Dataset Information

Ventilation-Like Mechanical Strain Modulates the Inflammatory Response of BEAS2B Epithelial Cells.

ABSTRACT: Protective mechanical ventilation is aimed at preventing ventilator-induced lung injury while ensuring sufficient gas exchange. A new approach focuses on the temporal profile of the mechanical ventilation. We hypothesized that the temporal mechanical strain profile modulates inflammatory signalling. We applied cyclic strain with various temporal profiles to human bronchial epithelial cells (BEAS2B) and assessed proinflammatory response. The cells were subjected to sinusoidal, rectangular, or triangular strain profile and rectangular strain profile with prestrain set to 0, 25, 50, or 75% of the maximum stain, static strain, and strain resembling a mechanical ventilation-like profile with or without flow-controlled expiration. The BEAS2B response to mechanical load included altered mitochondrial activity, increased superoxide radical levels, NF-kappaB translocation, and release of interleukin-8. The response to strain was substantially modulated by the dynamics of the stimulation pattern. The rate of dynamic changes of the strain profile correlates with the degree of mechanical stress-induced cell response.

SUBMITTER: Spassov SG

PROVIDER: S-EPMC6607724 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Ventilation-Like Mechanical Strain Modulates the Inflammatory Response of BEAS2B Epithelial Cells.

Spassov Sashko G SG Kessler Christoph C Jost Rebecca R Schumann Stefan S

Oxidative medicine and cellular longevity 20190619

Protective mechanical ventilation is aimed at preventing ventilator-induced lung injury while ensuring sufficient gas exchange. A new approach focuses on the temporal profile of the mechanical ventilation. We hypothesized that the temporal mechanical strain profile modulates inflammatory signalling. We applied cyclic strain with various temporal profiles to human bronchial epithelial cells (BEAS2B) and assessed proinflammatory response. The cells were subjected to sinusoidal, rectangular, or tri ...[more]

PMID: 31320981

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Project description:Knee osteoarthritis (KOA) is a degenerative disease resulting from mechanical overload, where direct physical impacts on chondrocytes play a crucial role in disease development by inducing inflammation and extracellular matrix degradation. However, the signaling cascades that sense these physical impacts and induce the pathogenic transcriptional programs of KOA remain to be defined, which hinders the identification of novel therapeutic approaches. Recent studies have implicated a crucial role of Hippo signaling in osteoarthritis. Since Hippo signaling senses mechanical cues, we aimed to determine its role in chondrocyte responses to mechanical overload. Here we show that mechanical loading induces the expression of inflammatory and matrix-degrading genes by activating the nuclear factor-kappaB (NFκB) pathway in a Hippo-dependent manner. Applying mechanical compressional force to 3-dimensional cultured chondrocytes activated NFκB and induced the expression of NFκB target genes for inflammation and matrix degradation (i.e., IL1β and ADAMTS4). Interestingly, deleting the Hippo pathway effector YAP or activating YAP by deleting core Hippo kinases LATS1/2 blocked the NFκB pathway activation induced by mechanical loading. Consistently, treatment with a LATS1/2 kinase inhibitor abolished the upregulation of IL1β and ADAMTS4 caused by mechanical loading. Mechanistically, mechanical loading activates Protein Kinase C (PKC), which activates NFκB p65 by phosphorylating its Serine 536. Furthermore, the mechano-activation of both PKC and NFκB p65 is blocked in LATS1/2 or YAP knockout cells, indicating that the Hippo pathway is required by this mechanoregulation. Additionally, the mechanical loading-induced phosphorylation of NFκB p65 at Ser536 is blocked by the LATS1/2 inhibitor Lats-In-1 or the PKC inhibitor AEB-071. Our study suggests that the interplay of the Hippo signaling and PKC controls NFκB-mediated inflammation and matrix degradation in response to mechanical loading. Chemical inhibitors targeting Hippo signaling or PKC can prevent the mechanoresponses of chondrocytes associated with inflammation and matrix degradation, providing a novel therapeutic strategy for KOA.

Project description:An excessive pulmonary inflammatory response could explain the poor prognosis of chronic obstructive pulmonary disease (COPD) patients submitted to invasive mechanical ventilation. The aim of this study was to evaluate the response to normal tidal volume mechanical ventilation in an elastase-induced murine model of pulmonary emphysema. In this model, two time points, associated with different levels of lung inflammation but similar lung destruction, were analyzed. C57BL/6 mice received a tracheal instillation of 5 IU of porcine pancreatic elastase (Elastase mice) or the same volume of saline (Saline mice). Fourteen (D14) and 21 (D21) days after instillation, mice were anesthetized, intubated, and either mechanically ventilated (MV) or maintained on spontaneous ventilation (SV) during two hours. As compared with Saline mice, Elastase mice showed a similarly increased mean chord length and pulmonary compliance at D14 and D21, while bronchoalveolar lavage cellularity was comparable between groups. Lung mechanics was similarly altered during mechanical ventilation in Elastase and Saline mice. Activated alveolar macrophages CD11bmid were present in lung parenchyma in both Elastase SV mice and Elastase MV mice at D14 but were absent at D21 and in Saline mice, indicating an inflammatory state with elastase at D14 only. At D14, Elastase MV mice showed a significant increase in percentage of neutrophils in total lung, as compared with Elastase SV mice. Furthermore, alveolar macrophages of Elastase MV mice at D14 overexpressed Gr1, and monocytes showed a trend to overexpression of CD62L, compared with Elastase SV mice. In an elastase-induced model of pulmonary emphysema, normal tidal volume mechanical ventilation may produce an increase in the proportion of pulmonary neutrophils, and an activation of alveolar macrophages and pulmonary monocytes. This response seems to be observed only when the emphysema model shows an underlying inflammation (D14), reflected by the presence of activated alveolar macrophages CD11bmid.

Dataset Information

Ventilation-Like Mechanical Strain Modulates the Inflammatory Response of BEAS2B Epithelial Cells.

Publications

Ventilation-Like Mechanical Strain Modulates the Inflammatory Response of BEAS2B Epithelial Cells.

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