◽  
Inhibitory Effect ◽  
Airway Smooth Muscle Cell ◽  
Characteristic Change ◽  
Airway Smooth Muscle Cells ◽  
Channel Blockers ◽  
Asthma Patients ◽  
Underlying Mechanisms

Hyperplasia of airway smooth muscle cells (ASMCs) is a characteristic change of chronic asthma patients. However, the underlying mechanisms that trigger this process are not yet completely understood. Store-operated Ca2+ (SOC) entry (SOCE) occurs in response to the intracellular sarcoplasma reticulum (SR)/endoplasmic reticulum (ER) Ca2+ store depletion. SOCE plays an important role in regulating Ca2+ signaling and cellular responses of ASMCs. Stromal interaction molecule (STIM)1 has been proposed as an ER/SR Ca2+ sensor and translocates to the ER underneath the plasma membrane upon depletion of the ER Ca2+ store, where it interacts with Orai1, the molecular component of SOC channels, and brings about SOCE. STIM1 and Orai1 have been proved to mediate SOCE of ASMCs. In this study, we investigated whether STIM1/Orai1-mediated SOCE is involved in rat ASMC proliferation. We found that SOCE was upregulated during ASMC proliferation accompanied by a mild increase of STIM1 and a significant increase of Orai1 mRNA expression, whereas the proliferation of ASMCs was partially inhibited by the SOC channel blockers SKF-96365, NiCl2, and BTP-2. Suppressing the mRNA expression of STIM1 or Orai1 with specific short hairpin RNA resulted in the attenuation of SOCE and ASMC proliferation. Moreover, after knockdown of STIM1 or Orai1, the SOC channel blocker SKF-96365 had no inhibitory effect on the proliferation of ASMCs anymore. These results suggested that STIM1/Orai1-mediated SOCE is involved in ASMC proliferation.

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.

β-Catenin regulates airway smooth muscle contraction

2010 ◽  
Vol 299 (2) ◽  
pp. L204-L214 ◽  
Author(s):  
Sepp R. Jansen ◽  
Anna M. Van Ziel ◽  
Hoeke A. Baarsma ◽  
Reinoud Gosens
Keyword(s):  
Smooth Muscle ◽  
Plasma Membrane ◽  
Airway Smooth Muscle ◽  
Glycogen Synthase ◽  
Force Production ◽  
Smooth Muscle Contraction ◽  
Cell Contact ◽  
Force Transmission ◽  
Tension Development ◽  
Cell Cell

β-Catenin is an 88-kDa member of the armadillo family of proteins that is associated with the cadherin-catenin complex in the plasma membrane. This complex interacts dynamically with the actin cytoskeleton to stabilize adherens junctions, which play a central role in force transmission by smooth muscle cells. Therefore, in the present study, we hypothesized a role for β-catenin in the regulation of smooth muscle force production. β-Catenin colocalized with smooth muscle α-actin (sm-α-actin) and N-cadherin in plasma membrane fractions and coimmunoprecipitated with sm-α-actin and N-cadherin in lysates of bovine tracheal smooth muscle (BTSM) strips. Moreover, immunocytochemistry of cultured BTSM cells revealed clear and specific colocalization of sm-α-actin and β-catenin at the sites of cell-cell contact. Treatment of BTSM strips with the pharmacological β-catenin/T cell factor-4 (TCF4) inhibitor PKF115-584 (100 nM) reduced β-catenin expression in BTSM whole tissue lysates and in plasma membrane fractions and reduced maximal KCl- and methacholine-induced force production. These changes in force production were not accompanied by changes in the expression of sm-α-actin or sm-myosin heavy chain (MHC). Likewise, small interfering RNA (siRNA) knockdown of β-catenin in BTSM strips reduced β-catenin expression and attenuated maximal KCl- and methacholine-induced contractions without affecting sm-α-actin or sm-MHC expression. Conversely, pharmacological (SB-216763, LiCl) or insulin-induced inhibition of glycogen synthase kinase-3 (GSK-3) enhanced the expression of β-catenin and augmented maximal KCl- and methacholine-induced contractions. We conclude that β-catenin is a plasma membrane-associated protein in airway smooth muscle that regulates active tension development, presumably by stabilizing cell-cell contacts and thereby supporting force transmission between neighboring cells.

Functional significance of increased airway smooth muscle in asthma and COPD

1993 ◽  
Vol 74 (6) ◽  
pp. 2771-2781 ◽  
Author(s):  
R. K. Lambert ◽  
B. R. Wiggs ◽  
K. Kuwano ◽  
J. C. Hogg ◽  
P. D. Pare
Keyword(s):  
Smooth Muscle ◽  
Computational Model ◽  
Muscle Mass ◽  
Airway Smooth Muscle ◽  
Muscle Thickness ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Wall Stiffness ◽  
Airway Mechanics ◽  
Muscle Shortening

Using a computational model, we investigated the effect of the morphologically determined increased airway smooth muscle mass, adventitial mass, and submucosal mass observed in patients with asthma and chronic obstructive pulmonary disease (COPD) on the increase in airway resistance in response to a bronchoconstricting stimulus. The computational model of Wiggs et al. (J. Appl. Physiol. 69: 849–860, 1990) was modified in such a way that smooth muscle shortening was limited by the maximal stress that the muscle could develop at the constricted length. Increased adventitial thickness was found to increase constriction by reducing parenchymal interdependence. Increased submucosal thickness led to greater luminal occlusion for any degree of smooth muscle shortening. Increased muscle thickness allowed greater smooth muscle shortening against the elastic loads provided by parenchymal interdependence and airway wall stiffness. We found that for constant airway mechanics, as reflected by the passive area-pressure curves of the airways, the increased muscle mass is likely to be the most important abnormality responsible for the increased resistance observed in response to bronchoconstricting stimuli in asthma and COPD. For a given maximal muscle stress, greater muscle thickness allows the development of greater tension and thus more constriction of the lumen.

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