Role of the extracellular matrix in the genesis of ventilator-induced lung injury

Cruz, Fernanda Ferreira; Rocco, Patricia R. M.; Pelosi, Paolo

doi:10.1007/s00063-017-0376-8

Cited by 8 publications

(9 citation statements)

References 28 publications

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“…Excessive mechanical stresses associated with mechanical ventilation have also been associated with extracellular matrix (ECM) remodeling through the upregulation and increased deposition of matrix components like collagens and fibronectin as well as their breakdown, for example by MMPs 29 . Our RNAseq data indicated that expression of specific ECM related genes was also altered in AF/S chips, including collagens, glycoproteins (selection), serpins, MMPs, and Lysyl oxidase homologs (LOXLs)-related genes (Figure 5a).…”

Section: Resultsmentioning

confidence: 99%

“…Excessive mechanical stresses, such as those that occur during mechanical ventilation, have been shown to both alter the expression of ECM molecules and their breakdown, e.g. by matrix metalloproteinases (MMPs) 42 . Since the low donor number in our RNAseq analysis limited the statistical power and might mask relevant changes, we performed further analysis of multiple groups of ECM-related genes detected by the RNAseq analysis, i.e., collagens, glycoproteins (selection), SERPINS, MMPs, and LOXLs (Fig.…”

Section: Effects Of Airflow and Stretch Application On Ecm-related Gene Expression By Airway Epithelial Chip Culturesmentioning

confidence: 99%

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Breathing on Chip: Dynamic flow and stretch tune cellular composition and accelerate mucociliary maturation of airway epitheliumin vitro

Nawroth

Roth

Schadewijk

et al. 2021

Preprint

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Human lung function is intricately linked to the mechanics of breathing; however, it remains unknown whether and how these mechanical cues shape human lung cellular biology. While respiration-related strains and fluid flows have been suggested to promote alveolar epithelial cell function, the study of such fundamental mechanisms in the conducting airway epithelium has been hindered by the lack of suitable in vitro airway models. Here, we developed a model of human bronchial airway epithelium using well-differentiated primary cell cultures on a commercial Organs-on-Chips platform that enables the application of breathing-associated airflow and cyclic strain. It furthermore features optional endothelial cell co-culture to allow for crosstalk with the vascular compartment. Using this model, we evaluated the impact of airflow and physiological levels of cyclic strain on airway epithelial cell differentiation and function. Our findings suggest that breathing-associated mechanical stimulation changes epithelial composition, reduces secretion of IL-8, and downregulates gene expression of matrix metalloproteinase 9, fibronectin, and other extracellular matrix (ECM) factors. These results indicate that breathing-associated forces are important modulators of airway epithelial cell biology and that their fine-tuned application could generate models of specific epithelial phenotypes and pathologies.

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Section: Resultsmentioning

confidence: 99%

Section: Effects Of Airflow and Stretch Application On Ecm-related Gene Expression By Airway Epithelial Chip Culturesmentioning

confidence: 99%

Breathing on Chip: Dynamic flow and stretch tune cellular composition and accelerate mucociliary maturation of airway epitheliumin vitro

Nawroth

Roth

Schadewijk

et al. 2021

Preprint

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show abstract

“…This longitudinal tension produced by the mechanical ventilator also induces various cellular responses including mechanical stress associated molecular signaling, ROS generation, gene expression, and cellular remodeling (Birukov, 2009), leading to damage directly to ECs, which can be observed at the ultrastructural level (Dreyfuss and Saumon, 1998). This persistent VILI associated mechanical stress during ventilation leads to further dysregulation of the pulmonary capillary endothelium, leading to protein rich fluid leakage from the capillaries to the interstitium and continuing into the alveoli, resulting in life-threatening pulmonary edema (Cruz et al, 2018). Once lung damage occurs, lung ECs express pro-inflammatory cytokines and signaling molecules to further exacerbate vascular permeability, vascular tone, leukocyte recruitment, and apoptosis (Villar et al, 2014).…”

