Dataset Information

Three Alveolar Phenotypes Govern Lung Function in Murine Ventilator-Induced Lung Injury.

ABSTRACT: Mechanical ventilation is an essential lifesaving therapy in acute respiratory distress syndrome (ARDS) that may cause ventilator-induced lung injury (VILI) through a positive feedback between altered alveolar mechanics, edema, surfactant inactivation, and injury. Although the biophysical forces that cause VILI are well documented, a knowledge gap remains in the quantitative link between altered parenchymal structure (namely alveolar derecruitment and flooding), pulmonary function, and VILI. This information is essential to developing diagnostic criteria and ventilation strategies to reduce VILI and improve ARDS survival. To address this unmet need, we mechanically ventilated mice to cause VILI. Lung structure was measured at three air inflation pressures using design-based stereology, and the mechanical function of the pulmonary system was measured with the forced oscillation technique. Assessment of the pulmonary surfactant included total surfactant, distribution of phospholipid aggregates, and surface tension lowering activity. VILI-induced changes in the surfactant included reduced surface tension lowering activity in the typically functional fraction of large phospholipid aggregates and a significant increase in the pool of surface-inactive small phospholipid aggregates. The dominant alterations in lung structure at low airway pressures were alveolar collapse and flooding. At higher airway pressures, alveolar collapse was mitigated and the flooded alveoli remained filled with proteinaceous edema. The loss of ventilated alveoli resulted in decreased alveolar gas volume and gas-exchange surface area. These data characterize three alveolar phenotypes in murine VILI: flooded and non-recruitable alveoli, unstable alveoli that derecruit at airway pressures below 5 cmH2O, and alveoli with relatively normal structure and function. The fraction of alveoli with each phenotype is reflected in the proportional changes in pulmonary system elastance at positive end expiratory pressures of 0, 3, and 6 cmH2O.

SUBMITTER: Smith BJ

PROVIDER: S-EPMC7338482 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Three Alveolar Phenotypes Govern Lung Function in Murine Ventilator-Induced Lung Injury.

Smith Bradford J BJ Roy Gregory S GS Cleveland Alyx A Mattson Courtney C Okamura Kayo K Charlebois Chantel M CM Hamlington Katharine L KL Novotny Michael V MV Knudsen Lars L Ochs Matthias M Hite R Duncan RD Bates Jason H T JHT

Frontiers in physiology 20200630

Mechanical ventilation is an essential lifesaving therapy in acute respiratory distress syndrome (ARDS) that may cause ventilator-induced lung injury (VILI) through a positive feedback between altered alveolar mechanics, edema, surfactant inactivation, and injury. Although the biophysical forces that cause VILI are well documented, a knowledge gap remains in the quantitative link between altered parenchymal structure (namely alveolar derecruitment and flooding), pulmonary function, and VILI. Thi ...[more]

PMID: 32695013

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Project description:BackgroundMechanical 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.MethodsGSE11434 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.ResultsA 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.ConclusionIn 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.

Dataset Information

Three Alveolar Phenotypes Govern Lung Function in Murine Ventilator-Induced Lung Injury.

Publications

Three Alveolar Phenotypes Govern Lung Function in Murine Ventilator-Induced Lung Injury.

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