On the mechanism of mucosal folding  in normal and asthmatic airways

Wiggs, Barry; Hrousis, C A; Drazen, Jeffrey M.; Kamm, Roger D.

doi:10.1152/jappl.1997.83.6.1814

Cited by 247 publications

(273 citation statements)

References 20 publications

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“…These regions would be directly exposed to without the influence of the surface film. Additionally, airway walls are not smooth and have ridges and folds; the ratio of the height of the ridges to the diameter will be amplified during constriction (35). The in a nonsmooth walled tube are amplified, depending on the ratio of the height of the ridge and the airway diameter (12).…”

Section: Shear Stress Amplification In Heterogenous Constrictionmentioning

confidence: 99%

Modeling airflow-related shear stress during heterogeneous constriction and mechanical ventilation

Nucci

Suki²,

Lutchen³

2003

Journal of Applied Physiology

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Nucci, Gianluca, Bé la Suki, and Kenneth Lutchen. Modeling airflow-related shear stress during heterogeneous constriction and mechanical ventilation. J Appl Physiol 95: 348-356, 2003. First published March 21, 2003 10.1152/ japplphysiol.01179.2001.-Ventilator-induced lung injury has been proposed as being caused by overdistention and closure and reopening of small airways and alveoli. Here we investigate the possibility that heterogeneous constriction increases airflow-related shear stress to a dangerously high level that may be sufficient to cause injury to the epithelial cells during mechanical ventilation. We employed an anatomically consistent model of the respiratory system, based on Horsfield morphometric data, and solved for the time evolution of pressure and flow along the airway tree during mechanical ventilation. We simulated constant-flow ventilation with passive expiration in two different conditions: baseline and highly heterogeneous constriction. The constriction was applied with two strategies: establishing a simple diameter reduction or adding also a length shortening. The shear stress distribution on airway walls was analyzed for airways ranging from the trachea to the acini. Our results indicate that 1) heterogeneous constriction can amplify the maximal values of shear stress up to 50-fold, with peak values higher than 0.6 cmH 2O; 2) the highest shear stress is found in pathways constricted by 60-80%; 3) simultaneous diameter reduction and shortening amplifies the shear stresses by three-to fourfold, with shear stresses reaching 2 cmH 2O; and 4) there is a range of airways (diameters from 0.6 to 0.3 mm at baseline) that appear to be at risk of very high stresses. We conclude that elevated airflow-related shear stress on the epithelial cell layer can occur during heterogeneous constriction and conjecture that this may constitute a mechanism contributing to ventilator-induced lung injury. lung mechanics; ventilator-induced lung injury; simulation model MECHANICAL VENTILATION (MV) is often required to manage patients with acute respiratory failure (ARF) of different origins, including those associated with abnormalities in respiratory mechanics (31). However, there is considerable experimental evidence that MV itself can also cause or exacerbate lung injury, resulting in so-called ventilator-induced lung injury (VILI) (9,23,28). The mechanisms associated with VILI have not yet been fully elucidated. Two mechanisms have received the most attention. One is related to high airway pressures during MV, termed barotrauma, causing excessive overdistension of alveolar structures (26). More recently, it has become evident that injury results more from overstretching the alveolar tissues than from high pressures, and hence it is now termed volutrauma (10). Another potential mechanism is the repeated recruitment and derecruitment of atelectatic lung units (28). In principle, opening a collapsed airway would require very high-pressure drops across the fluid plug blocking the airway (13). During the process o...

