Disrupting Actin-Myosin-Actin Connectivity in Airway Smooth Muscle as a Treatment for Asthma?

Lavoie, Tera; Dowell, Maria; Lakser, Oren; Gerthoffer, William T.; Fredberg, Jeffrey J.; Seow, Chun Y.; Mitchell, Richard W.; Solway, Julian

doi:10.1513/pats.200808-078rm

Cited by 40 publications

(36 citation statements)

References 42 publications

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“…Our system could also be used to study the bronchoprotective effect of deep inspiration observed in people (66). Because the airways remain within their native architecture, and because fluctuationinduced relengthening has molecular determinants that differ from those of isometric force (9,(14)(15)(16)(17), it may be a useful platform for discovering novel pharmacologic agents that potentiate breathing-induced airway dilatation (67). For example, we have previously shown that latrunculin B (14), dexamethasone (17), and mitogen-activated protein kinase kinase inhibition (15) potentiate force fluctuation-induced relengthening of contracted canine tracheal smooth muscle strips, and unpublished observations in our laboratory suggest that latrunculin B potentiates breathinginduced reversal of bronchoconstriction.…”

Section: Discussionmentioning

confidence: 99%

Dilatation of the Constricted Human Airway by Tidal Expansion of Lung Parenchyma

Lavoie¹,

Krishnan

Siegel³

et al. 2012

Am J Respir Crit Care Med

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Rationale: In the normal lung, breathing and deep inspirations potently antagonize bronchoconstriction, but in the asthmatic lung this salutary effect is substantially attenuated or even reversed. To explain these findings, the prevailing hypothesis focuses on contracting airway smooth muscle and posits a nonlinear dynamic interaction between actomyosin binding and the tethering forces imposed by tidally expanding lung parenchyma. Objective: This hypothesis has never been tested directly in bronchial smooth muscle embedded within intraparenchymal airways. Our objective here is to fill that gap. Methods: We designed a novel system to image contracting intraparenchymal human airways situated within near-normal lung architecture and subjected to dynamic parenchymal expansion that simulates breathing. Measurements and Main Results: Reversal of bronchoconstriction depended on the degree to which breathing actually stretched the airway, which in turn depended negatively on severity of constriction and positively on the depth of breathing. Such behavior implies positive feedbacks that engender airway instability. Overall conclusions: These findings help to explain heterogeneity of airflow obstruction as well as why, in people with asthma, deep inspirations are less effective in reversing bronchoconstriction.Keywords: airway; smooth muscle; bronchoconstriction; stretch; asthma Among all factors known to antagonize bronchoconstriction in a healthy lung, a deep breath is among the most effective (1-5). In the asthmatic lung, however, this protective phenomenon is substantially attenuated, and during a spontaneous asthmatic attack it is sometimes even reversed (1, 6, 7). Some have suggested that the inability of a deep breath to dilate the constricted asthmatic airway might be an important cause of excessive airway narrowing (1,6,8).To explain these observations, a new conceptual framework has called attention to the role of airway smooth muscle (ASM) and the dynamic load against which it must contract (9). With each breath (10), lung parenchyma exerts a distending force on intrapulmonary airways and stretches the bands of ASM that they contain. In this conceptual framework, these tidal stretches perturb the binding of myosin to actin, causing the myosin molecule to detach from actin much sooner than it would have otherwise and thus reducing the myosin duty cycle (11-13). As a result, the contracted ASM band within a bronchoconstricted airway relengthens and thus partially relieves the bronchoconstriction. Importantly, such force fluctuation-induced muscle relengthening has molecular determinants that differ from those that determine isometric force (9, 14-17). As such, the length of contracting ASM becomes equilibrated dynamically, not statically as assumed in earlier models (18,19), and the force generated by the muscle at any instant can be dramatically less than the force predicted by the isometric force length curve (11,20).This mechanistic framework provides a plausible basis to explain how the effects of deep breath...

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Section: Discussionmentioning

confidence: 99%

Dilatation of the Constricted Human Airway by Tidal Expansion of Lung Parenchyma

Lavoie¹,

Krishnan

Siegel³

et al. 2012

Am J Respir Crit Care Med

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“…These results demonstrated that the force produced by ASM in response to a given stimulus is greater in a static environment than a dynamic environment. Oscillating strains at amplitude that is thought to prevail in vivo during breathing maneuvers also caused elongation of the contracted muscle (128,130,160). This later phenomenon is now referred to as force fluctuation-induced relengthening (FFIR).…”

Section: Muscle Factorsmentioning

confidence: 99%

“…The mechanisms underlying FFIR are not well understood but the length of the actin filaments seems to play a role (160). Collectively, these studies have shown that the force (66,84,85,128,186,198,242) and the stiffness (66,84,128,198) of ASM, as well as the length of the contracted ASM (128,130,160,186), are affected by length oscillations (66,84,85,128,130,160,186,198,242) or simply by an acute stretch (242). Considering these phenomena together, one can envision the following in vivo vicious cycle.…”

