Cellular Stress Failure in Ventilator-injured Lungs

Vlahakis, Nicholas E.; Hubmayr, Rolf D.

doi:10.1164/rccm.200408-1036so

Cited by 189 publications

(130 citation statements)

References 255 publications

(253 reference statements)

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“…This model holds implications not only for the ways in which epithelial cells sense and respond to mechanical stimulation in general but also for the pathophysiology of certain lung diseases. Widespread use of positive pressure mechanical ventilation in the treatment of respiratory disorders is known to exacerbate existing lung damage (61)(62)(63). This injury might be exacerbated or mitigated by the activation of pro-inflammatory or protective signaling pathways in the lung.…”

Section: Discussionmentioning

confidence: 99%

A Dystroglycan/Plectin Scaffold Mediates Mechanical Pathway Bifurcation in Lung Epithelial Cells

Takawira¹,

Budinger

Hopkinson³

et al. 2011

Journal of Biological Chemistry

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In alveolar epithelial cells (AECs), the membrane-anchored proteoglycan dystroglycan (DG) is a mechanoreceptor that transmits mechanical stretch forces to activate independently the ERK1/2 and the adenosine 5-monophosphate-activated protein kinase (AMPK) signaling cascades in a process called pathway bifurcation. We tested the hypothesis that the cytoskeleton cross-linker plectin, known to bind both DG and AMPK in muscle cells, acts as a scaffold to regulate DG-mediated mechanical stimulation and pathway bifurcation. We demonstrate that plectin and DG form a complex in AECs and that this complex interacts with ERK1/2 and AMPK. Plectin knockdown reduces DG interaction with AMPK but not with ERK1/2. Despite this, mechanoactivation of both signaling pathways is significantly attenuated in AECs deficient in plectin. Thus, DG has the dual role of mechanical receptor and scaffold for ERK1/2, whereas plectin acts as a scaffold for AMPK signaling but is also required for DG-mediated ERK1/2 activation. We conclude that the DG-plectin complex plays a central role in transmitting mechanical stress from the extracellular matrix to the cytoplasm.In the lung, alveolar epithelial cells (AECs) 3 not only mediate the exchange of gases between the circulation system of the host and its external environment but are also highly responsive to a number of mechanical forces (1). These forces include deformation and strain that occur during lung expansion and relaxation from breathing movements, and shear stress during the distension of the airway walls and blood vessels from bulk air and blood flow (2). Over the past few years, there has been increasing interest in identifying molecules that "sense" physical forces on the cell surface and in defining the signaling pathways activated by mechanical stimulation (1, 3-6). Stretch-activated ion channels, integrins, cell-cell adhesion molecules, cytoskeleton elements, and the extracellular matrix (ECM) have all been implicated in transducing mechanical signals in a manner that is detectable as chemical signals (e.g. protein phosphorylation) in the cytoplasm of the stimulated cell (1, 7).We are interested in investigating the molecular underpinnings of cellular responses to physical force in rat AECs. In particular, we have previously tested the hypothesis that matrix molecules secreted by cultured AECs and transmembrane matrix receptors on the substratum surface of these cells are crucial molecular links in the process of "converting" a mechanical stimulus in the form of cyclic stretching into a cytoplasmic signal (8). Specifically, in prior studies we demonstrated that rat AECs assemble an ECM rich in fibers composed of the ␣3, ␤1, and ␥1 subunits of laminin (laminin-311), complexed with perlecan and nidogen (8). This complex transmits mechanosignals in the form of stretch, via the matrix receptor dystroglycan (DG), to activate ERK1/2 (8). Moreover, we have also shown that DG is required for stretch-induced activation of the adenosine 5Ј-monophosphate-activated protein kinase (AMPK) sign...

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Section: Discussionmentioning

confidence: 99%

A Dystroglycan/Plectin Scaffold Mediates Mechanical Pathway Bifurcation in Lung Epithelial Cells

Takawira¹,

Budinger

Hopkinson³

et al. 2011

Journal of Biological Chemistry

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“…Adherent lung parenchymal cells, which are exposed to mechanical ventilation with high volumes and transpulmonary pressure, experience reversible plasma membrane wounds [126][127][128] and, as a result, initiate pro-inflammatory signalling cascades [129]. Cells possess a vast repertoire of genomic and physiomic responses to deforming stress, most of which occur in the absence of structural lesions [130]; however, the evidence for the existence of wounded lung cells in patients with VALI and in experimental models of VILI is compelling [126,127] and therefore the hypothesis that wounded lung cells are important transducers of injurious stress is attractive.…”

