Chronic Effects of Mechanical Force on Airways

Tschumperlin, Daniel J.; Drazen, Jeffrey M.

doi:10.1146/annurev.physiol.68.072304.113102

Cited by 130 publications

(97 citation statements)

References 138 publications

(133 reference statements)

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“…However, tiotropium has no effect on inflammatory markers in sputum (IL-6, CXCL8 and myeloperoxidase) or in the circulation (IL-6 and CRP) of COPD patients, despite a reduction in exacerbations [170]. Anticholinergics (and other bronchodilators) may reduce the mechanical forces in the lung due to airway closure and this might reduce the expression of TGF-b and other mediators released in response to the mechanical strain of epithelial cells [171,172]. This may have beneficial effects on systemic inflammation.…”

Section: -4xmentioning

confidence: 99%

Systemic manifestations and comorbidities of COPD

Barnes¹,

Celli²

2009

European Respiratory Journal

1,465

1,113

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Increasing evidence indicates that chronic obstructive pulmonary disease (COPD) is a complex disease involving more than airflow obstruction. Airflow obstruction has profound effects on cardiac function and gas exchange with systemic consequences. In addition, as COPD results from inflammation and/or alterations in repair mechanisms, the ''spill-over'' of inflammatory mediators into the circulation may result in important systemic manifestations of the disease, such as skeletal muscle wasting and cachexia. Systemic inflammation may also initiate or worsen comorbid diseases, such as ischaemic heart disease, heart failure, osteoporosis, normocytic anaemia, lung cancer, depression and diabetes. Comorbid diseases potentiate the morbidity of COPD, leading to increased hospitalisations, mortality and healthcare costs. Comorbidities complicate the management of COPD and need to be evaluated carefully. Current therapies for comorbid diseases, such as statins and peroxisome proliferator-activated receptor-agonists, may provide unexpected benefits for COPD patients. Treatment of COPD inflammation may concomitantly treat systemic inflammation and associated comorbidities. However, new broad-spectrum anti-inflammatory treatments, such as phosphodiesterase 4 inhibitors, have significant side-effects so it may be necessary to develop inhaled drugs in the future. Another approach is the reversal of corticosteroid resistance, for example with effective antioxidants. More research is needed on COPD comorbidities and their treatment.

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Section: -4xmentioning

confidence: 99%

Systemic manifestations and comorbidities of COPD

Barnes¹,

Celli²

2009

European Respiratory Journal

1,465

1,113

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“…As a consequence of its effect on airway calibre and ASM length, lung volume as a determinant of lung function has recently received more attention [30,196]. MCCLEAN et al [13] produced a chronic decrease in lung volume (25% below FRC) in sheep by restricting their chests with a corset, and examined the subsequent in vitro contractility of ASM from these animals after 4 weeks.…”

Section: Effects Of Chronic Lung-volume Alteration and Smooth Muscle mentioning

confidence: 99%

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

An¹,

Bai²,

Bates³

et al. 2007

European Respiratory Journal

342

298

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Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma.As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling.Anti-inflammatory therapy, however, does not ''cure'' asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM.In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

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“…In actual bronchi, cilia sweep upward to remove debris from the lungs, but since our model was symmetric in the x and y directions (without strain) we did not expect an overall directionality. The effects of dynamic strain on ciliary motion were not considered in this work, although it has been previously shown that mechanical stimulation leads to intra-and intercellular Ca 2ϩ signaling that would increase ciliary beat frequency (5,56,66). Therefore, the increase in overall infection rate that we see is unlikely to be due to any changes in ciliary beat frequency or coordination.…”

Section: Discussionmentioning

confidence: 93%

“…In particular, several different in vitro models of the bronchial airway wall have been used to demonstrate that mechanical stress, at levels relevant to bronchoconstriction, can itself induce changes in gene and protein expression in epithelial cells and fibroblasts that are consistent with airway wall remodeling events, as well as matrix remodeling and smooth muscle cell (SMC) migration and proliferation (11,12,31,42,60,66,73).…”

mentioning

confidence: 99%

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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Chronic Effects of Mechanical Force on Airways

Cited by 130 publications

References 138 publications

Systemic manifestations and comorbidities of COPD

Systemic manifestations and comorbidities of COPD

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

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

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