Biomechanics of liquid–epithelium interactions in pulmonary airways

Ghadiali, Samir N.; Gaver, Donald P.

doi:10.1016/j.resp.2008.04.008

Cited by 88 publications

(80 citation statements)

References 113 publications

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“…Using an experimental approach originally described by Bilek et al (1) and Kay et al (10), we confirmed the group's observation that the tension of an advancing air-liquid interface in a microchannel is sufficiently large to deform and wound epithelial lining cells. This injury mechanism is thought to explain lung damage associated with the cyclic recruitment and derecruitment ("opening and collapse") of unstable units (7,9,12). Not only were we able to show that the compressive stress of an advancing air-liquid interface produces cell blebbing ( Fig.…”

Section: Discussionmentioning

confidence: 75%

Determinants of plasma membrane wounding by deforming stress

Oeckler¹,

Lee

Park

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Once excess liquid gains access to air spaces of an injured lung, the act of breathing creates and destroys foam and thereby contributes to the wounding of epithelial cells by interfacial stress. Since cells are not elastic continua, but rather complex network structures composed of solid as well as liquid elements, we hypothesize that plasma membrane (PM) wounding is preceded by a phase separation, which results in blebbing. We postulate that interventions such as a hypertonic treatment increase adhesive PM-cytoskeletal (CSK) interactions, thereby preventing blebbing as well as PM wounds. We formed PM tethers in alveolar epithelial cells and fibroblasts and measured their retractive force as readout of PM-CSK adhesive interactions using optical tweezers. A 50-mOsm increase in media osmolarity consistently increased the tether retractive force in epithelial cells but lowered it in fibroblasts. The osmo-response was abolished by pretreatment with latrunculin, cytochalasin D, and calcium chelation. Epithelial cells and fibroblasts were exposed to interfacial stress in a microchannel, and the fraction of wounded cells were measured. Interventions that increased PM-CSK adhesive interactions prevented blebbing and were cytoprotective regardless of cell type. Finally, we exposed ex vivo perfused rat lungs to injurious mechanical ventilation and showed that hypertonic conditioning reduced the number of wounded subpleural alveolus resident cells to baseline levels. Our observations support the hypothesis that PM-CSK adhesive interactions are important determinants of the cellular response to deforming stress and pave the way for preclinical efficacy trials of hypertonic treatment in experimental models of acute lung injury. alveolar epithelial cell; acute lung injury; interfacial stress; osmotic response; cytoprotection THE SYNDROME OF ventilator-induced lung injury (VILI) contributes to the morbidity and mortality of critically ill patients (25). The clinical manifestations of the syndrome are indistinguishable from those of all-cause acute lung injury and at their core reflect a mechanotransduction event, i.e., the effects of deforming stress on cell and tissue injury, remodeling, and repair. The complex topographical distributions of lung mechanical properties, and hence of parenchymal stress and strain together with the numerous and nuanced injury manifestations, make it very difficult to establish mechanistic cause and effect relationships on the scale of interest, e.g., that of individual cells. Our research, therefore, focuses on a very specific mechanotransduction event, namely physical stress-related epithelial cell wounding and repair, which we believe contributes to the pathogenesis VILI.In the current study, we present a body of work in which we have explored the effects of hypertonic exposure on cell wounding in experimental models ranging from individual cells to rodent VILI preparations. The experiments were not designed to test the preclinical efficacy of an intervention, but rather to explore a cell bio...

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Section: Discussionmentioning

confidence: 75%

Determinants of plasma membrane wounding by deforming stress

Oeckler¹,

Lee

Park

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Note that the unit collapsing at endexpiration remains "loose" if they reopen and receive gas during the next inspiration, otherwise they become "sticky" atelectasis with time. While the most frequent loose atelectasis follows a quite definite spatial orientation (from non-dependent to dependent lung) (25,26), the reabsorption atelectasis arises both in the most dependent lung regions (where the inspiratory pressure isn't sufficient to open the gravitational dependent collapsed units) and wherever an airway obstruction occurs for non-gravitational reasons; (III) To open a given unit the applied pressure must overcome at least four distinct forces (ignoring the gas movement): (i) The surface tension forces (27). These are likely lower in the "loose" atelectasis, where some gas is still present, than in the "sticky" atelectasis, where all the water molecules are in contact with each other; (ii) The pressure superimposed to that given unit (22,23); (iii) The pressure likely due to the interaction between neighboring units collapsed in an isogravitational plane (28);…”

Section: Inspiratory Recruitmentmentioning

confidence: 99%

Positive end-expiratory pressure: how to set it at the individual level

Gattinoni¹,

Collino²,

Maiolo³

et al. 2017

Ann. Transl. Med.

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Abstract:The positive end-expiratory pressure (PEEP), since its introduction in the treatment of acute respiratory failure, up to the 1980s was uniquely aimed to provide a viable oxygenation. Since the first application, a large debate about the criteria for selecting the PEEP levels arose within the scientific community. Lung mechanics, oxygen transport, venous admixture thresholds were all proposed, leading to PEEP recommendations from 5 up to 25 cmH 2 O. Throughout this period, the main concern was the hemodynamics. This paradigm changed during the 1980s after the wide acceptance of atelectrauma as one of the leading causes of ventilator induced lung injury. Accordingly, the PEEP aim shifted from oxygenation to lung protection. In this framework, the prevention of lung opening and closing became an almost unquestioned dogma. Consequently, as PEEP keeps open the pulmonary units opened during the previous inspiratory phase, new methods were designed to identify the 'optimal' PEEP during the expiratory phase.The open lung approach requires that every collapsed unit potentially openable is opened and maintained open. The methods to assess the recruitment are based on imaging (computed tomography, electric impedance tomography, ultrasound) or mechanically-driven gas exchange modifications. All the latest assume that whatever change in respiratory system compliance is due to changes in lung compliance, which in turn is uniquely function of the recruitment. Comparative studies, however, showed that the only possible approach to measure the amount of collapsed tissue regaining inflation is the CT scan. In fact, all the other methods estimate as recruitment the gas entry in pulmonary units already open at lower PEEP, but increasing their compliance at higher PEEP. Since higher PEEP is usually more indicated (also for oxygenation) when the recruitability is higher, as occurs with increasing severity, a meaningful PEEP selection requires the assessment of recruitment. The Berlin definition may help in this assessment.

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“…For example, the interactions responsible for epithelial injury during airway reopening are fundamentally multiscale, since air-liquid interfacial dynamics affect global lung mechanics, while surface tension forces operate at the molecular and cellular scales. Consequently, a combination of computational and experimental techniques is being used to elucidate the mechanisms of surface-tension induced lung injury (Ghadiali and Gaver, 2008). Computational approaches have also been applied to toxicodynamic modeling of silver and carbon nanoparticle effects on mouse lung function (Mukherjee et al, 2013) and to uncover underlying mechanisms of disease, such as emphysema (Suki and Parameswaran, 2014).…”

Section: Needsmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

122

103

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SummaryModels of the outer epithelia of the human body -namely the skin, the intestine and the lung -have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.

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Biomechanics of liquid–epithelium interactions in pulmonary airways

Cited by 88 publications

References 113 publications

Determinants of plasma membrane wounding by deforming stress

Determinants of plasma membrane wounding by deforming stress

Positive end-expiratory pressure: how to set it at the individual level

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

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