Section: Cell Wounding and Repairmentioning

confidence: 99%

Ventilator-associated lung injury: a search for better therapeutic targets

Oeckler¹,

Hubmayr²

2007

Eur Respir J

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a continuum of injury that may arise from a number of primary insults.Localised injury may progress due to trauma from mechanical ventilation, a finding that has led to intense debate in the clinical and experimental literature over optimal ventilator management. The implementation of low tidal volume strategies has led to an improvement in outcomes; however, mortality remains unacceptably high.In the current review, ventilator-associated lung injury is examined, as it relates to the pathophysiological changes beyond direct airway trauma in ALI and ARDS, and an attempt is made to provide a historical perspective to outline potential current and future pitfalls in the use of surrogate end-points and the discovery of potential biomarkers. The systemic responses that lead to multi-organ dysfunction, the leading causes of morbidity and mortality in ALI and ARDS, are caused by pro-inflammatory signalling cascades and the activation of such diverse mediators as reactive oxygen species, immune response elements, apoptotic constituents and coagulation proteins.These areas are examined, including key mediators, and possible future areas of interest are discussed, including the potential of an ''acute lung injury chip'' to integrate measured surrogate biomarkers with real-time clinical information to improve patient outcomes.

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“…(8) interdependent effects of lung volume, transpulmonary pressure, surface tension and transcapillary tension on the alveolocapillary membrane. (37,38) These forces, at the cellular level, are transmitted and supported by the cytoskeleton of the cell.…”

Section: Vili: From Discovery To Mechanical Determinantsmentioning

confidence: 99%

Citoesqueleto e mecanotransdução na fisiopatologia da lesão pulmonar induzida por ventilador

Taniguchi¹,

Caldini

Velasco

et al. 2010

J. bras. pneumol.

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Although mechanical ventilation is an important therapy, it can result in complications. One major complication is ventilator-induced lung injury, which is caused by alveolar hyperdistension, leading to an inflammatory process, with neutrophilic infiltration, hyaline membrane formation, fibrogenesis and impaired gas exchange. In this process, cellular mechanotransduction of the overstretching stimulus is mediated by means of the cytoskeleton and its cell-cell and cell-extracellular matrix interactions, in such a way that the mechanical stimulus of ventilation is translated into an intracellular biochemical signal, inducing endothelial activation, pulmonary vascular permeability, leukocyte chemotaxis, cytokine production and, possibly, distal organ failure. Clinical studies have shown the relationship between pulmonary distension and mortality in patients with ventilator-induced lung injury. However, although the cytoskeleton plays a fundamental role in the pathogenesis of ventilator-induced lung injury, there have been few in vivo studies of alterations in the cytoskeleton and in cytoskeleton-associated proteins during this pathological process.Keywords: Respiration, artificial; Cytoskeleton; Cell adhesion molecules; Focal adhesions; Mechanotransduction, cellular. ResumoA ventilação mecânica é uma terapia importante, mas pode resultar em complicações. Uma das mais relevantes é a lesão pulmonar induzida por ventilador. Devido à hiperdistensão alveolar, o pulmão inicia um processo inflamatório, com infiltrado neutrofílico, formação de membrana hialina, fibrogênese e prejuízo de troca gasosa. Nesse processo, a mecanotransdução da hiperdistensão celular é mediada através do citoesqueleto da célula e de suas interações com a matriz extracelular e com as células vizinhas, de modo que o estímulo mecânico da ventilação se traduz em sinalização bioquímica intracelular, desencadeando ativação endotelial, permeabilidade vascular pulmonar, quimiotaxia leucocitária, produção de citocinas e, possivelmente, lesão de órgãos à distância. Estudos clínicos demonstram essa relação entre distensão pulmonar e mortalidade em pacientes com lesão pulmonar induzida por ventilador. Entretanto, apesar de o citoesqueleto ter um papel fundamental na patogênese da lesão pulmonar induzida por ventilador, a literatura carece de estudos utilizando modelos in vivo sobre as alterações do citoesqueleto e de suas proteínas associadas durante esse processo patológico. Subsequent studies focused on the mechanical factors that triggered VILI, such as peak inspiratory pressure and V T .(9-12) Dreyfuss et al. confirmed the findings of Webb and Tierney and demonstrated that V T was the major determinant of alveolar injury and alveolocapillary membrane injury, which gave rise to the term "volutrauma". (13,14) In an important study, they compared rats ventilated with high V T and negative pressure (through a negative pressure ventilator, known as iron lung) with rats ventilated with high pressure and low V T (with thoracoabdominal movement restricte...

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Cellular Stress Failure in Ventilator-injured Lungs

Cited by 189 publications

References 255 publications

A Dystroglycan/Plectin Scaffold Mediates Mechanical Pathway Bifurcation in Lung Epithelial Cells

A Dystroglycan/Plectin Scaffold Mediates Mechanical Pathway Bifurcation in Lung Epithelial Cells

Ventilator-associated lung injury: a search for better therapeutic targets

Citoesqueleto e mecanotransdução na fisiopatologia da lesão pulmonar induzida por ventilador

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