Ceramides, Autophagy, and Apoptosis Mechanisms of Ventilator-induced Lung Injury and Potential Therapeutic Targets.
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ABSTRACT:
SUBMITTER: Mandell EW
PROVIDER: S-EPMC6423105 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS). Paradoxically, mechanical ventilation also creates excessive mechanical stress that directly augments lung injury, a syndrome known as ventilator-induced lung injury (VILI). The pathobiology of VILI and ARDS shares many inflammatory features including increases in lung vascular permeability due to loss of endothelial cell barrier integrity resulting in alveolar flooding. While there have been advances in the understanding of certain elements of VILI and ARDS pathobiology, such as defining the importance of lung inflammatory leukocyte infiltration and highly induced cytokine expression, a deep understanding of the initiating and regulatory pathways involved in these inflammatory responses remains poorly understood. Prevailing evidence indicates that loss of endothelial barrier function plays a primary role in the development of VILI and ARDS. Thus this review will focus on the latest knowledge related to 1) the key role of the endothelium in the pathogenesis of VILI; 2) the transcription factors that relay the effects of excessive mechanical stress in the endothelium; 3) the mechanical stress-induced posttranslational modifications that influence key signaling pathways involved in VILI responses in the endothelium; 4) the genetic and epigenetic regulation of key target genes in the endothelium that are involved in VILI responses; and 5) the need for novel therapeutic strategies for VILI that can preserve endothelial barrier function.
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Project description:In this study we provide evidence on potential mechanisms involved in H2S mediated protection against VILI. H2S down-regulates genes that are involved in oxidative stress and pro-inflammatory cell responses. H2S regulates ECM remodelling, a mechanism which may contribute to H2S-mediated lung protection. In addition, H2S inhalation activates anti-apoptotic and anti-inflammatory genes, and genes controlling the vascular permeability. The functional relevance of Atf3 underscores the potential of H2S to limit lung injury. We utilized a microarray approach for large scale analysis of target genes in order to elucidate the therapeutic effects of H2S in VILI. This study demonstrates the influence of supplemental H2S on gene expression in a model of VILI. In addition to describing the genes differentially regulated in VILI, the present study focused on newly identified H2S target genes within several functional groups, including anti-inflammatory and anti-apoptotic pathways, regulation of extracellular matrix (ECM) remodelling and angiogenesis. Gene expression analysis of control group, allowed to breathe spontaneously synthetic air and mice ventilated with synthetic air or synthetic air with 80 ppm H2S for 6 hours.
2014-06-03 | E-GEOD-58169 | biostudies-arrayexpress
Project description:In this study we provide evidence on potential mechanisms involved in H2S mediated protection against VILI. H2S down-regulates genes that are involved in oxidative stress and pro-inflammatory cell responses. H2S regulates ECM remodelling, a mechanism which may contribute to H2S-mediated lung protection. In addition, H2S inhalation activates anti-apoptotic and anti-inflammatory genes, and genes controlling the vascular permeability. The functional relevance of Atf3 underscores the potential of H2S to limit lung injury. We utilized a microarray approach for large scale analysis of target genes in order to elucidate the therapeutic effects of H2S in VILI. This study demonstrates the influence of supplemental H2S on gene expression in a model of VILI. In addition to describing the genes differentially regulated in VILI, the present study focused on newly identified H2S target genes within several functional groups, including anti-inflammatory and anti-apoptotic pathways, regulation of extracellular matrix (ECM) remodelling and angiogenesis.
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Project description:Recently, we have shown that inhalation of hydrogen sulfide (H2S) protects against ventilator-induced lung injury (VILI). In the present study, we aimed to determine the underlying molecular mechanisms of H2S-dependent lung protection by analyzing gene expression profiles in mice. C57BL/6 mice were subjected to spontaneous breathing or mechanical ventilation in the absence or presence of H2S (80 parts per million). Gene expression profiles were determined by microarray, sqRT-PCR and Western Blot analyses. The association of Atf3 in protection against VILI was confirmed with a Vivo-Morpholino knockout model. Mechanical ventilation caused a significant lung inflammation and damage that was prevented in the presence of H2S. Mechanical ventilation favoured the expression of genes involved in inflammation, leukocyte activation and chemotaxis. In contrast, ventilation with H2S activated genes involved in extracellular matrix remodelling, angiogenesis, inhibition of apoptosis, and inflammation. Amongst others, H2S administration induced Atf3, an anti-inflammatory and anti-apoptotic regulator. Morpholino mediated reduction of Atf3 resulted in elevated lung injury despite the presence of H2S. In conclusion, lung protection by H2S during mechanical ventilation is associated with down-regulation of genes related to oxidative stress and inflammation and up-regulation of anti-apoptotic and anti-inflammatory genes. Here we show that Atf3 is clearly involved in H2S mediated protection.
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