Section: Muscle Factorsmentioning

confidence: 99%

Airway Smooth Muscle in Asthma Symptoms: Culprit but Maybe Innocent

Bossé¹,

Paré²,

Boss³

2012

Lung Diseases - Selected State of the Art Reviews

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“…Other changes in asthmatic ASM cells may reside in the filamentous organization of the contractile apparatus as it has been proposed that the myosin thick filaments are less prone to disruption following mechanical strain 4,17 . Additionally, there is evidence that actin filament polymerization may underlie the altered behaviour of asthmatic ASM 18,19 . In this case, whereas mechanical stretch leads to shortening actin filaments and derangement of myosin filament assembly, in asthmatic ASM longer actin filaments are associated with refractoriness of thick myosin filament derangement following mechanical stretch, thus supporting greater force-generating capacity.…”

mentioning

confidence: 99%

“…Other changes in asthmatic ASM cells may reside in the filamentous organization of the contractile apparatus as it has been proposed that the myosin thick filaments are less prone to disruption following mechanical strain 4,17 . Additionally, there is evidence that actin filament polymerization may underlie the altered behaviour of asthmatic ASM 18,19 . We have shown that WNT-5A protein expression is increased in ASM cells isolated from asthmatics compared to non-asthmatic individuals 23 and WNT-5A expression has been associated with Th2-high asthma 24 .…”

mentioning

confidence: 99%

Regulation of actin dynamics by WNT-5A: Implications for human airway smooth muscle contraction

Koopmans

Kumawat

Halayko

et al. 2016

3.2 Airway Cell Biology and Immunopathology

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A defining feature of asthma is airway hyperresponsiveness (AHR), which underlies the exaggerated bronchoconstriction response of asthmatics. The role of the airway smooth muscle (ASM) in AHR has garnered increasing interest over the years, but how asthmatic ASM differs from healthy ASM is still an active topic of debate. WNT-5A is increasingly expressed in asthmatic ASM and has been linked with Th2-high asthma. Due to its link with calcium and cytoskeletal remodelling, we propose that WNT-5A may modulate ASM contractility. We demonstrated that WNT-5A can increase maximum isometric tension in bovine tracheal smooth muscle strips. In addition, we show that WNT-5A is preferentially expressed in contractile human airway myocytes compared to proliferative cells, suggesting an active role in maintaining contractility. Furthermore, WNT-5A treatment drives actin polymerisation, but has no effect on intracellular calcium flux. Next, we demonstrated that WNT-5A directly regulates TGF-β1-induced expression of α-SMA via ROCK-mediated actin polymerization. These findings suggest that WNT-5A modulates fundamental mechanisms that affect ASM contraction and thus may be of relevance for AHR in asthma.Asthma is a disease characterized by chronic inflammation of the large and small airways, and estimated to affect 235 million people worldwide 1 . A defining feature of asthma is airway hyperresponsiveness (AHR), which underlies the exaggerated bronchoconstriction response of asthmatics. While it is clear that the airway smooth muscle (ASM) is essential in mediating airway constriction typical of AHR in asthma, there remains much debate concerning the root cause of altered ASM contraction and AHR. The mass of ASM is generally greater in the airway wall of asthmatics due to cellular hyperplasia or hypertrophy, but whether or not the ASM behaves differently in terms of contractility is still controversial. Asthmatic ASM does not appear to produce more force per cell [2][3][4] , but evidence from isolated human ASM cells suggests that asthmatic ASM exhibits greater shortening capacity [5][6][7] . Not all studies have reproduced this finding in whole ASM tissue 2,4,8 , suggesting that the mechanical properties of the surrounding extracellular tissue matrix may also be altered in asthma. In this regard it is notable that the ASM of asthmatics does appear to respond differently to strain induced by tidal breathing. In healthy individuals, deep inspiration causes a bronchodilatory effect that can prevent or alleviate airway narrowing, whereas this response is largely absent in asthmatics [9][10][11][12][13] . Insights into the mechanisms that may underpin altered contractility of ASM are diverse and not fully conclusive. Some studies 5,14,15 , but not all 6,16 , show increased expression of myosin light chain kinase (MLCK) in ASM samples from asthmatics. Similarly, there may be increased abundance of myosin heavy chain in asthmatic ASM 15 , however not all studies prove this to be the case 5,16 . Other changes in asthmatic ASM cells may r...

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Disrupting Actin-Myosin-Actin Connectivity in Airway Smooth Muscle as a Treatment for Asthma?

Cited by 40 publications

References 42 publications

Dilatation of the Constricted Human Airway by Tidal Expansion of Lung Parenchyma

Dilatation of the Constricted Human Airway by Tidal Expansion of Lung Parenchyma

Airway Smooth Muscle in Asthma Symptoms: Culprit but Maybe Innocent

Regulation of actin dynamics by WNT-5A: Implications for human airway smooth muscle contraction

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