Section: Endothelial Injury In Vilimentioning

confidence: 99%

Pulmonary Endothelial Mechanical Sensing and Signaling, a Story of Focal Adhesions and Integrins in Ventilator Induced Lung Injury

et al. 2019

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Patients with critical illness such as acute lung injury often undergo mechanical ventilation in the intensive care unit. Though lifesaving in many instances, mechanical ventilation often results in ventilator induced lung injury (VILI), characterized by overdistension of lung tissue leading to release of edemagenic agents, which further damage the lung and contribute to the mortality and progression of pulmonary inflammation. The endothelium is particularly sensitive, as VILI associated mechanical stress results in endothelial cytoskeletal rearrangement, stress fiber formation, and integrity loss. At the heart of these changes are integrin tethered focal adhesions (FAs) which participate in mechanosensing, structure, and signaling. Here, we present the known roles of FA proteins including c-Src, talin, FAK, paxillin, vinculin, and integrins in the sensing and response to cyclic stretch and VILI associated stress. Attention is given to how stretch is propagated from the extracellular matrix through integrins to talin and other FA proteins, as well as signaling cascades that include FA proteins, leading to stress fiber formation and other cellular responses. This unifying picture of FAs aids our understanding in an effort to prevent and treat VILI.

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“…It could be inferred that the immune system might 20 Disease Markers also be involved in the VILI development. Indeed, a previous study has already raised concerns about involvement of the immune system in VILI [40]. We used CIBERSORT to analyze the immune cell composition in VILI samples and found that the proportion of M0 macrophages and activated mast cells was significantly higher in the VILI group than in the control.…”

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confidence: 93%

Transcriptome-Wide Gene Expression in a Murine Model of Ventilator-Induced Lung Injury

et al. 2021

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Background. Mechanical ventilation could lead to ventilator-induced lung injury (VILI), but its underlying pathogenesis remains largely unknown. In this study, we aimed to determine the genes which were highly correlated with VILI as well as their expressions and interactions by analyzing the differentially expressed genes (DEGs) between the VILI samples and controls. Methods. GSE11434 was downloaded from the gene expression omnibus (GEO) database, and DEGs were identified with GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using DAVID. Next, we used the STRING tool to construct protein-protein interaction (PPI) network of the DEGs. Then, the hub genes and related modules were identified with the Cytoscape plugins: cytoHubba and MCODE. qRT-PCR was further used to validate the results in the GSE11434 dataset. We also applied gene set enrichment analysis (GSEA) to discern the gene sets that had a significant difference between the VILI group and the control. Hub genes were also subjected to analyses by CyTargetLinker and NetworkAnalyst to predict associated miRNAs and transcription factors (TFs). Besides, we used CIBERSORT to detect the contributions of different types of immune cells in lung tissues of mice in the VILI group. By using DrugBank, small molecular compounds that could potentially interact with hub genes were identified. Results. A total of 141 DEGs between the VILI group and the control were identified in GSE11434. Then, seven hub genes were identified and were validated by using qRT-PCR. Those seven hub genes were largely enriched in TLR and JAK-STAT signaling pathways. GSEA showed that VILI-associated genes were also enriched in NOD, antigen presentation, and chemokine pathways. We predicted the miRNAs and TFs associated with hub genes and constructed miRNA-TF-gene regulatory network. An analysis with CIBERSORT showed that the proportion of M0 macrophages and activated mast cells was higher in the VILI group than in the control. Small molecules, like nadroparin and siltuximab, could act as potential drugs for VILI. Conclusion. In sum, a number of hub genes associated with VILI were identified and could provide novel insights into the pathogenesis of VILI and potential targets for its treatment.

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Role of the extracellular matrix in the genesis of ventilator-induced lung injury

Cited by 8 publications

References 28 publications

Breathing on Chip: Dynamic flow and stretch tune cellular composition and accelerate mucociliary maturation of airway epitheliumin vitro

Breathing on Chip: Dynamic flow and stretch tune cellular composition and accelerate mucociliary maturation of airway epitheliumin vitro

Pulmonary Endothelial Mechanical Sensing and Signaling, a Story of Focal Adhesions and Integrins in Ventilator Induced Lung Injury

Transcriptome-Wide Gene Expression in a Murine Model of Ventilator-Induced Lung Injury

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