Smooth muscle length adaptation and actin filament length: a network model of the cytoskeletal dysregulation

2005 ◽  
Vol 83 (10) ◽  
pp. 923-931 ◽  
Author(s):  
Jeffrey J Fredberg ◽  
Paulo S.P Silveira
Keyword(s):  
Smooth Muscle ◽  
Simple Model ◽  
Airway Smooth Muscle ◽  
Actin Filament ◽  
Actin Filaments ◽  
Muscle Mechanics ◽  
Muscle Length ◽  
Potential Effect ◽  
Airway Smooth Muscle Cell ◽  
Filament Length

Length adaptation of the airway smooth muscle cell is attributable to cytoskeletal remodeling. It has been proposed that dysregulated actin filaments may become longer in asthma, and that such elongation would prevent a parallel-to-series transition of contractile units, thus precluding the well-known beneficial effects of deep inspirations and tidal breathing. To test the potential effect that actin filament elongation could have in overall muscle mechanics, we present an extremely simple model. The cytoskeleton is represented as a 2-D network of links (contractile filaments) connecting nodes (adhesion plaques). Such a network evolves in discrete time steps by forming and dissolving links in a stochastic fashion. Links are formed by idealized contractile units whose properties are either those from normal or elongated actin filaments. Oscillations were then imposed on the network to evaluate both the effects of breathing and length adaptation. In response to length oscillation, a network with longer actin filaments showed smaller decreases of force, smaller increases in compliance, and higher shortening velocities. Taken together, these changes correspond to a network that is refractory to the effects of breathing and therefore approximates an asthmatic scenario. Thus, an extremely simple model seems to capture some relatively complex mechanics of airway smooth muscle, supporting the idea that dysregulation of actin filament length may contribute to excessive airway narrowing.Key words: asthma, actin filaments, series-to-parallel transition, mechanics, length adaptation.

Latrunculin B increases force fluctuation-induced relengthening of ACh-contracted, isotonically shortened canine tracheal smooth muscle

2005 ◽  
Vol 98 (2) ◽  
pp. 489-497 ◽  
Author(s):  
M. L. Dowell ◽  
O. J. Lakser ◽  
W. T. Gerthoffer ◽  
J. J. Fredberg ◽  
G. L. Stelmack ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Actin Filament ◽  
Isometric Force ◽  
Muscle Length ◽  
Tracheal Smooth Muscle ◽  
Filament Length ◽  
Latrunculin B ◽  
Force Fluctuation ◽  
Reference Length

We hypothesized that differences in actin filament length could influence force fluctuation-induced relengthening (FFIR) of contracted airway smooth muscle and tested this hypothesis as follows. One-hundred micromolar ACh-stimulated canine tracheal smooth muscle (TSM) strips set at optimal reference length ( Lref) were allowed to shorten against 32% maximal isometric force (Fmax) steady preload, after which force oscillations of ±16% Fmax were superimposed. Strips relengthened during force oscillations. We measured hysteresivity and calculated FFIR as the difference between muscle length before and after 20-min imposed force oscillations. Strips were relaxed by ACh removal and treated for 1 h with 30 nM latrunculin B (sequesters G-actin and promotes depolymerization) or 500 nM jasplakinolide (stabilizes actin filaments and opposes depolymerization). A second isotonic contraction protocol was then performed; FFIR and hysteresivity were again measured. Latrunculin B increased FFIR by 92.2 ± 27.6% Lref and hysteresivity by 31.8 ± 13.5% vs. pretreatment values. In contrast, jasplakinolide had little influence on relengthening by itself; neither FFIR nor hysteresivity was significantly affected. However, when jasplakinolide-treated tissues were then incubated with latrunculin B in the continued presence of jasplakinolide for 1 more h and a third contraction protocol performed, latrunculin B no longer substantially enhanced TSM relengthening. In TSM treated with latrunculin B + jasplakinolide, FFIR increased by only 3.03 ± 5.2% Lref and hysteresivity by 4.14 ± 4.9% compared with its first (pre-jasplakinolide or latrunculin B) value. These results suggest that actin filament length, in part, determines the relengthening of contracted airway smooth muscle.

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.

scholarly journals Transient stretch induces cytoskeletal fluidization through the severing action of cofilin

2018 ◽  
Vol 314 (5) ◽  
pp. L799-L807 ◽  
Author(s):  
Bo Lan ◽  
Ramaswamy Krishnan ◽  
Chan Yong Park ◽  
Rodrigo A. Watanabe ◽  
Ronald Panganiban ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Airway Smooth Muscle ◽  
Actin Filaments ◽  
Muscle Cells ◽  
Contractile Force ◽  
Airway Smooth Muscle Cell ◽  
Airway Smooth Muscle Cells ◽  
Airway Wall ◽  
Contractile Forces