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Section: Shear Stress Amplification In Heterogenous Constrictionmentioning

confidence: 99%

Modeling airflow-related shear stress during heterogeneous constriction and mechanical ventilation

Nucci

Suki²,

Lutchen³

2003

Journal of Applied Physiology

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“…In the work reported here, we use a unique coculture system of mechanically stressed human bronchial epithelial cells (HBECs) and unstressed human lung fibroblasts (HLFs) to investigate whether the two cell types communicate with each other in response to the mechanical stress in a way that is relevant to matrix remodeling. The mechanical stress was applied in the form of a hydrostatic pressure difference across the epithelial cell layer to mimic the normal stresses that develop in the folds of a buckled airway (12). Cocultured fibroblasts were not exposed to a mechanical stimulus but were in contact with the epithelial layer via soluble mediators.…”

mentioning

confidence: 99%

Mechanical stress is communicated between different cell types to elicit matrix remodeling

Swartz

Tschumperlin

Kamm

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

241

158

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Tissue remodeling often reflects alterations in local mechanical conditions and manifests as an integrated response among the different cell types that share, and thus cooperatively manage, an extracellular matrix. Here we examine how two different cell types, one that undergoes the stress and the other that primarily remodels the matrix, might communicate a mechanical stress by using airway cells as a representative in vitro system. Normal stress is imposed on bronchial epithelial cells in the presence of unstimulated lung fibroblasts. We show that (i) mechanical stress can be communicated from stressed to unstressed cells to elicit a remodeling response, and (ii) the integrated response of two cell types to mechanical stress mimics key features of airway remodeling seen in asthma: namely, an increase in production of fibronectin, collagen types III and V, and matrix metalloproteinase type 9 (MMP-9) (relative to tissue inhibitor of metalloproteinase-1, TIMP-1). These observations provide a paradigm to use in understanding the management of mechanical forces on the tissue level.airway wall remodeling ͉ airway epithelium ͉ asthma ͉ lung fibroblasts I n the past two decades, it has been well established that many cells are sensitive to mechanical forces and can change their phenotype and surrounding extracellular matrix (ECM) in response to changes in their mechanical environment. However, it has not been established how mechanical forces are managed on a tissue level, in which different cell types share a common ECM and may alter their mechanical environment by inducing other cells to remodel the ECM.The airway wall is an example of a mechanically active tissue (e.g., bronchoconstriction) composed of multiple cell types that share a common extracellular matrix. It is known that patients with poorly controlled asthma develop structural changes in the airway wall: the subepithelial layers significantly thicken (1-4) and there is deposition of collagen types III and V, among other fibrous proteins, beneath the basement membrane (4, 5). The major consequences of airway remodeling are altered tissue mechanics and airway hyperresponsiveness (6).The remodeling process in asthma has been attributed to the effects of the inflammatory response that characterizes the disease, but this sequence of events has only been inferentially established. We propose an alternative hypothesis for airway wall remodeling in asthma, namely that the mechanical stress associated with bronchoconstriction that is imposed on bronchial epithelial cells could, itself, stimulate and amplify airway wall remodeling in the absence of inflammatory agents. Specifically, we hypothesize that, when airway epithelial cells are subjected to mechanical stress, they act in concert with subepithelial fibroblasts to modulate the fibrous structure of the airway in response to this mechanical stress.This hypothesis, if true, would provide two key insights. First, it would challenge the idea that airway wall remodeling in asthma is solely the consequence of inflam...

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“…To ponder the physiological relevance of the strain we applied to our in vitro models, we first considered that the strain magnitude within any bronchoconstricted airway wall is highly nonuniform; SMCs on the outer perimeter shorten to cause compression of the airway wall (25), but since the internal perimeter remains constant (maintained by the basement membrane), the epithelium buckles into the lumen (34,40,58,74). Furthermore, strain varies radially from the epithelium to the subepithelium due to geometry, buckling, and different mechanical properties of epithelial vs. subepithelial regions.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, strain varies radially from the epithelium to the subepithelium due to geometry, buckling, and different mechanical properties of epithelial vs. subepithelial regions. Finally, strain profiles are different in bronchoconstricted airways of normal vs. asthmatic patients, because of the mechanics and increased thickness of the remodeled airway wall (35,53,54,74) as well as increased contractile forces of asthmatic SMCs (8,25,57). A number of studies (29,30,32,34,47,58) have shown that in models of induced (e.g., by methacholine or histamine) bronchoconstriction, the maximum level of SMC shortening (i.e., that which causes complete closure of the lumen) is 30 -40%.…”

