Beneficial and harmful effects of oscillatory mechanical strain on airway smooth muscle

Abstract

Airway smooth muscle (ASM) cells are constantly under mechanical strain as the lung cyclically expands and deflates, and this stretch is now known to modulate the contractile function of ASM. However, depending on the experimental conditions, stretch is either beneficial or harmful limiting or enhancing contractile force generation, respectively. Stretch caused by a deep inspiration is known to be beneficial in limiting or reversing airway constriction in healthy individuals, and oscillatory stretch lowers contractile force and stiffness or lengthens muscle in excised airway tissue strips. Stretch in ASM culture has generally been reported to cause increased contractile function through increases in proliferation, contractile protein content, and organization of the cell cytoskeleton. Recent evidence indicates the type of stretch is critically important. Growing cells on flexible membranes where stretch is non-uniform and anisotropic leads to pro-contractile changes, whereas uniform biaxial stretch causes the opposite effects. Furthermore, the role of contractile tone might be important in modulating the response to mechanical stretch in cultured cells. This report will review the contrasting evidence for modulation of contractile function of ASM, both in vivo and in vitro, and summarize the recent evidence that mechanical stress applied either acutely within 2 h or chronically over 11 d is a potent stimulus for cytoskeletal remodelling and stiffening. We will also point to new data suggesting that perhaps some of the difference in response to stretch might lie with one of the fundamental differences in the ASM environment in asthma and in culture--the presence of elevated contractile tone.

Development and characterization of a 3D multicell microtissue culture model of airway smooth muscle

“…Although not possible with the current iteration of microfabricated tissue gauges, it may also be important to determine whether applying dynamic mechanical strain alters the contractility of ASM in 3D microtissues. In traditional 2D cultures of ASM, dynamic mechanical strain can have potent effects, acutely eliciting cytoskeletal fluidization (40) and depending on the exact nature of the strain regime it can elicit chronic changes in ASM phenotype and function (22,44), but it is currently unclear whether 3D cell geometry may alter these responses.…”

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

“…These observations are consistent with decreased Rho activation, which is in contrast to the increased Rho-A activation observed in response to predominantly uniaxial strain [231] and would appear to represent anticontractile effects of strain rather than pro-contractile effects of strain as occurring with primarily uniaxial strain. Furthermore, increases in amount of myosin light chain kinase after 11 days of strain seem to occur primarily in uniaxially strained cells [243,246]. Interestingly, proliferation is reduced in cells grown on laminin and subjected to lower strains of 4% compared with cells grown on collagen with either 0 or 4% strain.…”

“…Furthermore, while the ability to relax and decrease cell stiffness following acute stretches in cultured cells (whether they have been exposed to strain or not) is unaltered and the response is comparable to that of intact tissues [52,246], the ability to recover following such stretches is significantly altered by previous exposure to chronic strain. In single cells lifted from culture dishes and then subjected to large acute stretches of 12% (simulating stretches caused by sighs) followed by smaller stretches of 2% (simulating tidal breathing), cells that had been grown under conditions of chronic cyclic strain for several days recovered their stiffness rapidly within tens of seconds, compared with cells that were not grown under chronic cyclic strain, which recovered after .100 s [246]. This more rapid recovery following an acute stretch may be important as it is reminiscent of the more rapid re-narrowing (and thus lack of bronchodilatory effect) observed following a deep inspiration in asthma [20,35,138,139].…”

“…This method results in uneven strain across the membranes with biaxial strain (i.e. the stretch is the same in every direction in a two-dimensional plane) of ,10% in the central region, changing gradually to uniaxial stretch of 10% in the radial direction near the membrane edge [246,247]. After 2-4 days, the cells in the region of predominantly uniaxial strain re-orient, forming a ring of cells aligned circumferentially, while cells in the central region do not show any particular preferred direction.…”

Regulation of 130-kDa Smooth Muscle Myosin Light Chain Kinase Expression by an Intronic CArG Element

“…This conclusion should, however, be viewed with caution because it is possible that the alterations in proliferation are secondary to impaired contractility. In vascular, airway, and bladder smooth muscle, mechanical strain can induce smooth muscle cell proliferation (45)(46)(47). A decreased mechanical stimulus in CArG knock-out mice may thus also impair intestinal smooth muscle cell proliferation, resulting in attenuated intestinal elongation.…”