With every deep inspiration (DI) or sigh, the airway wall stretches, as do the airway smooth muscle cells in the airway wall. In response, the airway smooth muscle cell undergoes rapid stretch-induced cytoskeletal fluidization. As a molecular mechanism underlying the cytoskeletal fluidization response, we demonstrate a key role for the actin-severing protein cofilin. Using primary human airway smooth muscle cells, we simulated a DI by imposing a transient stretch of physiological magnitude and duration. We used traction microscopy to measure the resulting changes in contractile forces. After a transient stretch, cofilin-knockdown cells exhibited a 29 ± 5% decrease in contractile force compared with prestretch conditions. By contrast, control cells exhibited a 67 ± 6% decrease ( P < 0.05, knockdown vs. control). Consistent with these contractile force changes with transient stretch, actin filaments in cofilin-knockdown cells remained largely intact, whereas actin filaments in control cells were rapidly disrupted. Furthermore, in cofilin-knockdown cells, contractile force at baseline was higher and rate of remodeling poststretch was slower than in control cells. Additionally, the severing action of cofilin was restricted to the release phase of the transient stretch. We conclude that the actin-severing activity of cofilin is an important factor in stretch-induced cytoskeletal fluidization and may account for an appreciable part of the bronchodilatory effects of a DI.

A human airway smooth muscle cell line that retains physiological responsiveness

1989 ◽  
Vol 256 (2) ◽  
pp. C329-C335 ◽  
Author(s):  
R. A. Panettieri ◽  
R. K. Murray ◽  
L. R. DePalo ◽  
P. A. Yadvish ◽  
M. I. Kotlikoff
Keyword(s):  
Smooth Muscle ◽  
Cell Line ◽  
Airway Smooth Muscle ◽  
Cytosolic Calcium ◽  
Airway Smooth Muscle Cell ◽  
Airway Smooth Muscle Cells ◽  
Functional Coupling ◽  
Functional Responses ◽  
Human Airway Smooth Muscle ◽  
Human Airway

We report the development of a nontransformed line of human airway smooth muscle cells retaining smooth muscle-specific contractile protein expression and physiological responsiveness to agonists implicated in inflammatory airway diseases. Specific responses to histamine, leukotrienes, bradykinin, platelet-activating factor, substance P, and thromboxane analogues are demonstrated as well as functional coupling to beta-adrenergic receptors. The cell line was characterized using indirect immunofluorescence, as well as electrophoretic separation and immunoblot analysis of smooth muscle-specific actin. Functional responses were assessed by measurements of cytosolic calcium and stimulation of adenosine 3',5'-cyclic monophosphate production. The cells retain their responsiveness over many population doublings and should be a useful model to examine specific receptor-effector mechanisms, as well as the effects of neurohumoral agents on the regulation of airway smooth muscle growth and differentiation.

scholarly journals Novel phosphodiesterases inhibitors from the group of purine-2,6-dione derivatives as potent modulators of airway smooth muscle cell remodelling

2019 ◽  
Vol 865 ◽  
pp. 172779 ◽  
Author(s):  
Katarzyna Wójcik-Pszczoła ◽  
Grażyna Chłoń-Rzepa ◽  
Agnieszka Jankowska ◽  
Eugenie Ellen ◽  
Artur Świerczek ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Airway Smooth Muscle ◽  
Muscle Cell ◽  
Airway Smooth Muscle Cell

Cytoskeletal mechanics in adherent human airway smooth muscle cells: probe specificity and scaling of protein-protein dynamics

2004 ◽  
Vol 287 (3) ◽  
pp. C643-C654 ◽  
Author(s):  
Marina Puig-de-Morales ◽  
Emil Millet ◽  
Ben Fabry ◽  
Daniel Navajas ◽  
Ning Wang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Dynamics ◽  
Airway Smooth Muscle ◽  
Power Law ◽  
Density Lipoprotein ◽  
Airway Smooth Muscle Cell ◽  
Airway Smooth Muscle Cells ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Lateral Displacements

We probed elastic and loss moduli in the adherent human airway smooth muscle cell through a variety of receptor systems, each serving as a different molecular window on cytoskeletal dynamics. Coated magnetic microbeads were attached to the cell surface via coating-receptor binding. A panel of bead coatings was investigated: a peptide containing the sequence RGD, vitronectin, urokinase, activating antibody against β1-integrin, nonactivating antibody against β1-integrin, blocking antibody against β1-integrin, antibody against β1-integrin, and acetylated low-density lipoprotein. An oscillatory mechanical torque was applied to the bead, and resulting lateral displacements were measured at baseline, after actin disruption by cytochalasin D, or after contractile activation by histamine. As expected, mechanical moduli depended strongly on bead type and bead coating, differing at the extremes by as much as two orders of magnitude. In every case, however, elastic and loss moduli increased with frequency f as a weak power law, f  x−1. Moreover, with few exceptions, data could be scaled such that elastic and frictional responses depended solely on the power law exponent x. Taken together, these data suggest that power law behavior represents a generic feature of underlying protein-protein dynamics.

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