A Continuous-Binding Cross-Linker Model for Passive Airway Smooth Muscle

American Journal of Physiology-Lung Cellular and Molecular Phys

et al. 2011

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. Could an increase in airway smooth muscle shortening velocity cause airway hyperresponsiveness? Am J Physiol Lung Cell Mol Physiol 300: L121-L131, 2011. First published October 22, 2010; doi:10.1152/ajplung.00228.2010.-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 Ϯ 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 Ͻ 0.001) and after the simulated deep breaths (P ϭ 0.002); 2) ASM strips with a higher isotonic velocity exhibited a greater total shortening during the force oscillation protocol (P Ͻ 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 forcegenerating 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.trachealis; cross-bridge model; latchbridge; deep inspiration; oscillation ONE OF THE DEFINING FEATURES of asthma is airway hyperresponsiveness (AHR), an increase in the magnitude and/or sensitivity of the response to bronchoconstricting stimuli. Many factors have been identified that could contribute to AHR, including an increase in the capacity of airway smooth muscle (ASM) to generate force, airway wall thickening, alterations in the mechanical properties of the lung parenchyma or the airway wall, and abnormal neural control (5). It has also been suggested that an increase in the shortening velocity of ASM could cause AHR (2,31,41). This has been proposed based on two lines of evidence. First, in vivo studies have shown that the airways of both normal and asthmatic subjects dilate transiently when a deep inspiration is taken during induced bronchoconstriction, but that the subsequent reconstriction is more rapid in asthmatics (23,25,35). Second, in vitro measurements have shown that bronchial ASM cells taken from asthmatic patients have an increased shortening velocity relative to controls (29) as do human bronchial ASM sensitized ...

Section: Discussionmentioning

confidence: 99%

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

Bullimore

Siddiqui

American Journal of Physiology-Lung Cellular and Molecular Phys

et al. 2011

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“…As such, there is an obvious degree of uncertainty about the inflation branches (and hence the extent of the hysteresis and bistability). Similarly, we have not included a passive ASM component (e.g., Donovan et al (28)), and this might be reasonably expected to contribute disproportionately to the inflation branch. However, perhaps it is more important to emphasize that isolated airway bistability of the sort considered here (akin to Affonce and Lutchen (1)) is not strictly necessary for coupled airway models that drive clustered ventilation defect formation; instead, feedback mechanisms via airflow and parenchymal tethering (2) could introduce bistability in coupled systems, even where isolated airways lack such behavior.…”

Section: Discussionmentioning

confidence: 99%

Airway Bistability Is Modulated by Smooth Muscle Dynamics and Length-Tension Characteristics

2016

Biophysical Journal

Airway closure has important implications for lung disease, especially asthma; in particular, the prospect of bistability between open and closed (or effectively closed) airway states has been thought to play a prominent role in airway closure associated with the formation of clustered ventilation defects in asthma. However, many existing analyses of closure consider only static airway equilibria; here we construct, to our knowledge, a new model wherein airway narrowing and closure dynamics are modulated by coupling the airway to cross-bridge models of airway smooth muscle dynamics and force generation. Using this model, we show that important qualitative features of airway pressure-radius hysteresis loops are highly dependent on both airway smooth muscle dynamics, and the length-tension relationship. Furthermore, we show that two recent experimental results from intact bronchial segments are both expressions of the same phenomenon: that a monotonically increasing lengthtension relationship, with sharply higher tension at longer lengths, is needed to drive the observed changes in low-compliance regions of the baseline pressure-radius curve. We also explore the potential implications of this finding for airway closure in coupled airway models.

“…For example, airway wall thickening has been thought to play a role, both in terms of reduced luminal area (Niimi et al, 2000, 2003) but also via wall stiffening or changes in compliance (Cojocaru et al, 2008; Pare et al, 2007). Airway smooth muscle is also an oft-cited culprit, in terms of thickening (Johnson et al, 2001; Seow et al, 1998; James et al, 2012), or shortening velocity (Bullimore et al, 2011); but also the so-called fluidization response (Krishnan et al, 2008; Donovan et al, 2010), and in particular the response to deep inspirations (Donovan et al, 2012; LaPrad et al, 2010). SERCA pump expression has also been implicated (Mahn et al, 2009).…”

Section: Multiscale Modellingmentioning

confidence: 99%

Phenotype, endotype and patient-specific computational modelling for optimal treatment design in asthma

Drug Discovery Today: Disease Models

Tawhai

2015

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Understanding and treatment of asthma is significantly complicated by the heterogeneous spectrum of phenotypes associated with the disease. Recent advances in phenotype classification promise more targeted therapies, but these categories are based on constellations of largely external measurements and are not necessarily indicative of underlying pathophysiology. We propose that computational modelling is a valuable tool that allows the disease spectrum to be decomposed not into phenotypes but rather into groups organized by underlying dysfunction, referred to by some authors as endotypes. By breaking down the asthmatic spectrum in this way, therapies can be targeted more directly to the underlying defects. This would be not only an important improvement in its own right, but also an important step toward the ultimate goal of patient-specific modelling.