Section: Discussionmentioning

confidence: 99%

“…Compressive stress in the bronchial airways occurs when smooth muscle shortens, making the airway constrict; this can occur, for example, during breath-holding, and frequently occurs in asthma. The stress and strain profiles in the airway wall during bronchoconstriction are highly nonuniform, particularly with regards to the epithelium, which buckles to maintain constant perimeter (40,41,58,74). In asthma, bronchoconstriction occurs more frequently, due to hyperresponsive SMCs (24,25), and at greater magnitude, due to both hyperreactive SMCs and the remodeled airway wall (41,57,58,74), which lead to fewer and deeper folds in the buckled epithelial layer in response to constriction.…”

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confidence: 99%

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Effects of dynamic compression on lentiviral transduction in an in vitro airway wall model

Tomei¹,

Choe²

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Tomei AA, Choe MM, Swartz MA. Effects of dynamic compression on lentiviral transduction in an in vitro airway wall model. Am J Physiol Lung Cell Mol Physiol 294: L79-L86, 2008. First published November 16, 2007 doi:10.1152/ajplung.00062.2007.-Asthmatic patients are more susceptible to viral infection, and we asked whether dynamic strain on the airway wall (such as that associated with bronchoconstriction) would influence the rate of viral infection of the epithelial and subepithelial cells. To address this, we characterized the barrier function of a three-dimensional culture model of the bronchial airway wall mucosa, modified the culture conditions for optimization of ciliogenesis, and compared epithelial and subepithelial green fluorescent protein (GFP) transduction by a pWpts-GFP lentivirus, pseudotyped with VSV-G, under static vs. dynamic conditions. The model consisted of human lung fibroblasts, bronchial epithelial cells, and a type I collagen matrix, and after 21 days of culture at air liquid interface, it exhibited a pseudostratified epithelium comprised of basal cells, mucus-secreting cells, and ciliated columnar cells with beating cilia. Microparticle tracking revealed partial coordination of mucociliary transport among groups of cells. Slow dynamic compression of the airway wall model (15% strain at 0.1 Hz over 3 days) substantially enhanced GFP transduction of epithelial cells and underlying fibroblasts. Fibroblast-only controls showed a similar degree of transduction enhancement when undergoing dynamic strain, suggesting enhanced transport through the matrix. Tight junction loss in the epithelium after mechanical stress was observed by immunostaining. We conclude that dynamic compressive strain such as that associated with bronchoconstriction may promote transepithelial transport and enhance viral transgene delivery to epithelial and subepithelial cells. This finding has significance for asthma pathophysiology as well as for designing delivery strategies of viral gene therapies to the airways. mechanical stress; three-dimensional model; asthma; bronchoconstriction; ciliogenesis; human ASTHMA AND AIRWAY SUSCEPTIBILITY to viral infections have long been correlated clinically (2,9,16,26,36,61,62). Asthma is associated with recruitment of inflammatory cells, remodeling and thickening of the reticular basement membrane, subepithelial fibrosis, and airway smooth muscle hyperresponsiveness and hyperreactivity (reviewed in Refs. 7,17,19,21,23,25,48,70). The epithelial barrier function of asthmatic airways is often damaged (35), possibly increasing susceptibility to viral infection. Moreover, it has been shown that epithelial cells from asthmatic patients express a higher number of viral receptors on their surface (4, 62), which when activated exacerbate epithelial secretion of cytokines like granulocyte-macrophage colony-stimulating factor, interleukin (IL)-6, IL-8, IL-11, and RANTES that help maintain a persistent inflammatory state (46).Nevertheless, inflammatory mediators are only part of the story, as ...

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On the mechanism of mucosal folding in normal and asthmatic airways

Cited by 247 publications

References 20 publications

Modeling airflow-related shear stress during heterogeneous constriction and mechanical ventilation

Modeling airflow-related shear stress during heterogeneous constriction and mechanical ventilation

Mechanical stress is communicated between different cell types to elicit matrix remodeling

Effects of dynamic compression on lentiviral transduction in an in vitro airway wall model

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